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• applications(array)
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    • Application(array)
      • id632
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      • abstract_of_study<p>\n Malaria due to <em>Plasmodium falciparum</em> infection is a major cause of human suffering and an economic drain in many parts of sub-Saharan Africa. The current malaria control programs in endemic areas have relied mainly on three key strategies i.e. use of effective artemisinin-based combination therapies (ACTs), insecticide-treated bednets (ITNs) and indoor residual spraying (IRS). Widescale deployment of these control tools has significantly reduced the burden of malaria in endemic areas. However, challenges such as the emergence of parasite resistance to antimalarial drugs and vector resistance to insecticides used in ITNs and IRS calls for additional and novel tools. Historically, vaccines have proven to be one of the most cost-effective means of preventing infectious diseases and saving lives. Therefore, a malaria vaccine could be an important additional tool that could complement the existing malaria control strategies.</p>\n<p>\n <span style=\"font-size: 12px;\">The RTS,S/AS01</span>_E<span style=\"font-size: 12px;\"> is the only vaccine at the most advanced stage of clinical development and the first to be tested in a large phase III clinical trial in children and infants in malaria endemic areas of sub-Saharan Africa. In these phase III studies, the vaccine was shown to be safe, immunogenic and provided moderate protection against malaria. However, vaccine efficacy waned with time and further research is needed to explore alternative vaccination schedules to those tested and other strategies to improve its efficacy. The proposed study will evaluate the efficacy, safety and immunogenicity of RTS,S/AS01</span>_E<span style=\"font-size: 12px;\"> vaccine administered using different schedules from those tested in the phase III trials, with or without fractional doses, early Dose 4 and yearly doses, in children 5-17 months of age in a malaria endemic area of Siaya County, western Kenya. Results from this study will aid in the ongoing evaluation of RTS,S and will be critical in the development of malaria vaccine-based control strategies which, in combination with other interventions, may contribute to the global malaria elimination efforts.</span></p>\n
      • study_title<div>\n Efficacy, safety and immunogenicity study of GSK <span style=\"font-size: 12px;\">Biologicals’ candidate malaria vaccine (SB257049) </span><span style=\"font-size: 12px;\">evaluating schedules with or without fractional doses, </span><span style=\"font-size: 12px;\">early Dose 4 and yearly doses, in children 5-17 months </span><span style=\"font-size: 12px;\">of age.</span></div>\n
      • laymans_summary<div>\n <strong>What was the main purpose of the study?</strong></div>\n<div>\n Malaria is a sickness that one can get from the bite of a mosquito carrying the malaria parasite. Malaria causes high fever, chills and can lead to serious problems. Problems include low blood levels, loss of consciousness and sometimes death. Young children have the biggest risk for getting very sick and dying from malaria.</div>\n<div>\n Vaccination is a means of protection against a disease. A vaccine increases body’s ability to fight off a particular infection. A malaria vaccine has been developed to protect children against malaria.</div>\n<div>\n The aim of this study was to find out how well the malaria vaccine (RTS,S/AS01E- which will be referred as RTS,S in this document) worked against malaria (vaccine efficacy) when given in different doses and at various schedules. The researchers were also interested in knowing if the vaccine continued to be well tolerated in children at those doses and schedules.</div>\n<div>\n  </div>\n<div>\n <strong>When and where did the study take place?</strong></div>\n<div>\n A total of 1500 children from Kenya and Ghana participated in this study (750 Kenya, 750 Ghana)</div>\n<div>\n  </div>\n<div>\n <div>\n <strong>Who took part in the study?</strong></div>\n <div>\n Studies have a list of requirements for participants who can take part or cannot take part in the study.</div>\n <div>\n The children were included in the study if they:</div>\n <div>\n •Were a boy or a girl, aged 5–17 months.</div>\n <div>\n •Had previously received 3 injections of diphtheria, tetanus, pertussis, and hepatitis B vaccine and at least 3 doses of oral polio vaccine.</div>\n <div>\n •Were healthy, without any history of serious illness.</div>\n <div>\n Children were excluded from the study if they:</div>\n <div>\n • Were under the care of an orphanage.</div>\n <div>\n • Were taking long-term medication which could affect their immune responses or unapproved medicines/ vaccines before the study start.</div>\n <div>\n • Had a history of allergy to the vaccine contents or had a history of serious illness that would make the study vaccine unsafe.</div>\n <div>\n <strong><span lang=\"EN-US\">Which<span style=\"letter-spacing: 0.1pt;\"> </span></span>medicines<span style=\"letter-spacing: -0.2pt;\"> </span>were<span style=\"letter-spacing: -0.2pt;\"> </span>studied?</strong></div>\n <div>\n RTS,S-Malaria vaccine</div>\n <div>\n - In this study, a standard vaccine dose (full dose) and smaller amounts called fractional dose (1/5th of the volume)were tested.</div>\n <div>\n Rabies vaccine</div>\n <div>\n - In this study the rabies vaccine was given as a comparator vaccine.</div>\n <div>\n - Comparator is a non-malaria vaccine, helpful to see the malaria vaccine protects against malaria as compared to the comparator.</div>\n <div>\n <strong>What happened during the study?</strong></div>\n <div>\n This was an open-label study, which means that the study doctors and the parents of the children knew which vaccine was given.</div>\n <div>\n Children were randomly assigned to a group using a computer program to receive one of the malaria vaccine combinations or the rabies comparator vaccine.</div>\n <div>\n Depending on the group, children received 3, 4, 5 or 6 injections of vaccine at various times. The vaccine injections were given in the arm. The details of the groups and vaccination schedules were as shown in the study design below.</div>\n <div>\n <img alt=\"\" src=\"data:image/png;base64,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
      • short_titleMal 094
      • protocol_noECCT/18/01/01
      • version_no1
      • date_of_protocol06-04-2017
      • study_drugMalaria Vaccine RTS,S AS01E
      • disease_conditionMalaria
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines1
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameRabipur (inactivated rabies virus) vaccine
      • comparator_registeredYes
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresstsang@kemricdc.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi0
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantDr Tony Sang
      • declaration_date123-01-2018
      • declaration_principal_investigatorDr Simon Kariuki
      • declaration_date223-01-2018
      • placebo_presentYes
      • study_objectives<div>\n <strong>General Objective</strong></div>\n<ol>\n <li>\n The overall objective of the proposed study is to evaluate the safety, immunogenicity and efficacy of the candidate malaria vaccine RTS,S/AS01E in vaccination schedules with or without fractional doses, early Dose 4 and yearly doses, in children 5-17 months of age living in a malaria endemic area of western Kenya.</li>\n</ol>\n<div>\n  </div>\n<div>\n <strong>Specific Objectives</strong></div>\n<ol>\n <li>\n To evaluate the efficacy of RTS,S/AS01E primary schedule with or without fractional doses, early dose 4 and yearly doses</li>\n <li>\n To assess efficacy against prevalent P. falciparum infections (defined by a positive blood slide) of each RTS,S/AS01E schedule at cross sectional visits</li>\n <li>\n To describe the antibody response to the anti-circumsporozoite protein of P. falciparum (anti-CS) and hepatitis B surface antigen (anti-HBs) in a subset of subjects for each schedule.</li>\n <li>\n To assess the safety of RTS,S/AS01E for each schedule in terms of serious adverse events (SAEs), unsolicited adverse events (AEs) and AEs of specific interest.</li>\n <li>\n To assess the reactogenicity of RTS,S/AS01E in a subset of subjects terms of solicited local and general AEs.</li>\n <li>\n To assess the safety of RTS,S/AS01E in a subset of subjects in terms of biochemistry (alanine aminotransferase [ALT], creatinine) and hematology (hemoglobin, white blood cells [WBC], platelets) parameters.</li>\n <li>\n To describe the anti-CS antibody response in a subset of subjects in terms of avidity.</li>\n</ol>\n
      • principal_inclusion_criteria<div>\n All subjects must satisfy ALL the following criteria at study entry:</div>\n<ul>\n <li>\n Subjects’ parent(s)/LAR(s) who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. return for follow-up visits).</li>\n <li>\n Signed or thumb-printed and witnessed informed consent obtained from the parent(s)/LAR(s) of the subject prior to performance of any study specific procedure. Where parent(s)/LAR(s) are illiterate, the consent form will be countersigned by an independent witness.</li>\n <li>\n A male or female between, and including, five and 17 months of age at the time of the first vaccination.</li>\n <li>\n Healthy subjects as established by medical history and clinical examination before entering into the study.</li>\n <li>\n Previously received three documented doses of diphtheria, tetanus, pertussis, hepatitis B vaccine (DTPHepB), and at least three doses of oral polio vaccine.</li>\n</ul>\n<div>\n  </div>\n
      • principal_exclusion_criteria<ul>\n <li>\n Child in care. Please refer to the glossary of terms for the definition of child in care.</li>\n <li>\n Use of a drug or vaccine that is not approved for that indication (by one of the following regulatory authorities: Food and Drug Administration [FDA; USA] or European Union member state or WHO [with respect to prequalification]) other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day -29 to Day 0), or planned use during the study period.</li>\n <li>\n Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.</li>\n <li>\n Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone ( 0.5 mg/kg/day (for pediatric subjects) or equivalent. Inhaled and topical steroids are allowed.</li>\n <li>\n Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting seven days before each dose and ending seven days after each dose of vaccine administration. (For example, the measles and yellow fever vaccines which are administered at nine months of age according to the standard EPI can be administered to study subjects provided that they are given at least seven days before or at least seven days after any dose of study vaccine).</li>\n <li>\n Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product (pharmaceutical product or device).</li>\n <li>\n Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).</li>\n <li>\n Family history of congenital or hereditary immunodeficiency.</li>\n <li>\n History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.</li>\n <li>\n History of anaphylaxis post-vaccination.</li>\n <li>\n History of any, or documented, serious adverse reaction to rabies vaccination.</li>\n <li>\n Contraindication to rabies vaccination (Rabipur is contraindicated in subjects with an history of a severe hypersensitivity to any of the ingredients in the vaccine. Note that the vaccine contains polygeline and residues of chicken proteins, and may contain traces of neomycin, chlortetracycline and amphotericin B) [Refer to the Rabipur SmPC, 2010].</li>\n <li>\n Major congenital defects.</li>\n <li>\n Serious chronic illness.</li>\n <li>\n History of any neurological disorders or seizures.</li>\n <li>\n Acute disease and/or fever at the time of enrolment.\n <ul>\n <li>\n <span style=\"white-space:pre\">​</span>Fever is defined as temperature ≥ 37.5°C/99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C/100.4°F for rectal route.</li>\n <li>\n Subjects with a minor illness (such as mild diarrhea, mild upper respiratory infection) without fever may, be enrolled at the discretion of the investigator.</li>\n </ul>\n </li>\n <li>\n Administration of immunoglobulins and/or any blood products during the period starting three months before the first dose of study vaccine or planned administration during the study period.</li>\n <li>\n Moderate or severe malnutrition at screening defined as weight for age Z-score < -2 (by WHO growth standard) [WHO, 2006].</li>\n <li>\n Hemoglobin concentration < 8 g/dl at screening.</li>\n <li>\n Same sex twins (to avoid misidentification).</li>\n <li>\n Maternal death.</li>\n <li>\n Prior receipt of an investigational malaria vaccine.</li>\n</ul>\n<div>\n  </div>\n
      • primary_end_points<p>\n <strong>Efficacy: Incremental efficacy of a schedule with a fractional third dose at Month 2 over the standard schedule</strong></p>\n<p>\n To demonstrate the superiority of a 3-dose schedule of GSK Biologicals’ malaria vaccine RTS,S/AS01_E with a fractional third dose at Month 2 compared to a standard schedule of RTS,S/AS01_E with three full doses in terms of vaccine efficacy against clinical malaria (primary case definition) over 12 months post-Dose 3.</p>\n<p>\n <em>Criterion:</em></p>\n<p>\n <em>The lower limit of the 95% CI of the incremental vaccine efficacy estimate is above 0.</em></p>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<div>\n The study will be conducted at the Siaya County Referral Hospital and up to 6 other surrounding health facilities (Ng’iya, Kogelo, Ting’wang’i, Mulaha, Nyathengo and Bar Olengo). These health facilities are located in Karemo Division of Siaya County and lie within the catchment area of the Kenya Medical Research Institute (KEMRI) and Centers for Disease Control and Prevention (CDC) Health and Demographic Surveillance System (HDSS)</div>\n<div>\n The key study staff will include the following:</div>\n<ul>\n <li>\n Co-PI - Dr Aaron Samuels, MD, MHS</li>\n <li>\n Co-PI - Dr Simon Kariuki, PhD</li>\n <li>\n Study Medical Officer - Dr Paul Ndaya Oloo, MD, MSc</li>\n <li>\n Study Pediatrician – Dr Martina Oneko, MD, Paed</li>\n <li>\n Pharmacist - Dr Tony Sang, BPharm</li>\n <li>\n Lab Manager – Kephas Otieno, MSc</li>\n <li>\n Data Manager – Kelvin Onoka BSc</li>\n <li>\n Study Coordinator - TBD</li>\n <li>\n Regulatory Affairs Officer – TBD</li>\n</ul>\n<div>\n Additionally, each of the sites will have the following personnel:</div>\n<ul>\n <li>\n Clinical Officers - 2</li>\n <li>\n Nurses - 2</li>\n <li>\n Laboratory Technicians/ Phlebotomist -1</li>\n <li>\n Data Officers -1</li>\n <li>\n QA/QC officers -1</li>\n</ul>\n<div>\n  </div>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n CDC IRB approved the study on </p>\n<p>\n KEMRI SERU approved the study on</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration5 years
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindNo
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorRabies vaccine
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states2
      • number_of_sites6
      • multi_country_listKenya\nGhana
      • data_monitoring_committeeYes
      • total_enrolment_per_site750
      • total_participants_worldwide1500
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenNo
      • population_adolescentNo
      • population_above_18No
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyInformed consent for subject participation will be sought from parent(s)/guardian(s).
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameAaron
      • investigator1_middle_name
      • investigator1_family_nameSamuels
      • investigator1_qualificationMD
      • investigator1_professional_addressP.O. Box 1578, Kisumu, 40100
      • investigator1_telephone+254 724 255 633
      • investigator1_emailamsamuels@cdc.gov
      • organisations_transferred_Yes
      • number_participants750
      • notification
      • approval_date06-03-2018
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted16-03-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<div>\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"100%\">\n <thead>\n <tr>\n <th style=\"width:25.72%;\">\n <p>\n <strong>Name of sponsor: GlaxoSmithKline Biologicals SA</strong></p>\n </th>\n <th style=\"width:39.58%;\">\n <p>\n <strong>Name of finished product:</strong></p>\n <p>\n GlaxoSmithKline Biologicals’ candidate <em>Plasmodium falciparum</em> malaria vaccine RTS,S/AS01_E</p>\n </th>\n <th style=\"width:34.7%;\">\n <p>\n <strong>Name of active substance:</strong></p>\n <p>\n RTS,S antigen, AS01_E adjuvant</p>\n </th>\n </tr>\n </thead>\n </table>\n <p>\n <strong>Study title:</strong> Phase IIb randomized, open-label, controlled, multi-center study of the efficacy, safety and immunogenicity of GSK Biologicals’ candidate malaria vaccine RTS,S/AS01_E evaluating schedules with or without fractional doses, early Dose 4 and yearly doses, in children 5-17 months of age living in sub-Saharan Africa.</p>\n <p>\n <strong>Principal/Coordinating investigator:</strong> Dr. Simon Kariuki, KEMRI/CDC/CGHR, Kisumu, Kenya and Prof. Tsiri Agbenyega, KNUST, School of Medical Science, Kumasi, Ghana.</p>\n <p>\n <strong>Study centers</strong><strong>:</strong> The study was conducted at 2 centers in 2 countries: 1 center in Siaya, Kenya and 1 center in Presbyterian Hospital, Agogo, Ghana.</p>\n <p>\n <strong>Publication(s):</strong> Samuels AM, Ansong D, Kariuki SK, et al. Lancet Infect Dis. 2022;22(9):1329-1342. Erratum in: Lancet Infect Dis. 2022 Sep 9.</p>\n <p>\n <strong>Study period</strong><strong>:</strong></p>\n <p>\n Study initiation date: 28 September 2017</p>\n <p>\n Study completion date: 14 November 2022</p>\n <p>\n End of study date: 26 April 2023</p>\n <p>\n <strong>Phase of development:</strong> Phase IIb</p>\n <p>\n <strong>Sequence of analyses: </strong></p>\n <ul>\n <li>\n A first interim analysis was performed on data collected up to Month 21 (Visit 25) to evaluate the primary objective and relevant secondary objectives, comprising efficacy data to Month 20 and immunogenicity and safety data to Month 21.</li>\n <li>\n A second interim analysis was performed on data collected up to Month 33 (Visit 31) to evaluate relevant secondary objectives, comprising efficacy data to Month 32 and immunogenicity and safety data to Month 33.</li>\n <li>\n The final analysis was performed at study end (Month 50) on efficacy, immunogenicity and safety data collected up to Month 50 (Visit 38) to evaluate relevant secondary objectives.</li>\n </ul>\n <p>\n <strong>Objectives:</strong></p>\n <table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n <thead>\n <tr>\n <th style=\"width:306px;\">\n <p align=\"center\">\n <strong>OBJECTIVES</strong></p>\n </th>\n <th style=\"width:270px;\">\n <p align=\"center\">\n <strong>ENDPOINTS</strong></p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"width:306px;\">\n <p>\n <strong>Primary Objective</strong></p>\n </td>\n <td style=\"width:270px;\">\n <p>\n <strong>Primary Endpoint</strong></p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Efficacy:</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To demonstrate the superiority of a 3-dose schedule of GSK’s malaria vaccine RTS,S/AS01_E with a fractional (Fx) third dose at Month 2 compared to a standard schedule of RTS,S/AS01_E with 3 full doses in terms of vaccine efficacy (VE) against clinical malaria (primary case definition) over 12 months post-Dose 3.</li>\n </ul>\n <p style=\"margin-left:21.6pt;\">\n <em>Criterion: T</em><em>he lower limit of the 95% confidence interval (CI) of the incremental VE estimate is above 0.</em></p>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of clinical malaria meeting the primary case definition from Month 2.5 up to Month 14.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <p>\n <strong>Secondary Objectives</strong></p>\n </td>\n <td style=\"width:270px;\">\n <p>\n <strong>Secondary Endpoints</strong></p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Efficacy:</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the incremental VE against clinical malaria of a schedule with a Fx third dose at Month 2 versus a schedule with 3 full doses (primary and secondary case definitions) over 12 months post-Dose 3.</li>\n <li>\n To assess the incremental VE against clinical malaria, over 7 and 12 months post-Dose 3, of a schedule with a Fx third dose at Month 7 versus a schedule with a Fx third dose at Month 2.</li>\n <li>\n To assess the incremental VE against clinical malaria, over 7 and 12 months post-Dose 3, of a schedule with a Fx third dose at Month 7 versus a schedule with 3 full doses.</li>\n <li>\n To assess the incremental VE against clinical malaria, over 12 months post-Dose 4, post-Dose 5 and post-Dose 6 of a schedule with a Fx third dose at Month 2 and yearly Fx doses versus a schedule with full doses at Month 0, Month 1, Month 2 and yearly full doses.</li>\n <li>\n To assess the incremental VE against clinical malaria, over 12 months post-Dose 4, of a schedule with a Fx third dose at Month 7 versus a standard schedule with 4 full doses at 0,1,2,20 months.</li>\n <li>\n To assess the VE and impact of each RTS,S/AS01_E schedule over the entire study period by measuring the efficacy against clinical malaria at Months 14, 20, 26, 32, 38 and 50.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of clinical malaria meeting the primary and secondary case definitions from Day 0 up to Month 50.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the prevalence of <em>P. falciparum</em> infections of each RTS,S/AS01_E schedule at cross-sectional visits (monthly from Month 0-20 and every 3 months thereafter till study end).</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The prevalence of <em>P. falciparum</em> infections defined by positive blood slide at each cross-sectional survey.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the VE against incident <em>P. falciparum</em> infections defined by positive blood slide over the entire study period.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of incident <em>P. falciparum</em> infections from Day 0 to Month 50.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Immunogenicity:</strong> Immune response to the CS and HBs antigens (immunogenicity sub-cohort)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To describe the antibody response to the anti-circumsporozoite protein of <em>P. falciparum</em> (anti-CS) for each schedule.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n Anti-CS antibody concentrations and seropositivity measured before Dose 1, 1 month post-Dose 2 (group Fx017-20 only), before and 1 month post-Dose 3, before and 1 month after Dose 4, before and 1 month after each yearly dose and at study end (Month 50).</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To describe the antibody response to the hepatitis B surface antigen (anti-HBs) for each schedule.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n Anti-HBs antibody concentrations, seropositivity and seroprotection measured before Dose 1, 1 month post-Dose 2 (group Fx017-20 only), before and 1 month post-Dose 3, before and 1 month after Dose 4, before and 1 month after each yearly dose and at study end (Month 50).</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Safety and reactogenicity:</strong> All participants</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the safety of RTS,S/AS01_E for each schedule in terms of serious adverse events (SAEs), unsolicited adverse events (AEs) and AEs of specific interest (AESI).</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of SAEs (all, fatal and related) during the whole study period according to the Medical Dictionary for Regulatory Activities (MedDRA) classification.</li>\n <li>\n The occurrence of AEs and SAEs leading to withdrawal from further vaccination from Dose 1 (Day 0) up to Month 50, according to the MedDRA classification.</li>\n <li>\n The occurrence of severe malaria cases and cerebral malaria cases during the whole study period.</li>\n <li>\n The occurrence of potential immune-mediated diseases (pIMDs) from Day 0 up to Month 50, according to the MedDRA classification.</li>\n <li>\n The occurrence of meningitis from Day 0 up to Month 50, according to the MedDRA classification.</li>\n <li>\n The occurrence of seizures within 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine, according to the MedDRA classification.</li>\n <li>\n The occurrence of generalized convulsive seizure within 7 days (day of vaccination and 6 subsequent days) after each dose of study vaccine, according to the Brighton Collaboration guidelines.</li>\n <li>\n The occurrence of unsolicited AEs within 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine, according to the MedDRA classification.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Safety and reactogenicity:</strong> Reactogenicity (reactogenicity sub-cohort)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the reactogenicity of RTS,S/AS01_E in terms of solicited local and general AEs.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of solicited local and general AEs in the first 50 participants enrolled in each group within 4 days (day of vaccination and 3 subsequent days) after Dose 3 of study vaccine (all groups including controls) after Dose 4 (groups R012-20, R012-14, Fx012-14 and Fx017‑20), after Dose 5 (groups R012-14, Fx012-14 and Fx017-20) and after Dose 6 (groups R012-14 and Fx012-14).</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the safety of RTS,S/AS01_E in terms of biochemistry (alanine aminotransferase [ALT], creatinine) and hematology (hemoglobin, white blood cells [WBCs], platelets) parameters.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The concentration of biochemistry (ALT, creatinine) and hematology (hemoglobin, WBCs, platelets) parameters in the first 50 participants (25 participants per site) enrolled in each group (reactogenicity sub-cohort) before Dose 3, 7 days post‑Dose 3 and 30 days post-Dose 3.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n Results of the tertiary objective and endpoint are provided in the body of the report.</p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n <strong>Methodology:</strong> This study was a Phase IIb, randomized, open-label, controlled, multi‑center study with 5 parallel groups, conducted in children aged 5-17 months.</p>\n <table align=\"center\" border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:16.38%;height:30px;\">\n <p align=\"center\">\n <strong>Protocol study group naming</strong></p>\n </td>\n <td style=\"width:16.42%;height:30px;\">\n <p align=\"center\">\n <strong>SAP study group naming</strong></p>\n </td>\n <td style=\"width:67.2%;height:30px;\">\n <p align=\"center\">\n <strong>Vaccination schedule</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n R012-20</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n R012-20</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n RTS,S/AS01_E full dose at Months 0, 1 and 2 + full dose at Month 20</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n R012-14-mD</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n R012-14</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n RTS,S/AS01_E full dose at Months 0, 1 and 2 + yearly full doses at Months 14, 26 and 38</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n Fx012-14-mFxD</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n Fx012-14</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n RTS,S/AS01_E full dose at Months 0 and 1 + RTS,S/AS01_E 1/5^th dose at Months 2, 14, 26 and 38</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n Fx017-mFxD</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n Fx017-20</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n RTS,S/AS01_E full dose at Months 0 and 1 + RTS,S/AS01_E 1/5^th dose at Months 7, 20 and 32</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n Control</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n Control</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n Rabies vaccine at Months 0, 1 and 2</p>\n </td>\n </tr>\n </tbody>\n </table>\n <div style=\"clear:both;\">\n  </div>\n <p>\n SAP = Statistical Analysis Plan</p>\n <p>\n NOTE: group naming in the Clinical Study Report is aligned with the SAP/analyses tables.</p>\n <ul>\n <li>\n Sampling schedule</li>\n </ul>\n <p>\n For the evaluation of anti-CS responses, anti-HBs responses, biochemistry (ALT, creatinine) parameters and hematology (hemoglobin, WBCs, platelets) parameters, a sub-cohort of 50 participants (25 participants per site) enrolled in each group had tests performed on blood drawn at the timepoints described in the table below. In addition, a small amount of blood was taken every month up until Month 20 and thereafter every 3 months in all participants for the evaluation of <em>P. falciparum</em> infections.</p>\n <p>\n  </p>\n</div>\n<p>\n  </p>\n<div>\n <table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"99%\">\n <tbody>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 1</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 2</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 4</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 5</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 6</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 10</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 11</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 12</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 18</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 19</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 24</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 25</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 27</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 28</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 30</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 31</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 33</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 34</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 38</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Study group</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Type of blood sampling</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Scr</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>D0</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M2</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M2 + 7d</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M3</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M7</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M7 + 7d</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M8</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M14</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M15</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M20</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M21</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M26</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M27</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M32</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M33</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M38</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M39</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M50</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>R012-20</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>R012-14</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Fx012-14</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Fx017-20</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Control</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n NOTE: At screening, hemoglobin was assessed in all participants screened. Hematology and biochemistry were tested in blood samples from a sub-cohort consisting of the first 50 participants enrolled in each group and immunogenicity was tested in the same sub-cohort.</p>\n <p>\n Scr: Screening; M: Month; D: Day</p>\n <p>\n  </p>\n</div>\n<p>\n  </p>\n<ul>\n <li>\n Efficacy surveillance</li>\n</ul>\n<ul>\n <li>\n Capture of malaria cases: malaria cases were captured by passive case detection (PCD). Parents/legally acceptable representatives were advised to present their child to the health center if the child was unwell. Care was administered according to local recommendations. All children with fever and/or history of fever had a blood sample taken for the evaluation of VE. All anti-malaria treatments administered during the study were recorded in the participant’s electronic case report form (eCRF).</li>\n <li>\n Cross-sectional surveys were performed monthly from Month 0-20 and every 3 months thereafter till study end to evaluate VE against incident and prevalent <em>P. falciparum </em>infections.</li>\n <li>\n The research team at each study center provided all screened participants with an insecticide-treated bednet, and malaria diagnosis and treatment was ensured.</li>\n</ul>\n<table align=\"center\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:100.0%;\">\n <ul>\n <li>\n Safety monitoring</li>\n </ul>\n <ul>\n <li>\n This study was overseen by a formally constituted Independent Data Monitoring Committee operating under a charter.</li>\n </ul>\n <ul>\n <li>\n Each participant was observed for at least 30 minutes after vaccination to evaluate and treat any acute AEs.</li>\n <li>\n Cases of severe malaria and cerebral malaria were reported as SAEs, as applicable, as part of the safety surveillance for the duration of the study and clinical details of each case were reported in a specific eCRF screen.</li>\n </ul>\n <p style=\"margin-left:43.2pt;\">\n Case definitions adapted from the World Health Organization case definitions of severe malaria and cerebral malaria were used as reference for diagnosis.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:100.0%;\">\n <ul>\n <li>\n All AEs, SAEs and SAEs leading to withdrawal from further vaccination were reported, as applicable, for the duration of the study.</li>\n <li>\n AESIs comprised meningitis and pIMDs reported for the duration of the study, and seizures occurring within 30 days post-vaccination. Clinical details according to the Brighton Collaboration guidelines pertaining to seizures occurring within 7 days of vaccination were to be documented in a specific eCRF screen.</li>\n </ul>\n <p style=\"margin-left:43.2pt;\">\n All AESIs were to be reported as SAEs.</p>\n <ul>\n <li>\n Solicited local and general AEs were collected in the reactogenicity sub-cohort during 4 days (day of vaccination and 3 subsequent days) after Dose 3 of study vaccine (all groups including controls) after Dose 4 (R012-20, R012-14, Fx012-14 and Fx017-20 groups), after Dose 5 (R012-14, Fx012-14 and Fx017-20 groups) and after Dose 6 (R012-14 and Fx012-14 groups). On the day of vaccination, reactogenicity evaluation was carried out by the study physician at the study center. On Days 1, 2 and 3 after vaccination, trained study personnel visited the children to record solicited AEs on diary cards.</li>\n <li>\n Unsolicited AEs were collected during 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine. Unsolicited AEs were captured through passive surveillance at inpatient and outpatient facilities and during study visits.</li>\n <li>\n Biochemistry (ALT, creatinine) and hematology (hemoglobin, WBCs, platelets) parameters were assessed in the reactogenicity sub-cohort before Dose 3, 7 days post-Dose 3 and 30 days post‑Dose 3.</li>\n </ul>\n <ul>\n <li>\n Case definitions</li>\n </ul>\n <p>\n <u>Clinical malaria and <em>P. falciparum</em> infection</u></p>\n <table align=\"center\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:576px;\" width=\"576\">\n <tbody>\n <tr>\n <td colspan=\"2\" style=\"width:576px;height:11px;\">\n <p>\n <strong>Case definitions of clinical malaria</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:104px;height:11px;\">\n <p>\n <strong>Primary case definition</strong></p>\n </td>\n <td style=\"width:472px;height:11px;\">\n <p>\n <em>P. falciparum</em> asexual parasitemia >5000 parasites/μL</p>\n <p>\n <strong>AND</strong> presence of fever (axillary temperature ³37.5°C) at the time of presentation</p>\n <p>\n <strong>AND</strong> occurring in a child who is unwell and brought for treatment to a healthcare facility</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:104px;height:11px;\">\n <p>\n <strong>Secondary case definition</strong></p>\n </td>\n <td style=\"width:472px;height:11px;\">\n <p>\n <em>P. falciparum</em> asexual parasitemia >0 parasites/μL</p>\n <p>\n <strong>AND</strong> presence of fever (axillary temperature ³37.5°C) at the time of presentation or history of fever within 24 hours of presentation</p>\n <p>\n <strong>AND</strong> occurring in a child who is unwell and brought for treatment to a healthcare facility</p>\n </td>\n </tr>\n </tbody>\n </table>\n <div style=\"clear:both;\">\n  </div>\n <ul>\n <li>\n  </li>\n </ul>\n </td>\n </tr>\n </tbody>\n</table>\n<div style=\"clear:both;\">\n  </div>\n<p>\n  </p>\n<table align=\"center\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:100.0%;\">\n <p>\n <strong>Case definition of incident <em>P. falciparum</em> infection</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:100.0%;\">\n <p>\n A documented <em>P. falciparum</em> asexual parasite density >0 detected by blood slide reading at a cross-sectional survey or as captured by the secondary case definition of clinical malaria (active detection of infection [ADI] and PCD)</p>\n </td>\n </tr>\n </tbody>\n</table>\n<div style=\"clear:both;\">\n  </div>\n<p>\n  </p>\n<table align=\"center\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:100.0%;\">\n <p>\n <strong>Case definition of prevalent <em>P. falciparum</em> infection</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:100.0%;\">\n <p>\n A documented <em>P. falciparum</em> asexual parasite density >0 detected by blood slide reading at a cross-sectional survey (ADI).</p>\n </td>\n </tr>\n </tbody>\n</table>\n<div style=\"clear:both;\">\n  </div>\n<p>\n <strong>Number of participants</strong> <strong>(planned and analyzed):</strong> Approximately 1500 participants (300 per group) were planned to be randomized in this study; 2157 participants were enrolled (signed an informed consent form), 1609 were randomized, 1500 received at least 1 dose of vaccine and 1333 were eligible for analyses in the per protocol set (PPS) for efficacy.</p>\n<p>\n <strong>Diagnosis and main criteria for inclusion:</strong> Healthy male or female participants aged 5-17 months at the time of the first vaccination, and who had previously received 3 documented doses of diphtheria, tetanus, pertussis, hepatitis B vaccine (DTP/HepB), and at least 3 doses of oral polio vaccine, were eligible for enrolment.</p>\n<p>\n <strong>Study intervention, dose, mode of administration and lot number:</strong></p>\n<ul>\n <li>\n RTS,S/AS01_E, administered by intramuscular (IM) injection in the deltoid:</li>\n</ul>\n<ul>\n <li>\n Per 0.5 mL dose:<br />\n 25 mg RTS,S antigen;<br />\n AS01_E adjuvant: 25 mg 3‑O‑desacyl‑4’‑monophosphoryl lipid A (MPL), 25 mg QS-21 with liposomes.</li>\n <li>\n Per Fx 0.1 mL dose:<br />\n 5 mg RTS,S antigen;<br />\n AS01_E adjuvant: 5 mg MPL, 5 mg QS-21 with liposomes.</li>\n <li>\n From the reconstituted vaccine vial, 0.1 mL was withdrawn to administer a Fx dose of RTS,S/AS01_E.</li>\n</ul>\n<ul>\n <li>\n Rabies vaccine (<em>Rabipur</em>) administered by IM injection in the deltoid:</li>\n</ul>\n<ul>\n <li>\n Per 1.0 mL dose: 2.5 IU rabies virus.</li>\n</ul>\n<ul>\n <li>\n Lot numbers:</li>\n</ul>\n<ul>\n <li>\n RTS,S: AMALA002A, AMALA009G, AMALA010B, AMALA011B, AMALA013C</li>\n <li>\n AS01_E: AA1EA005A, AA1EA007A, AA1EA008B, AA1EA008A, AA1EA009A, AA1EA013A</li>\n <li>\n <em>Rabipur</em> antigen: DEXTA542AY, DEXTG218AZ, DEXTG223AZ</li>\n <li>\n <em>Rabipur</em> diluent: DEXTA542AZ, DEXTG218AY, DEXTG223AY</li>\n</ul>\n<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td colspan=\"5\" style=\"width:100.0%;\">\n <p align=\"center\">\n <strong>Vaccine dose details for RTS,S/AS01_E study groups</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;height:47px;\">\n <p>\n <strong>Study Group</strong></p>\n </td>\n <td style=\"width:16.16%;height:47px;\">\n <p align=\"center\">\n <strong>Vaccination months</strong></p>\n </td>\n <td style=\"width:18.04%;height:47px;\">\n <p align=\"center\">\n <strong>RTS,S per vaccination (μg)</strong></p>\n </td>\n <td style=\"width:18.36%;height:47px;\">\n <p align=\"center\">\n <strong>AS01_E per vaccination (μg)</strong></p>\n </td>\n <td style=\"width:29.42%;height:47px;\">\n <p align=\"center\">\n <strong>Volume administered per vaccination (mL)</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;\">\n <p>\n <strong>R012-20</strong></p>\n </td>\n <td style=\"width:16.16%;\">\n <p align=\"center\">\n 0, 1, 2, 20</p>\n </td>\n <td style=\"width:18.04%;\">\n <p align=\"center\">\n 25–25–25-25</p>\n </td>\n <td style=\"width:18.36%;\">\n <p align=\"center\">\n 25–25–25-25</p>\n </td>\n <td style=\"width:29.42%;\">\n <p align=\"center\">\n 0.5–0.5–0.5-0.5</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;\">\n <p>\n <strong>R012-14</strong></p>\n </td>\n <td style=\"width:16.16%;\">\n <p align=\"center\">\n 0, 1, 2, 14, 26, 38</p>\n </td>\n <td style=\"width:18.04%;\">\n <p align=\"center\">\n 25–25–25-25-25-25</p>\n </td>\n <td style=\"width:18.36%;\">\n <p align=\"center\">\n 25–25–25-25-25-25</p>\n </td>\n <td style=\"width:29.42%;\">\n <p align=\"center\">\n 0.5–0.5–0.5-0.5-0.5-0.5</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;\">\n <p>\n <strong>Fx012-14</strong></p>\n </td>\n <td style=\"width:16.16%;\">\n <p align=\"center\">\n 0, 1, 2, 14, 26, 38</p>\n </td>\n <td style=\"width:18.04%;\">\n <p align=\"center\">\n 25–25–5-5-5-5</p>\n </td>\n <td style=\"width:18.36%;\">\n <p align=\"center\">\n 25–25–5-5-5-5</p>\n </td>\n <td style=\"width:29.42%;\">\n <p align=\"center\">\n 0.5–0.5–0.1-0.1-0.1-0.1</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;\">\n <p>\n <strong>Fx017-20</strong></p>\n </td>\n <td style=\"width:16.16%;\">\n <p align=\"center\">\n 0, 1, 7, 20, 32</p>\n </td>\n <td style=\"width:18.04%;\">\n <p align=\"center\">\n 25–25–5-5-5</p>\n </td>\n <td style=\"width:18.36%;\">\n <p align=\"center\">\n 25–25–5-5-5</p>\n </td>\n <td style=\"width:29.42%;\">\n <p align=\"center\">\n 0.5–0.5–0.1-0.1-0.1</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n <strong>Duration of study:</strong> The study duration was approximately 50 months per participant.</p>\n<p>\n <strong>Statistical methods:</strong></p>\n<p>\n <em>Analysis Sets</em></p>\n<ul>\n <li>\n The Enrolled Set included all participants who signed informed consent.</li>\n <li>\n The Exposed Set included all participants who received at least 1 dose of study vaccine. The Exposed Set analysis was performed per treatment actually administered.</li>\n <li>\n For the primary analysis of efficacy up to Month 14, the PPS for efficacy included all participants from the Exposed Set who fulfilled eligibility criteria and who received all 3 first vaccinations according to protocol procedures within the protocol specified intervals that contributed to the time at risk in the follow-up period starting 14 days post-Dose 3. <em>NOTE: elimination codes detailed in SAP further classified the participants included in the PPS for efficacy.</em></li>\n <li>\n The PPS for immunogenicity included all participants included in the Exposed Set who received all vaccinations according to protocol procedures within the protocol specified intervals, performed blood samplings for immunogenicity according to protocol intervals, met all eligibility criteria, did not use any medication or blood products forbidden by the protocol and did not have any reported underlying medical condition influencing immune responses. <em>NOTE: elimination codes detailed in SAP further classified the participants included in the PPS for immunogenicity.</em></li>\n</ul>\n<ul>\n <li>\n Immunogenicity sub-cohort: the first 50 participants (25 participants per site) enrolled in each group.</li>\n</ul>\n<ul>\n <li>\n The solicited safety set - including the reactogenicity sub-cohort - included all participants who received at least 1 dose of study vaccine and had solicited safety data.</li>\n</ul>\n<ul>\n <li>\n Reactogenicity sub-cohort: the first 50 participants (25 participants per site) enrolled in each group.</li>\n</ul>\n<p>\n <em>Demography</em></p>\n<ul>\n <li>\n Demographic characteristics (age and gender) and the baseline hemoglobin level were tabulated per study group overall, and by site, for each cohort (Exposed Set, PPS for efficacy and PPS for immunogenicity).</li>\n <li>\n The mean age at first vaccination (in months) (plus range and standard deviation [SD]) of the vaccinated participants as a whole and per group, were calculated.</li>\n</ul>\n<p>\n <em>Efficacy</em></p>\n<p>\n The primary analysis of efficacy was based on the PPS for efficacy.</p>\n<ul>\n <li>\n Measures of incidence (<em>P. falciparum</em> infection and clinical malaria)</li>\n</ul>\n<p>\n <u>First or only episode (Month 21 Interim Analysis only)</u></p>\n<p>\n VE against first or only episode of incident <em>P. falciparum</em> infection or clinical malaria was analyzed by Cox regression stratified by study site, and overall. The 95% CI and p-values of the VE estimates (1- Hazard Ratio) were calculated from this model. Cumulative incidence graphs were produced.</p>\n<p>\n <u>All episodes</u></p>\n<p>\n VE against all episodes of clinical malaria was analyzed by negative binomial regression allowing for interdependence between episodes within the same participant (non-linear mixed model with over dispersion parameter estimated from the random effect). The 95% CI and p-values of the VE estimates (1- Incidence Rate Ratio) were calculated from this model. Fourteen days following an episode meeting the case definition under evaluation was subtracted from the follow-up time. The distribution of the total number of events per participant was tabulated by group. Results per site and overall (adjusted for site as a fixed effect) were summarized in tables and forest plots.</p>\n<ul>\n <li>\n Measure of prevalence (<em>P. falciparum</em> infection)</li>\n</ul>\n<p>\n The prevalence of <em>P. falciparum</em> infection was evaluated on the cross-sectional ADI samples only. At each pre-defined timepoint the prevalence (number of participants with <em>P. falciparum</em> infection/total number of participants) of <em>P. falciparum</em> infection was calculated by group together with 95% CIs. Graphical presentations of the prevalence over time were produced. Results per site and overall were summarized in tables.</p>\n<p>\n The prevalence of gametocytemia was tabulated for each group (Fx017-20, Fx012‑14, R012-20, R012-14 and Control) at each cross-sectional visit. Within gametocyte positive slides, the proportion of male gametocytes was tabulated by group, timepoint and site. Within parasitemia positive participants the geometric mean was tabulated by group, timepoint and by site.</p>\n<ul>\n <li>\n Measure of impact (clinical malaria)</li>\n</ul>\n<p>\n The vaccine impact was estimated by the number of cases of clinical malaria averted over the relevant time frame per 1000 participants vaccinated. The number of cases averted was calculated as the difference of the estimated cases between the Control group and the vaccine group. Estimated cases in each group were calculated as the area under the curve of the incidence of clinical malaria over time and expressed as cumulative cases averted per 1000 participants followed up during the relevant period. Results per site and overall were summarized in tables.</p>\n<p>\n <em>Immunogenicity</em></p>\n<p>\n The primary analysis of immunogenicity was based on the PPS for immunogenicity; analyses on the Exposed Set were also performed.</p>\n<ul>\n <li>\n In the immunogenicity sub-cohort, the percentage of participants with seropositive (≥1.9 EU/mL) levels of anti-CS with 95% CI were determined at specified blood sampling timepoints in each group.</li>\n <li>\n In the immunogenicity sub-cohort, the percentage of participants with seropositive (³6.2 mIU/mL) and seroprotective levels (³10 mIU/mL) of anti-HBs with 95% CI were determined at specified blood sampling timepoints in each group.</li>\n <li>\n Anti-CS and -HBs antibody concentrations were summarized by geometric mean concentrations (GMCs) with 95% CI. Antibody concentrations 1 month after the third dose and each subsequent dose of study vaccine were also investigated using reverse cumulative distribution curves.</li>\n</ul>\n<p>\n <em>Safety and reactogenicity</em></p>\n<p>\n The primary analysis of safety was based on the Exposed Set. Analyses containing only solicited data were based on the solicited safety set.</p>\n<ul>\n <li>\n The percentage of participants reporting a SAE (all, fatal, related), pIMD or meningitis from Dose 1 (Day 0) until Month 50 (i.e. over 50 months’ surveillance per participant), classified by the MedDRA preferred term level, were tabulated with exact 95% CI.</li>\n <li>\n The percentage of participants reporting severe malaria cases (excluding cerebral malaria) and cerebral malaria cases from Day 0 up to Month 50 (i.e. over 50 months’ surveillance per participant) were tabulated with exact 95% CI.</li>\n <li>\n The percentage of participants with at least 1 report of an unsolicited AE, SAE (all, fatal, related) or seizure classified by the MedDRA preferred term level, occurring within 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine were tabulated with exact 95% CI.</li>\n <li>\n Among the reactogenicity sub-cohort:</li>\n</ul>\n<p>\n The percentage of participants reporting at least 1 local AE (solicited and unsolicited), general AE (solicited and unsolicited) and any AE (solicited and unsolicited) during the 4-day follow-up period post-Dose 3 of study vaccine (all groups including controls) post-Dose 4 (R012-20, R012-14, Fx012-14 and Fx017-20 groups), post-Dose 5 (R012-14, Fx012-14 and Fx017-20 groups) and post-Dose 6 (R012-14 and Fx012-14 groups) was tabulated with exact 95% CI. Similar tables were generated for Grade 3 AEs, AEs considered as causally related to vaccination and Grade 3 causally related AEs.</p>\n<p>\n The percentage by dose (for which solicited safety data were recorded) for each individual solicited local AE (any, Grade 3 and resulting in medically attended visit) and general AE (any, Grade 3, causally related, Grade 3 related, resulting in medically attended visit and for fever, temperature in 0.5°C increments) during the 4-day solicited follow-up period was tabulated with exact 95% CI.</p>\n<p>\n Biochemistry (ALT, creatinine) and hematology (hemoglobin, WBCs, platelets) values outside of the reference ranges were described for the reactogenicity sub‑cohort before Dose 3, 7 days post-Dose 3 and 30 days post-Dose 3. Frequency distribution of results by toxicity grades were tabulated by group.</p>\n<p>\n <strong>Summary:</strong></p>\n<p>\n <strong>Demographics</strong></p>\n<p>\n In the Exposed Set, demographic characteristics were similar across groups (Table 2.1). The mean age of participants ranged from 10.2 to 10.5 months across groups. A similar proportion of males and females were enrolled in all groups except for the R012-20 group in which more males (60.1%) than females (39.9%) were enrolled.</p>\n<p>\n Table 2.1         Summary of demography and baseline characteristics, Overall - Exposed Set</p>\n<table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <thead>\n <tr>\n <th style=\"width:31.28%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.84%;\">\n <p align=\"center\">\n <strong>R012-20<br />\n  N=298</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.84%;\">\n <p align=\"center\">\n <strong>R012-14<br />\n  N=294</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.84%;\">\n <p align=\"center\">\n <strong>Fx012-14<br />\n  N=304</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.84%;\">\n <p align=\"center\">\n <strong>Fx017-20<br />\n  N=311</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.8%;\">\n <p align=\"center\">\n <strong>Control<br />\n  N=293</strong></p>\n </th>\n </tr>\n <tr>\n <th style=\"width:31.28%;\">\n <p>\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.38%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"width:31.28%;\">\n <p>\n Age (Months) at first vaccination</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.38%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:31.28%;\">\n <p>\n    n</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 298</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 294</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 304</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 311</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 293</p>\n </td>\n <td style=\"width:6.38%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:31.28%;\">\n <p>\n    Mean</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.2</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.3</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.5</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.2</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.5</p>\n </td>\n <td style=\"width:6.38%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:31.28%;\">\n <p>\n    Standard Deviation</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 3.9</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 3.8</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 4.0</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 3.8</p>\n
      • implication_results<p>\n The fractional dose is likely to be adopted due to dose implications of giving the full dose, and the vaccine may become part of the national immunization programme as a routine vaccine.</p>\n
      • quantity_imported5480 doses
      • quantity_dispensed3227
      • quantity_destroyed1741
      • quantity_exportedNone
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      • final_date0000-00-00
      • modified2025-02-28 14:30:36
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        • telephone+254 724 255 633
        • emailamsamuels@cdc.gov
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        • given_nameSimon
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        • telephone+254 725 389 246
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        • addressRue de l’Institut 89, 1330 Rixensart, Belgium
        • telephone_number+32 2 656 81 11
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  • 1(array)
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      • abstract_of_study<div>\n Background</div>\n<div>\n Tuberculosis (TB) is the leading cause of death in HIV-positive individuals. Underdiagnosis of TB is a principal barrier to combatting the disease. In resource-limited settings, molecular diagnoses such as Xpert MTB/RIF are still not widely available and sputum samples can be difficult to produce, especially for very ill HIV-positive patients.</div>\n<div>\n  </div>\n<div>\n The Fujifilm SILVAMP TB LAM (FujiLAM; Fujifilm, Tokyo, Japan) is a novel (not commercialised) urine107 based point-of-care assay to diagnose TB in HIV-positive patients. A first study using urine frozen samples has reported a higher sensitivity of this test over the currently commercialised Alere Determine TB LAM Ag assay (AlereLAM).</div>\n<div>\n  </div>\n<div>\n At the time of the study preparations, a pandemic caused by a new coronavirus (SARS-CoV-2), is ongoing. Symptoms of coronavirus disease (CoViD-19) are similar to those of TB and people with suppressed immune systems may be particularly vulnerable to this disease.</div>\n<div>\n  </div>\n<div>\n Objectives</div>\n<div>\n The aim of this study is to investigate the diagnostic performance of FujiLAM in ambulatory HIV positive patients from fresh urine samples.</div>\n<div>\n  </div>\n<div>\n Primary objective: To assess the sensitivity of FujiLAM among patients with microbiological confirmed TB in two groups of HIV-positive patients: 1) ambulatory adult HIV-positive patients with signs and symptoms of TB regardless of their CD4 count (Group 1), and 2) ambulatory adult patients with advanced HIV disease and no signs and symptoms of TB (Group 2).</div>\n<div>\n  </div>\n<div>\n Secondary objectives: To assess the sensitivity of FujiLAM and AlereLAM in urine by level of CD4 among patients with microbiologically confirmed TB and among patients with probable TB or microbiologically confirmed TB, the diagnostic performance of algorithms including FujiLAM, the mortality at 6 months according to the FujiLAM result and the feasibility of using the FujiLAM at point-of-care and the test acceptability by test users, clinic managers and patients. To assess the prevalence of CoViD-19 among HIV-positive ambulatory patients with symptoms of TB, to describe the clinical features, the severity and the outcomes of the patients diagnosed with CoViD-19, and the proportion of patients co-infected with CoViD-19 and TB, to assess the proportion of HIV-positive patients exposed to SARS-CoV-2</div>\n<div>\n  </div>\n<div>\n Methods</div>\n<div>\n This prospective diagnostic study, will include two groups of ambulatory adult patients: 1) HIV positive patients with signs and symptoms of TB (Group 1), and 2) patients with advanced HIV disease (CD4 < 200 cells/μL or WHO Stage III/IV) and no signs and symptoms of TB (Group 2). In addition, a mix-methods approach will be used to assess the feasibility and acceptability of the test. Quantitative and qualitative methods using an exploratory design will be used for this purpose.</div>\n<div>\n  </div>\n<div>\n The study will take place in Homa Bay County Hospital in Kenya. This study is part of a multicentric study that includes other sites: the Mbarara Regional Reference Hospital in Uganda, Alto Maé Health Centre in Mozambique, and Eshowe Gateway Clinic (EGC) in Eshowe, KwaZulu-Natal, South Africa.</div>\n<div>\n  </div>\n<div>\n <div>\n Patients will be assessed for signs and symptoms of TB (cough, fever, weight loss, 138 night sweats). HIV139</div>\n <div>\n positive patients with signs and symptoms of TB and fulfilling other eligibility criteria will be invited to participate in the study as Group 1. HIV-positive patients with no signs and symptoms of TB, and with CD4 <200 cells/μL within the month prior to the consultation or in clinical Stage III/IV at the time of the consultation, and fulfilling other eligibility criteria will be invited to participate in the study as Group 2. All eligible patients will be proposed to sign an informed consent. For patients with no signs and symptoms of TB who are on clinical stage I/II and do not have a CD4 result within the month prior to the consultation, CD4 monitoring will be done by the study. In such case, patients will sign an informed consent before screening for eligibility.</div>\n <div>\n  </div>\n <div>\n Patients will receive a clinical exam, FujiLAM and AlereLAM in urine, Xpert MTB/RIF and MTB culture on sputum samples, and chest X-ray. The treating clinician will decide to treat for TB or not according to the clinical exam and the test results available except the Fuji LAM test results. Patients with signs and symptoms of TB not started on TB treatment will be re-assessed at a second consultation no later than 7 days (earlier if laboratory results are available earlier or if the patient requires a consultation earlier). In some cases a third consultation may be needed due to the clinical situation or to the delay in receiving some test results. Patient’s outcomes whether on TB treatment or not, will be assessed at 3 months and 6 months.</div>\n <div>\n  </div>\n <div>\n In addition to the TB investigations, patients with signs and symptoms of TB will be proposed optional CoViD-19 testing using conventional PCR or point-of-care PCR (GeneXpert SARS-CoV-2) at the first consultation and during follow-up if COVID-19 symptoms arise. Patients diagnosed with Covid-19 will be referred to the Homa Bay Ministry of Health Covid-19 centre for their management. All patients (symptomatic and asymptomatic) will be also proposed optional SARS-CoV-2 antibody testing at the first and last consultation.</div>\n <div>\n  </div>\n <div>\n The primary endpoint will be the sensitivity of FujiLAM calculated as the proportion of patients with a positive test result among patients with microbiological confirmed TB.</div>\n <div>\n  </div>\n <div>\n Secondary endpoints will be:</div>\n <div>\n - Sensitivity of FujijLAM and AlereLAM by level of CD4 among patients with microbiologically confirmed TB and among patients with probable TB or microbiologically confirmed TB</div>\n <div>\n - Specificity, positive and negative predictive values of FujiLAM</div>\n <div>\n - Diagnostic performance of algorithms combining AlereLAM or FujiLAM in urine with Xpert MTB/RIF in sputum</div>\n <div>\n - Median time to FujiLAM, AlereLAM and Xpert MTB/RIF test results</div>\n <div>\n - Mortality at 6 months according to the FujiLAM result.</div>\n <div>\n - Feasibility and acceptability of the FujiLAM test at point of care by test users, managers and patients.</div>\n <div>\n - Proportion of TB symptomatic patients diagnosed with CoViD-19 overall, by TB diagnosis, by severity of disease and by outcome.</div>\n <div>\n - Proportion of patients exposed to SARS-CoV-2.</div>\n <div>\n  </div>\n <div>\n A total of 200 HIV-positive patients with signs and symptoms of TB (Group 1) and 250 HIV-positive patients with no signs and symptoms of TB and CD4<200 or in stage III/IV (Group 2) will be recruited in Homa Bay.</div>\n <div>\n  </div>\n <div>\n <div>\n Patients’ informed consent will be obtained before enrolment in the study. The study 180 protocol, the information sheets, the consent forms and any other relevant documents will be submitted for approval to the National Ethics Committees in each country where the study will be conducted and to Médecins Sans Frontières (MSF) Ethics Review Board.</div>\n <div>\n  </div>\n <div>\n Expected results</div>\n <div>\n This research study would be among the first to provide evidence through a prospective study on the performance of FujiLAM, a novel point-of-care test to diagnose TB in HIV-positive patients in programmatic conditions. If the diagnostic performance of this test is proven to be good, the use of the test would allow rapid TB diagnosis and would potentially decrease mortality in HIV-positive patients.</div>\n <div>\n  </div>\n <div>\n The study will also inform WHO and the international scientific community on the diagnostic performance and other implementation aspects of using the test. The study will also provide additional evidence on CoViD-19 among HIV-positive patients.</div>\n </div>\n</div>\n<p>\n  </p>\n
      • study_title<div>\n Diagnostic performance of a novel lipoarabinomannan test (FujiLAM) to detect tuberculosis in HIV-positive patients in Kenya</div>\n
      • laymans_summary<div>\n Tuberculosis (TB) is the leading cause of death among individuals living with HIV. Many cases of TB are missed each year for various reasons including lack of appropriate tools for the diagnosis of tuberculosis in specific populations at risk. This hinders the efforts to combat the disease. A test called the GeneXpert is a standard in the diagnosis of TB in Kenya and many similar settings. The test looks for the genetic material of the bacteria causing tuberculosis and requires individuals with suspected tuberculosis to produce phlegm for testing. While this test shows good performance, it is not always available and some categories of individuals such as HIV patients who are very sick are unable to cough up the phlegm required for testing.</div>\n<div>\n  </div>\n<div>\n The purpose of this study is to assess the performance of a new test called the Fujifilm SILVAMP TB LAM or simply the Fuji-LAM test. The Fuji-LAM test is a test that can be done on urine to look for specific proteins that are produced by the bacteria that causes tuberculosis. This test offers an advantage over the tests that are based on phlegm because most patients can produce urine for testing even when they are very sick. Additionally, this test does not require a complex laboratory set up and it can therefore be used by health workers as they interact with the patient. This study will also look at how the new test compares with an existing test - AlereLAM - that is based on similar technology. Initial laboratory-based studies conducted on frozen urine samples show that the new test has better performance than the existing test. This study is different from the first studies because it is being conducted in real life settings rather than in a laboratory.</div>\n<div>\n  </div>\n<div>\n Tuberculosis shares certain symptoms with the ongoing COVID-19 pandemic and patients who have both diseases may experience worse outcomes. Because it might be difficult to accurately differentiate between early Tuberculosis and COVID19, individuals who agree to participate will be also offered COVID 19 tests to help distinguish between the two diseases and offer those with COVID19 appropriate treatment. This will also help us understand how COVID19 is affecting patients living with HIV and TB.</div>\n<div>\n  </div>\n<div>\n The study will be conducted at the Homa Bay County Hospital in Kenya. Individuals living with HIV with and without signs and symptoms of TB will be invited to take part. Individuals who agree to participate will be seen by the health workers in the study and will provide samples for testing using the FujiLAM test and other standard tests used to investigate individuals for suspected tuberculosis. We are also conducting similar studies in other African countries including Uganda, Mozambique and South Africa. This will enable us to assess the performance of the test in diverse settings.</div>\n<div>\n  </div>\n<div>\n Should the study find that the performance of the Fuji-LAM test is good, it will make recommendations on the use of the test. The use of the test may allow faster identification of TB particularly among persons living with HIV. This faster identification will allow earlier treatment and likely to reduce the deaths that are associated with TB among persons living with HIV.</div>\n
      • short_titleFujiLAM Study
      • protocol_noECCT/21/04/01
      • version_nov2.3
      • date_of_protocol23-09-2020
      • study_drugNot applicable
      • disease_conditionTuberculosis
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device1
      • product_type_chemical_name
      • product_type_medical_device_nameFUJI LAM Test Kit
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresswansiste07@gmail.com
      • applicant_covering_letter1
      • applicant_protocol1
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      • applicant_signed_declaration1
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      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
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      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data0
      • applicant_analysis_cert0
      • applicant_pictorial_sample0
      • applicant_gcp_training1
      • applicant_dsmb_charter0
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
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      • applicant_registration_ctr(null)
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      • declaration_applicantDr. Stephen Sitima Wanjala
      • declaration_date129-03-2021
      • declaration_principal_investigatorDr Stephen Sitima Wanjala
      • declaration_date229-03-2021
      • placebo_presentNo
      • study_objectives<p>\n <strong>Objectives</strong></p>\n<p>\n The aim of this study is to investigate the diagnostic performance of FujiLAM in ambulatory HIV290<br />\n positive patients.</p>\n<p>\n <strong>Primary objective</strong><br />\n To assess the sensitivity of FujiLAM among patients with microbiological confirmed TB in two groups of HIV-positive patients: 1) in ambulatory HIV-positive patients with signs and symptoms of TB regardless of their CD4 count (Group 1), and 2) in ambulatory patients with advanced HIV disease (CD4 below 200 cells/μL or WHO stage III/IV) and no signs and symptoms of TB (Group 2).</p>\n<p>\n <strong>Secondary objectives</strong><br />\n â‚‹ To assess the sensitivity of FujiLAM at different levels of CD4 count.<br />\n â‚‹ To assess the sensitivity of AlereLAM in urine and compare the diagnostic sensitivity of FujiLAM with AlereLAM.<br />\n â‚‹ To assess the diagnostic performance in the 24 hours following the first visit, of diagnostic algorithms combining FujiLAM or AlereLAM in urine with Xpert MTB/RIF in sputum.<br />\n â‚‹ To assess the specificity and predictive values of FujiLAM.<br />\n â‚‹ To compare FujiLAM and Xpert in urine results in patients with no sputum sample available.<br />\n â‚‹ To assess the time to FujiLAM, AlereLAM and Xpert MTB/RIF test results.<br />\n â‚‹ To assess the mortality at 6 months according to the FujiLAM result.<br />\n â‚‹ To assess the FujiLAM test inter-reader agreement<br />\n â‚‹ To assess the feasibility of using FujiLAM at point-of-care, and the test acceptability by test users, managers and patients.<br />\n â‚‹ To assess the prevalence of CoViD-19 in HIV-positive ambulatory patients with symptoms of TB, to describe the clinical features, the severity and the outcomes of the patients diagnosed with CoViD-19 and the proportion of patients co-infected with CoViD-19 and TB, to assess the proportion of HIV-positive patients exposed to SARS-CoV-2.</p>\n
      • principal_inclusion_criteria<p>\n Inclusion criteria<br />\n - 15 years of age or older<br />\n - HIV-positive<br />\n <strong>Group 1:</strong> At least one symptom of TB<br />\n <strong>Group 2</strong>: Advanced HIV disease (CD4 count less than 200cell/μl or clinical stage III/IV)<br />\n                AND No signs and symptoms of TB</p>\n<p>\n Signature of the informed consent for both groups</p>\n
      • principal_exclusion_criteria<p>\n Below 15 years</p>\n<p>\n Intake of anti-tuberculosis drugs for more than 5 days in the month prior to the consultation except preventive TB treatment.</p>\n
      • primary_end_points<p>\n Proportion of patients with a positive FujiLAM result among patients with microbiologically confirmed TB in ambulatory HIV-positive patients with signs and symptoms of TB (Group 1) and ambulatory HIV-positive patients with advanced HIV disease and no signs and symptoms of TB (Group 2).</p>\n
      • scope_diagnosis1
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety0
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyDiagnostic Study
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n <tbody>\n <tr>\n <td style=\"width:32px;\">\n <p>\n <strong>No</strong></p>\n </td>\n <td style=\"width:208px;\">\n <p>\n <strong>Name</strong></p>\n </td>\n <td style=\"width:185px;\">\n <p>\n <strong>Qualification</strong></p>\n </td>\n <td style=\"width:164px;\">\n <p>\n <strong>Role/Experience</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 1</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Milcah Akinyi</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n BsN</p>\n <p>\n APGD_CR,MSc HM</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study coordinator</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 2</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Dalmas Ochiel</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Registered clinical Officer</p>\n <p>\n Bsc Public Health</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study clinician</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 3</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Barnabas Ogere</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Registered Clinical Officer</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study clinician</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 4</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Polycarp Oyoo</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Registered Nurse</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study Nurse</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 5</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Eve Dorcas Awino</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Registered Nurse</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study Nurse</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 6</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Irene Akoth</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Laboratory Technologist</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study lab technician</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 7</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Lucy Nyadoya Were</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Diploma IT</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Data Entry Clerk</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 8</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Beryl Akinyi</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Diploma Social Work & Community Development</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Community mobiliser / Tracer</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_explanation<p>\n The primary objective of the study is to evaluate the performence of the FujiLAM test in comparison to known alternatives(Alere LAM, Culture). Kenya and the other countries included in the study deemed appropriate because of the high prevalence of HIV and TB with a significant proportion of patients having advanced HIV. Previous studies have shown that LAM based technology is best suited for advanced HIV patients. In light of this, the countries were chosen because, if successfull, the patients who are most likely to benefit from the diagnostic tool being evaluted will come from high HIV/TB burden countries. </p>\n
      • other_details_regulatory_notapproved<p>\n None</p>\n
      • other_details_regulatory_approved<p>\n Medecines Sans Frontieres IRB , October 2019</p>\n
      • other_details_regulatory_rejected<p>\n Not applicable</p>\n
      • other_details_regulatory_halted
      • estimated_duration24 months
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaHomabay County Teaching and Referral Hospital
      • single_site_physical_addressHomabay Town Kenya
      • single_site_contact_personDr. Stephen Wanjala
      • single_site_telephone0720284862
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states3
      • number_of_sites
      • multi_country_listUganda - Mbarara Teaching and Referral Hospital\nMozambique - Alto Maé Health Centre\nSouth Africa - Eshowe Gateway Clinic, KwaZulu Natal Province
      • data_monitoring_committeeNo
      • total_enrolment_per_site450 patients at Homabay County and Referral Hospital
      • total_participants_worldwide1870
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsNo
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameStephen
      • investigator1_middle_nameSitima
      • investigator1_family_nameWanjala
      • investigator1_qualificationMBChB, MSc Health Economics and Policy, MBA
      • investigator1_professional_addressP. O. Box 21340 - 00100
      • investigator1_telephone0720284862
      • investigator1_emailwansiste07@gmail.com
      • organisations_transferred_No
      • number_participantsA total of 450 patients will be recruited in Homabay Kenya. 200 of these will be HIV-positive patients with signs and symptoms of TB (Group 1) and 250 will be HIV-positive patients with no signs and symptoms of TB and CD4<200 or in stage III/IV (Group 2)
      • notification
      • approval_date04-11-2021
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted12-07-2021
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe application has been approved
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2021-11-04 19:09:19
      • created2021-03-29 15:20:58
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id635
        • application_id993
        • given_nameHelena
        • middle_name
        • family_nameHuerga
        • qualificationMD, MSc, PhD
        • professional_addressEPICENTRE, CLINICAL RESEARCH DEPARTMENT, 14-34 AVENUE JEAN JAURES, 75019, PARIS
        • telephone+32 493 83 78 95
        • emailHelena.HUERGA@epicentre.msf.org
        • created2021-03-29 16:00:08
        • modified2021-07-12 07:44:39
    • SiteDetail(array)
      • 0(array)
        • id879
        • application_id993
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2021-03-29 16:00:08
        • modified2021-07-12 07:44:39
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id490
        • application_id993
        • sponsorMedecins Sans Frontieres /Epicentre
        • sponsor_typeResearch Institution
        • contact_personHelena Huerga
        • addressEPICENTRE, CLINICAL RESEARCH DEPARTMENT, 14-34 AVENUE JEAN JAURES, 75019, PARIS
        • telephone_number+32 493 83 78 95
        • fax_number
        • cell_number+32 493 83 78 95
        • email_addressHelena.HUERGA@epicentre.msf.org
        • created2021-03-29 16:00:08
        • modified2021-07-12 07:44:39
  • 2(array)
    • Application(array)
      • id909
      • user_id404
      • trial_status_id1
      • abstract_of_study<div>\n Clinical Study Phase III</div>\n<div>\n Study Design- Multicentre, randomised, open-label, adaptative master protocol / platform study</div>\n<div>\n Primary Objective</div>\n<div>\n The primary objective is to compare the efficacy of alternative treatment strategies versus control on the risk of progression to severe respiratory disease</div>\n<div>\n Secondary Objectives</div>\n<div>\n The secondary objectives are:</div>\n<div>\n • To compare the safety of each study arm to control, up to Day 21 of follow-up</div>\n<div>\n • To compare the rate of hospitalisations due to COVID-19 in each study arm versus control</div>\n<div>\n • To compare the time to hospitalisation due to COVID-19 in each study arm versus control</div>\n<div>\n • To compare the disease-free rate in each study arm versus control</div>\n<div>\n • To compare the death rate in each study arm versus control</div>\n<div>\n • To compare time to worsening of SpO2 < 93in each study arm versus control</div>\n<div>\n • To compare the capacity to prevent severe progression between study arms</div>\n<div>\n • To identify risk factors for severe progression</div>\n<div>\n • To assess efficacy in sub-groups of patients e.g. with pre-existing conditions/co-morbidities, by age group, sex, BMI, timeframe between onset of symptoms and randomisation</div>\n<div>\n Dose Doses used are within those for the registered indications of the IPs</div>\n<div>\n Route of Administration Oral</div>\n<div>\n Duration of Treatment Up to 14 days depending on the treatment arm</div>\n<div>\n Study Duration Patient participation in the master study will be 22 days.</div>\n<div>\n Indication Mild / Moderate COVID-19</div>\n
      • study_title<div>\n An open-label, multicentre, randomised, adaptive platform trial of the safety and efficacy of several therapies, including antiviral therapies, versus control in mild /moderate cases of COVID-19</div>\n
      • laymans_summary<div>\n This is a multicentre, randomised, open-label, adaptive clinical study on the safety and efficacy of treatments for COVID-19 in patients treated on an out-patient basis. As there is no validated animal model for COVID-19, the efficacy of any potential treatment remains speculative beyond what is known about their pharmacokinetic and in-vitro data.</div>\n<div>\n Several repurposed drugs are currently being tested in severe cases or as prophylaxis, and the results may become available by the time the present study is initiated. At the same time, a number of other drug candidates are being evaluated for in-vitro efficacy or in small proof-ofconcept studies.In view of the rapidly evolving landscape in Africa, it was decided to select an adaptive design for the study in order to allow for the flexibility of adding or dropping arms or adjusting the randomisation ratio based on the data as it becomes available.</div>\n<div>\n Additionally, given that the control arm in the study may not be acceptable in some countries, it was decided to adopt a master platform-based approach to be allow for integration of data from all sites in the interim analyses, irrespective of their ability to have randomised patients in all treatment arms..</div>\n<div>\n In the context of COVID-19, and at the time of protocol development, patients may spontaneously present to hospital for diagnosis in various clinical contexts </div>\n<div>\n • asymptomatic, but perceived as at risk;</div>\n<div>\n • with viral syndrome without uncomplicated pneumonia, i.e. presence of fatigue, irregular fever, chills, muscle pain, sore throat, rhinitis, etc.;</div>\n<div>\n • with uncomplicated pneumonia, i.e. SpO2 > 94%, crackles on auscultation, irregular breathing difficulties but respiratory rate < 30/min;</div>\n<div>\n • moderate to severe pneumonia with SpO2 < 93%, with our without mental confusion, with our without respiratory rate > 30/min, with our without BP < 90/60mm Hg.</div>\n<div>\n All patients will be tested for the presence of SARS-CoV-2 using the available molecular assay. Different strategies will apply among the afore-mentioned four categories of patients who test positive for SARS-CoV-2:</div>\n<div>\n • asymptomatic patients will not be randomised but will be monitored by the medical team for disease progression based on national guidelines;</div>\n<div>\n • patients with viral syndrome, without uncomplicated pneumonia will be randomised in the study;</div>\n<div>\n • patients with uncomplicated pneumonia will be randomised in the study; and</div>\n<div>\n • patients with moderate to severe pneumonia will be hospitalised and potentially referred to other studies such as SOLIDARITY*.</div>\n<div>\n <div>\n Based on predictions, it is assumed that patients, both children and adults with mild / moderate forms of COVID-19 will be sent back home. Patients will be provided with national recommendation for home care or WHO recommendations is national ones are not available.</div>\n <div>\n However, in some countries, all patients, irrespective of severity, maybe be confined in a COVID-19-specific hospital area. This will not, however, be considered to be “hospitalisation for management of COVID-19” in the context of the study.</div>\n</div>\n<p>\n  </p>\n
      • short_titleANTICOV (01 COV)
      • protocol_noECCT/20/06/04
      • version_no4.0
      • date_of_protocol16-06-2020
      • study_drugHydroxychloroquine, Lopinavir/Ritonavir
      • disease_conditionMild/ Moderate infection with SARS-CoV-2
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameHydroxychloroquine, Lopinavir/Ritonavir
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressbnyaoke@dndi.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd0
      • applicant_prev_data0
      • applicant_stability_data0
      • applicant_analysis_cert1
      • applicant_pictorial_sample0
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement0
      • declaration_applicantDr. Borna Nyaoke
      • declaration_date119-06-2020
      • declaration_principal_investigatorDr. Bernhards Ragama Ogutu
      • declaration_date219-06-2020
      • placebo_presentNo
      • study_objectives<div>\n Primary Objective</div>\n<div>\n The primary objective is to compare the efficacy of alternative treatment strategies versus control on the risk of progression to severe respiratory disease</div>\n<div>\n Secondary Objectives</div>\n<div>\n The secondary objectives are:</div>\n<div>\n • To compare the safety of each study arm to control, up to Day 21 of follow-up</div>\n<div>\n • To compare the rate of hospitalisations due to COVID-19 in each study arm versus control</div>\n<div>\n • To compare the time to hospitalisation due to COVID-19 in each study arm versus control</div>\n<div>\n • To compare the disease-free rate in each study arm versus control</div>\n<div>\n • To compare the death rate in each study arm versus control</div>\n<div>\n • To compare time to worsening of SpO2 < 93in each study arm versus control</div>\n<div>\n • To compare the capacity to prevent severe progression between study arms</div>\n<div>\n • To identify risk factors for severe progression</div>\n<div>\n • To assess efficacy in sub-groups of patients e.g. with pre-existing conditions/co-morbidities, by age group, sex, BMI, timeframe between onset of symptoms and randomisation</div>\n
      • principal_inclusion_criteria<div>\n Inclusion Criteria</div>\n<div>\n 1. Male or female patients,</div>\n<div>\n 2. Adults greater or equal to18 years of age at the time of screening. Children > 12 years of age may be included if recommended by the DSMB after the first analysis.</div>\n<div>\n 3. COVID-19 confirmed by molecular biology for SARS-Cov2 according to national guidelines, based on result within 24 hours prior to screening.</div>\n<div>\n 4. Viral syndrome with or without uncomplicated pneumonia, defined as blood oxygen saturation level (SpO2) greater or equal to 94%.</div>\n<div>\n 5. Corrected QT interval (QTc - Fridericia) < 500 msec on ECG</div>\n<div>\n 6. Signed written consent from the patient or his/her representative.</div>\n<div>\n 7. Accepting and having the ability to be reached by telephone throughout the study.</div>\n<div>\n 8. Having designated a contact person who can be contacted in case of emergency.</div>\n
      • principal_exclusion_criteria<div>\n Non-inclusion Criteria</div>\n<div>\n 1. Abnormal physical examination findings:</div>\n<div>\n a) respiratory rate Non-inclusion Criteria</div>\n<div>\n 1. Abnormal physical examination findings:</div>\n<div>\n a) respiratory rate greater or equal to 25 per minute.</div>\n<div>\n b) blood pressure < 90/60 mmHg or > 160/100 mmHg.</div>\n<div>\n c) body weight < 45 kg for patients greater or equal to18 years of age and age adapted for children >12 years of age if inclusion is recommended by the DSMB after the first analysis.</div>\n<div>\n d) recurrent diarrhoea or vomiting episodes (> 3 in the last 24 hours) or hypokalaemia (< 3.5 mmol/L) or hyperkalaemia (> 5 mmol/L).</div>\n<div>\n 2. Known glucose-6-phosphate dehydrogenase (G6PD) deficiency.</div>\n<div>\n 3. Feeling unwell for more than 7 days prior to screening.</div>\n<div>\n 4. Severe cardiopathy or history of arrhythmia, renal or liver insufficiency.</div>\n<div>\n 5. History of congenital or acquired long QT-interval, family history of long QT arrythmia, cardiac disease such as heart failure, myocardial infarction, family history of sudden cardiac death, sudden cardiac death, bradycardia < 50 bpm.</div>\n<div>\n 6. Past history of retinopathy, such as spots or dark strings floating in the field of vision (floaters), blurred or fluctuating vision, impaired colour vision, dark or empty areas in vision.</div>\n<div>\n 7. History of severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis</div>\n<div>\n 8. End-organ compromise requiring admission to a resuscitation or continuous care unit or short-term life-threatening comorbidity with life expectancy < 3 months.</div>\n<div>\n 9. Known pregnancy or breast-feeding, unless recommended by the Data and Safety Monitoring Board after the first interim analysis.</div>\n<div>\n 10. Prior treatment with. lopinavir/ritonavir within 29 days prior to screening except if patients are receiving the same regimen as planned in this study. Patients randomised to lopinavir/ ritonavir will stop their current treatment and switch to the IP lopinavir / ritonavir. If randomised to other arms, patients will continue their current treatment with lopinavir/ritonavir.</div>\n<div>\n 11. Prior treatment with hydroxychloroquine within 29 days prior to screening or on-going at screening.</div>\n<div>\n 12. Use of concomitant medications that are contraindicated with hydroxychloroquine, known hypersensitivity to 4- aminoquinoline compounds (Amodiaquine, Chloroquine, Hydroxychloroquine) or quinine, concomitant treatment carrying risk of torsade de pointes, concomitant use of tamoxifen.</div>\n<div>\n 13. Use of concomitant medications that are contraindicated with lopinavir/ritonavir, known hypersensitivity, drugs with metabolism highly dependent on the isoform CYP3A with narrow therapeutic range, e.g. amiodarone, colchicine, simvastatin.</div>\n<div>\n 14. On-going treatment at screening with:</div>\n<div>\n • chronic systemic glucocorticosteroid > 40 mg daily;</div>\n<div>\n • immunosuppressive treatment;</div>\n<div>\n • azithromycin;</div>\n<div>\n • anti-arrhythmic agent.</div>\n<div>\n 15. For any new antiviral included in the study, prior treatment with the antiviral, presence of contraindication to its use or intake of concomitant medication proscribed with its use.</div>\n<div>\n 16. Unwilling or unable to comply with the requirements of the study protocol at any time during the study, e.g. no access to or not comfortable with use of a smartphone or with answering questions using a telephone, in the opinion of the Investigator.</div>\n<div>\n 17. Any other reason that makes it impossible to monitor the patient during the study.</div>\n
      • primary_end_points<div>\n The primary endpoint is SpO2 ≤ 93% within 21 days after randomisation to treatment, including death for any reason</div>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n To be provided</p>\n
      • other_details_explanation<div>\n At present, it seems that approximately 80% of patients infected with SARS-CoV-2 remain asymptomatic while 20% develop mild to severe symptoms. Once patients progress towards severe pneumonia, i.e. in approximately 10% of cases, sophisticated supportive treatment is required including oxygen, ventilation, vasopressors and antibacterial treatment. Significant healthcare resources are therefore needed to manage and care for these patients. To date, no treatment has shown confirmed efficacy in treating severe cases. It is therefore crucial to avoid, as far as possible, progression to severe disease.</div>\n<div>\n From a public health perspective, the primary objective of disease management is therefore to limit the number of COVID-19-related hospitalisations for oxygen therapy and/or intensive care to a number that is practicable, i.e. to treat patients before they become critically ill and require intensive care especially in low and middle income countries. It is also likely that early treatment in the most at-risk ones will also be the best way to reduce mortality.</div>\n
      • other_details_regulatory_notapproved<p>\n AVAREF- 18th June 2020</p>\n
      • other_details_regulatory_approved<p>\n None</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n Not applicable</p>\n
      • estimated_duration6 months
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindNo
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherYes
      • design_controlled_specifyAdaptive
      • design_controlled_comparatorParacetamol
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherYes
      • design_controlled_medicinal_specifyParacetamol as standard of care
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states15
      • number_of_sites2
      • multi_country_listGhana, Cameroon, Ivory Coast, Kenya, Democratic Republic of Congo, Sudan, Niger, Uganda, Senegal, Equatorial Guinea, Tanzania, Burkina Faso, Guinea, Ethiopia, Mozambique
      • data_monitoring_committeeYes
      • total_enrolment_per_siteApproximately 250-310 participants per site
      • total_participants_worldwide2500-3000
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenUnclear
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameBernhards
      • investigator1_middle_nameRagama
      • investigator1_family_nameOgutu
      • investigator1_qualificationMBChB, MMed, PhD
      • investigator1_professional_addressP. O.Box 2254 Nairobi
      • investigator1_telephone+254-733-812613
      • investigator1_emailogutu6@gmail.com
      • organisations_transferred_Yes
      • number_participantsApproximately 625
      • notification
      • approval_date18-09-2020
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted27-04-2021
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
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      • approved2
      • approved_reasonEdwardabwao
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      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2022-10-19 10:49:34
      • created2020-06-18 21:37:30
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id563
        • application_id909
        • given_nameBernhards
        • middle_nameRagama
        • family_nameOgutu
        • qualificationMBChB, MMed, PhD
        • professional_addressP. O.Box 2254 Nairobi
        • telephone+254-733-812613
        • emailogutu6@gmail.com
        • created2020-06-19 15:29:38
        • modified2021-04-27 14:24:16
    • SiteDetail(array)
      • 0(array)
        • id785
        • application_id909
        • county_id47
        • site_nameMbagathi Infectious Disease Hospital
        • physical_addressMbagathi Road Woodley /Kenyatta, Nairobi, Kenya
        • contact_details+254733729963
        • contact_personDr. Marybeth Maritim
        • site_capacity(null)
        • misc(null)
        • created2020-06-19 15:29:38
        • modified2021-04-27 14:24:16
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 1(array)
        • id786
        • application_id909
        • county_id47
        • site_nameKenyatta University Teaching, Referral and Research Hospital
        • physical_addressNorthern Bypass Rd., Kahawa West, Nairobi
        • contact_details+254721492634
        • contact_personDr. Victor Njom Miganda
        • site_capacity(null)
        • misc(null)
        • created2020-06-19 16:13:13
        • modified2021-04-27 14:24:16
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
    • Sponsor(array)
      • 0(array)
        • id438
        • application_id909
        • sponsorDrugs for Neglected Diseases initiative (DNDi)
        • sponsor_typeOthers
        • contact_personDr. Borna Nyaoke
        • addressTetezi Towers, 3rd Floor, George Padmore Road, Kilimani |P.O Box 21936 - 00505 | Nairobi | Kenya
        • telephone_number+254 20 3995031
        • fax_number
        • cell_number+254720734479
        • email_addressbnyaoke@dndi.org
        • created2020-06-19 15:29:38
        • modified2021-04-27 14:24:16
  • 3(array)
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      • abstract_of_study<p>\n <strong>TITLE: AN OPEN-LABEL, MULTICENTER STUDY TO ASSESS DISEASE ACTIVITY AND BIOMARKERS OF NEURONAL DAMAGE IN MINORITY PATIENTS WITH RELAPSING MULTIPLE SCLEROSIS RECEIVING TREATMENT WITH OCRELIZUMAB</strong></p>\n<p>\n <strong>PROTOCOL NUMBER: </strong>ML42071</p>\n<p>\n <strong>VERSION NUMBER: </strong>2</p>\n<p>\n <strong>EUDRACT NUMBER: </strong>2015-004616-37</p>\n<p>\n <strong>IND NUMBER: </strong>100,593</p>\n<p>\n <strong>NCT NUMBER: </strong><em>NCT04377555</em></p>\n<p>\n <strong>TEST PRODUCT: </strong>Ocrelizumab (RO4964913) (OCREVUS®)</p>\n<p>\n <strong>PHASE: </strong>IV</p>\n<p>\n <strong>INDICATION: </strong>Multiple Sclerosis</p>\n<p>\n <strong>SPONSOR: </strong>Genentech, Inc.</p>\n<p>\n <strong>Objectives and Endpoints</strong></p>\n<p>\n <strong>Primary Objective</strong></p>\n<ul>\n <li>\n The primary objective of this study is to assess disease activity during treatment with ocrelizumab over 48 weeks in <em>minorities represented by Black or African Americans with RMS </em>(AAwMS<em>) </em>and <em>Hispanic/Latinos with RMS (</em>HAwMS).</li>\n</ul>\n<p>\n  </p>\n<p>\n <strong>Secondary Objectives</strong></p>\n<ul>\n <li>\n The secondary objectives of this study are to evaluate other clinical measures of effectiveness, and biomarkers of disease activity and neuronal damage in serum, before and during treatment with ocrelizumab.</li>\n</ul>\n<p>\n <strong>Exploratory Objectives</strong></p>\n<ul>\n <li>\n The exploratory objectives of this study are to evaluate additional immune, ancestral, genomic, and other exploratory markers of disease and their correlations with disease severity and progression, including patient reported outcomes (PROs), before and during treatment with ocrelizumab.</li>\n</ul>\n<p>\n <strong>Safety Objectives</strong></p>\n<p>\n The safety objectives of this study are the following:</p>\n<ul>\n <li>\n Nature, frequency, severity, and timing of adverse events</li>\n <li>\n Adverse events related to biomarker sample collection (sub-study only)</li>\n <li>\n Vital signs, physical findings, and clinical laboratory results during and following ocrelizumab administration</li>\n</ul>\n<p>\n <strong>Study Design</strong></p>\n<p>\n <strong>Description of Study</strong></p>\n<p>\n This is an open-label, multicenter, Phase IV study that will be conducted at centers in the US including Puerto Rico <em>and Ex US sites (i.e., Kenya)</em>. Self-identified <em>Blacks or </em>AA and HA patients, aged 18−65 years of age, with a diagnosis of relapsing multiple sclerosis (RMS) in accordance with the 2017 revised McDonald criteria and an EDSS score of 0−5.5 points, at screening may be enrolled. Their treating neurologist must make an independent medical assessment and decision to initiate ocrelizumab treatment per label (USPI) as the most appropriate standard of care treatment for the patient.</p>\n<p>\n Patients will be evaluated at baseline, monitored, and followed for a 1-year period. Patients</p>\n<p>\n may continue in the study for a second year of treatment and follow-up (second year extension).</p>\n<p>\n Patients could be treatment naïve, or may be switching following treatment with up to two disease modifying therapies (DMT) (either interferon, glatiramer acetate, fingolimod, dimethyl fumarate (DMF), diroximel fumarate, teriflunomide, ozinamod, siponimod, and natalizumab).</p>\n<p>\n For patients switching over from fingolimod, DMF, diroximel fumarate, ozinamod, or siponimod, a minimum treatment-free period of 1 month is required before the baseline screening may be carried out. For patients switching from teriflunomide, an accelerated elimination procedure (per the product label) should be performed. Switch from natalizumab will require at least 4 months from last dose and a treatment duration of less than 1 year.</p>\n<p>\n Consistent with the USPI, ocrelizumab will be administered at a dose of 600 mg every</p>\n<p>\n 24 weeks. The first dose of ocrelizumab will be administered as two 300 mg IV infusions given</p>\n<p>\n 14 days apart. For the subsequent dose, ocrelizumab will be administered as a single 600 mg</p>\n<p>\n IV infusion after 24 weeks. A minimum interval of 22 weeks must be maintained between each</p>\n<p>\n 600 mg dose of ocrelizumab.</p>\n<p>\n An alternative shorter infusion of subsequent 600 mg ocrelizumab doses in patients who did not</p>\n<p>\n experience a serious infusion-related reaction (IRR) with any previous ocrelizumab infusion is described</p>\n<p>\n in Section 4.3.2.1.</p>\n<p>\n Treatment may be stopped at any time due to lack of clinical benefit, unacceptable toxicity, withdrawal of consent, patient or physician decision to discontinue treatment, death, or if the sponsor decides to close the trial, whichever occurs first.</p>\n<p>\n Assessments will include clinical, PROs, MRI, and peripheral blood draws, as detailed in the</p>\n<p>\n SOA. MRIs will be conducted at baseline, at Week 24, and at Week 48. MRIs will be read by a central reader. In case of MS relapse or worsening, the patient should have an unscheduled visit and a full assessment, as detailed in the SOA.</p>\n<p>\n All patients may continue for a second year extension. During the optional second year extension, patients will receive: 2 additional doses of ocrelizumab (at Weeks 48 and 72); clinical, PRO, and peripheral blood evaluations at Weeks 72 and 96; and one MRI at Week 96.</p>\n<p>\n All patients will be evaluated for safety throughout the study. In the case of early termination, the patient will be asked to return for an early termination visit.</p>\n<p>\n Patients who do not meet the criteria for participation in this study (screen failure) may qualify for two additional re-screening opportunities (for a total of three screenings per participant) at the investigator's discretion.</p>\n<p>\n <strong>Number of Patients</strong></p>\n<p>\n Approximately 150 patients will be enrolled including 75 self-identified AAwMS and 75 selfidentified HAwMS.</p>\n<p>\n  </p>\n<p>\n <strong>Target Population</strong></p>\n<p>\n Inclusion Criteria</p>\n<p>\n Patients must meet the following criteria for study entry:</p>\n<ul>\n <li>\n Ability to provide written informed consent and be compliant with the study protocol</li>\n <li>\n The treating neurologist’s independent medical assessment and decision to initiate the patient on ocrelizumab treatment as most appropriate standard of care for the patient</li>\n <li>\n Age 18-65 years inclusive at the time of signing Informed Consent Form</li>\n <li>\n Diagnosis of RMS in accordance with the revised 2017 McDonald Criteria (Thompson et al 2018) EDSS 0-5.5 inclusive at enrollment.</li>\n <li>\n Patients who self-identify as Black or African American or Hispanic/Latino American.</li>\n <li>\n Treatment-naïve patients, or initiating first or second switch from receiving treatment with any of the following classes of disease-modifying therapies (including FDA approved generic versions):</li>\n</ul>\n<p style=\"margin-left:.25in;\">\n <em>Class 1</em></p>\n<ul style=\"list-style-type:circle;\">\n <li>\n Interferons: (IFN)-β-1a (Avonex, Rebif), IFN-β-1b(Betaseron/Betaferon), Peg-Interferon Beta-1a (Plegridy) or</li>\n <li>\n Glatiramer acetate (Copaxone), including generic glatiramer acetate</li>\n</ul>\n<p style=\"margin-left:.25in;\">\n <em>Class 2</em></p>\n<ul style=\"list-style-type:circle;\">\n <li>\n Fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia)</li>\n <li>\n Dimethyl fumarate (Tecfidera), diroximel fumarate (Vumerity)</li>\n <li>\n Teriflunomide (Aubagio)</li>\n</ul>\n<p style=\"margin-left:.25in;\">\n <em>Class 3</em></p>\n<ul style=\"list-style-type:circle;\">\n <li>\n Natalizumab (Tysabri)</li>\n</ul>\n<p>\n For patients switching over from any of the Class 2 agents, at least 1-month of treatment free period between the last dose of the DMT and the initiation of screening Additionally, for patients switching from teriflunomide (Aubagio), an accelerated elimination procedure is required during the treatment free period (as per teriflunomide USPI, see below).</p>\n<p>\n â–ª After discontinuation of teriflunomide, elimination can be accelerated by either one of the following procedures:</p>\n<p>\n Administration of cholestyramine 8 g every 8 hours for 11 days. If</p>\n<p>\n cholestyramine 8 g three times a day is not well tolerated,</p>\n<p>\n cholestyramine 4 g three times a day can be used</p>\n<p>\n Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.</p>\n<p>\n If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly</p>\n<p>\n Note: Use of the accelerated elimination procedure may potentially</p>\n<p>\n result in return of disease activity if the patient had been</p>\n<p>\n responding to teriflunomide treatment</p>\n<p>\n ï‚· For patients switching over from Natalizumab, at least 4 months from last infusion and less than</p>\n<p>\n <em>1 year of total treatment duration</em></p>\n<p>\n · Disease duration from the onset of MS symptoms: any duration of the disease except for</p>\n<p>\n those patients with EDSS >5 where disease duration should be <15 years.</p>\n<p>\n · At least one documented clinical attack (for naïve patients) or suboptimal response, or poor</p>\n<p>\n adherence, or intolerance to prior DMT (for switch patients) in the past year, 2 documented clinical relapses within the last 2 years or 1 documented clinical relapse within 12 months of screening (but not within 30 days prior to screening) and/or at least one T1 Gd-enhancing lesion in the past year and/or at least one new or expanding T2 lesion in the past year at the time of enrollment. For active SPMS, documented evidence of disability progression independent of clinical relapse over the past 12 months from screening and at least one documented clinical relapse within the previous 2 years before screening or at least 1 T1 Gd enhancing lesion on MRI at screening if no clinical relapses within the previous 2 years.</p>\n<p>\n · For women of childbearing potential: agreement to remain abstinent (refrain from</p>\n<p>\n heterosexual intercourse) or use acceptable contraceptive methods during the treatment</p>\n<p>\n period and for 6 months after the final dose of ocrelizumab.</p>\n<p>\n A woman is considered to be of childbearing potential if she is postmenarchal, has not</p>\n<p>\n reached a postmenopausal state (12 continuous months of amenorrhea with no</p>\n<p>\n identified cause other than menopause), and has not undergone surgical sterilization</p>\n<p>\n (removal of ovaries and/or uterus). The definition of childbearing potential may be</p>\n<p>\n adapted for alignment with local guidelines or requirements.</p>\n<p>\n <strong>– </strong>The following are acceptable contraceptive methods (as defined by the guidelines):</p>\n<p>\n progesterone-only hormonal contraception, where inhibition of ovulation is not the</p>\n<p>\n primary mode of action; male or female condom with or without spermicide; and cap,</p>\n<p>\n diaphragm, or sponge with spermicide. More effective contraceptive methods</p>\n<p>\n (e.g., bilateral tubal ligation; male sterilization; copper intrauterine devices) may be</p>\n<p>\n used, but are not required.</p>\n<p>\n · <em>Neurologically stable for at least 30 days prior to randomization and baseline assessments</em></p>\n<p>\n Exclusion Criteria</p>\n<p>\n Patients who meet any of the following criteria will be excluded from study entry:</p>\n<p>\n · MS Related</p>\n<p>\n <strong>– </strong>Diagnosis of secondary progressive MS without relapses for at least 1 year (<em>nonactive or inactive SPMS)</em></p>\n<p>\n <strong>– </strong>PPMS</p>\n<p>\n · Patients with contraindication to gadolinium based contrast agent for MRI <em>and patients who cannot tolerate MRI procedure</em></p>\n<p>\n · Infection Related</p>\n<p>\n <strong>– </strong>Known presence of recurrent or chronic infection (e.g., HIV, syphilis, tuberculosis,</p>\n<p>\n <em>HPV</em>)</p>\n<p>\n <strong>– </strong>History of recurrent aspiration pneumonia requiring antibiotic therapy</p>\n<p>\n <strong>– </strong>History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, herpes zoster myelopathy)</p>\n<p>\n <strong>– </strong>Known active bacterial, viral, fungal, mycobacterial infection, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with</p>\n<p>\n IV antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to baseline visit</p>\n<p>\n · Cancer Related</p>\n<p>\n <strong>– </strong>History of cancer, including solid tumors and hematological malignancies (except basal cell, in situ squamous cell carcinomas of the skin, and in situ carcinoma of the cervix or the uterus that have been excised and resolved with documented clean margins on pathology)</p>\n<p>\n · Pregnant or lactating, or intending to become pregnant during the study</p>\n<p>\n <strong>– </strong>Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study drug.</p>\n<p>\n · Other Medical Conditions</p>\n<p>\n <strong>– </strong>History of or currently active primary or secondary immunodeficiency</p>\n<p>\n <strong>– </strong>History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies</p>\n<p>\n <strong>– </strong>History of alcohol or other drug abuse within 24 weeks prior to enrollment</p>\n<p>\n <strong>– </strong>History or known presence of systemic autoimmune disorders, potentially causing progressive neurologic disease (e.g., <em>rheumatoid arthritis</em>, lupus, anti-phospholipid antibody syndrome, Sjögren’s syndrome, Behçet’s disease)</p>\n<p>\n <strong>– </strong>Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study</p>\n<p>\n <strong>– </strong>Significant, uncontrolled disease, as defined by AMA guidelines or similar, such as cardiovascular (including congestive heart failure – NYHA grade 3 or 4, cardiac arrhythmia), uncontrolled hypertension, pulmonary (including chronic obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), gastrointestinal, or any other significant disease</p>\n<p>\n · Known presence or history of other neurologic disorders, including but not limited to, the</p>\n<p>\n following:</p>\n<p>\n <strong>– </strong>Progressive multifocal leukoencephalopathy, CNS or spinal cord tumor, potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency)</p>\n<p>\n <strong>– </strong>History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraparesis; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes</p>\n<p>\n [MELAS])</p>\n<p>\n <strong>– </strong>Neuromyelitis optica spectrum disorders (NMOSD)</p>\n<p>\n <strong>– </strong>Ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or ischemia</p>\n<p>\n of the spinal cord</p>\n<p>\n <strong>– </strong>Severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal</p>\n<p>\n cord compression)</p>\n<p>\n <strong>– </strong>Psychosis not yet controlled by a treatment</p>\n<p>\n · Drug Related</p>\n<p>\n <strong>– </strong>Systemic corticosteroid therapy within 4 weeks prior to baseline</p>\n<p>\n <strong>– </strong>Contraindications for, or intolerance to, oral or IV corticosteroids, including IV</p>\n<p>\n methylprednisolone, according to the country label, including hypersensitivity to any of</p>\n<p>\n the treatment drug constituents</p>\n<p>\n <strong>– </strong>Previous treatment with any other immunomodulatory or immunosuppressive medication not</p>\n<p>\n already listed above without appropriate washout as described in the applicable local label</p>\n<p>\n <strong>– </strong>If the washout requirements are not described in the applicable local label, then the washout</p>\n<p>\n period must be 5 times the half-life of the medication. The pharmacodynamic effects of the</p>\n<p>\n previous medication must also be considered when determining the required time for washout.</p>\n<p>\n · Prior DMT for MS</p>\n<p>\n <strong>– </strong>Previous treatment with natalizumab for more than 1-year and within 4 months of baseline</p>\n<p>\n visit.</p>\n<p>\n <strong>– </strong>Previous treatment with alemtuzumab or cladribine</p>\n<p>\n <strong>– </strong>Previous treatment with any anti-CD20 therapy</p>\n<p>\n <strong>– </strong>Previous treatment with cyclophosphamide, mitoxantrone, azathioprine, mycophenolate</p>\n<p>\n mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow</p>\n<p>\n transplantation</p>\n<p>\n <strong>– </strong>Previous or concurrent treatment with any investigational agent or treatment with any</p>\n<p>\n experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous</p>\n<p>\n insufficiency)</p>\n<p>\n · Vaccinations:</p>\n<p>\n <strong>– </strong>Receipt of a live vaccine, or attenuated, or inactivated / component vaccine within</p>\n<p>\n 6 weeks prior to first administration of ocrelizumab</p>\n<p>\n · Laboratory: Certain laboratory abnormalities or findings at screening, including the</p>\n<p>\n following:</p>\n<p>\n <strong>– </strong>Positive serum β-hCG</p>\n<p>\n <strong>– </strong>Positive for hepatitis B (hepatitis B surface antigen [HBsAg] positive or hepatitis B core</p>\n<p>\n antibody [total HBcAb] confirmed by positive viral DNA polymerase chain reaction</p>\n<p>\n [PCR])</p>\n<p>\n <strong>– </strong>Positive screening test for hepatitis C (positive hepatitis C antibodies)</p>\n<p>\n <strong>– </strong>AST or ALT ³2.0 ´upper limit of normal</p>\n<p>\n <strong>– </strong>Platelet count below lower limit of normal (LLN)</p>\n<p>\n <strong>– </strong>Absolute neutrophil count below LLN</p>\n<p>\n <strong>– </strong>Lymphocyte count below LLN</p>\n<p>\n <strong>– </strong>Serum IgG and/or IgM levels below LLN</p>\n<p>\n <strong>– </strong>Absolute CD4+ and CD8+ T Cell counts below LLN</p>\n<p>\n · Any previous use of IV immunoglobulins or plasmapheresis 3 months prior to baseline visit.</p>\n<p>\n  </p>\n<p>\n <strong>End of Study</strong></p>\n<p>\n The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis whichever occurs later. The end of the study is expected to occur 12 months after the last patient is enrolled for the main study.</p>\n<p>\n Note: Patients may opt into one additional year of treatment and evaluation as part of the second year extension.</p>\n<p>\n In addition, the Sponsor may decide to terminate the study at any time.</p>\n<p>\n  </p>\n<p>\n <strong>Length of Study</strong></p>\n<p>\n The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 5 years.</p>\n<p>\n  </p>\n<p>\n <strong>Investigational Medicinal Products</strong></p>\n<p>\n <strong>Test Product (Investigational Drug)</strong></p>\n<p>\n The investigational medicinal product (IMP) for this study is ocrelizumab.</p>\n<p>\n The ocrelizumab dose administered will be 600 mg every 24 weeks. The first dose of</p>\n<p>\n ocrelizumab will be administered as two 300 mg IV infusions given 14 days apart (Weeks 0 and</p>\n<p>\n 2). For the subsequent doses, ocrelizumab will be administered as a single 600-mg IV infusion every 24 weeks (Weeks 24, 48, and 72). A minimum interval of 22 weeks must be maintained</p>\n<p>\n between each dose of ocrelizumab. This dosing regimen is consistent with the dosing regimen</p>\n<p>\n used in the ocrelizumab USPI.</p>\n<p>\n  </p>\n<p>\n <strong>Non-Investigational Medicinal Products</strong></p>\n<p>\n In this study, non-investigational medicinal products will include premedication to the</p>\n<p>\n ocrelizumab infusion. The following premedication will be used:</p>\n<p>\n · Mandatory methylprednisolone (or an equivalent)</p>\n<p>\n · Mandatory antihistaminic drug (e.g., diphenhydramine)</p>\n<p>\n · Recommended oral analgesic/antipyretic (e.g., acetaminophen 1 g)</p>\n<p>\n  </p>\n<p>\n <strong>Statistical Methods</strong></p>\n<p>\n <strong>Primary Analysis</strong></p>\n<p>\n In this study, the analyses will be mostly descriptive and hypothesis-generating. Unless otherwise specified, statistical tests will be two sided and the statistical significance level will be</p>\n<p>\n 5%. Corresponding 95% confidence intervals will be presented as appropriate. No corrections</p>\n<p>\n for multiple testing will be applied to the primary, secondary, exploratory endpoint analyses.</p>\n<p>\n The statistical summaries will be descriptive if not otherwise specified. For continuous variables, the mean, median, standard deviation, 25th and 75th percentiles, minimum and maximum will be provided. For categorical variables, number and percentage in each category will be displayed. Full details of all statistical issues and planned statistical analyses will be specified in a separate Statistical Analysis Plan (SAP), which will be finalized prior to the locking of the study database.</p>\n<p>\n The spearman’s rank-correlation coefficient will be used to evaluate the relationship among the levels of biomarkers or between levels of biomarkers and clinical outcomes.</p>\n<p>\n <strong>Determination of Sample Size</strong></p>\n<p>\n Based on CHORDS study, MN30035, it is estimated that the proportion of AAwMS patients who will be free of protocol defined events during 48 weeks is 38%. Assuming the same expected proportion for HAwMS patients, this study is planned to enroll total 150 patients (75 in each patient cohort). This sample size can provide 95% confidence intervals of proportion of patient who will be free of protocol defined events in each patient cohort to be (27.0%, 49.9%) using the exact Clopper-Pearson method.</p>\n<p>\n <strong>Interim Analyses</strong></p>\n<p>\n Approximately three interim analyses may be performed during the course of the study,</p>\n<p>\n according to patient enrollment and availability of data of interest. Interim analyses may be</p>\n<p>\n used for internal decision making, hypothesis generation, abstract/publication for major MS</p>\n<p>\n conferences, or other purposes, as applicable. Details on the timing and scope of interim analyses will be described in the SAP.</p>\n<p>\n For the CSF sub-study, interim analyses may be performed when:</p>\n<p>\n · After approximately 50% patients in both the AAwMS and HAwMS cohort have undergone baseline CSF assessments</p>\n<p>\n · After approximately 100% patients in both the AAwMS and HAwMS cohort have undergone baseline CSF assessments</p>\n<p>\n · After approximately 50% of patients in each cohort (AAwMS and HAwMS) complete Week 48</p>\n<p>\n  </p>\n
      • study_title<div>\n AN OPEN-LABEL, MULTICENTER STUDY TO ASSESS DISEASE ACTIVITY AND BIOMARKERS OF NEURONAL DAMAGE IN MINORITY PATIENTS WITH RELAPSING MULTIPLE SCLEROSIS RECEIVING TREATMENT WITH OCRELIZUMAB</div>\n
      • laymans_summary<ul>\n <li>\n This research study is testing a drug called ocrelizumab in patients that have relapsing multiple sclerosis (RMS). </li>\n <li>\n Ocrelizumab is a type of drug called a monoclonal antibody.  Ocrelizumab has been shown to slow disability progression in multiple sclerosis (MS).  Monoclonal antibodies act like the body’s immune system and attach to certain cells that attack germs and other illnesses in the body.  Ocrelizumab attaches to certain types of white blood cells (B cells) that are thought to play a role in MS.</li>\n <li>\n The purpose of this study is to investigate the impact of ocrelizumab on RMS in Blacks or African Americans with multiple sclerosis (AAwMS) and Hispanic/Latino Americans with multiple sclerosis (HAwMS).  This study will also investigate the impact of ocrelizumab on certain biomarkers of RMS in Blacks or African American (AA) and Hispanic/Latino American (HA) minority patients with RMS.  A biomarker is a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease.</li>\n <li>\n Ocrelizumab is already approved for the treatment of MS in several countries including, the United States of America, Australia, Canada, the European Union, and others.  It was approved by the FDA March 28, 2017.  The purpose of this study is to specifically study the efficacy and safety of the ocrelizumab in Blacks or AA and HA patients with RMS, and to gain in-depth understanding of the underlying disease process.</li>\n <li>\n The purpose of this study is to find out what effects, good or bad, ocrelizumab has on RMS.  This study will also look at the way ocrelizumab may change certain biomarkers related to RMS in the body.</li>\n <li>\n A CSF sub-study will be optional and conducted at selected sites. 50 patients (~25 Blacks/AAwMS and ~25 HAwMS) will be optionally enrolled in the CSF sub-study. There will be a separate consent form for the CSF sub-study</li>\n <li>\n About 150 people aged 18-65 years with a diagnosis of RMS will take part in this study, including 75 self-identified Blacks or AAwMS and 75 self-identified HAwMS.</li>\n <li>\n This non-randomized open label study</li>\n <li>\n The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 5 years.</li>\n</ul>\n<p>\n  </p>\n
      • short_titleCHIMES
      • protocol_noECCT/21/03/07
      • version_no2
      • date_of_protocol16-12-2020
      • study_drugOcrelizumab
      • disease_conditionMultiple Sclerosis
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals1
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_nameOcrevus
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresshuwaida.bulhan@roche.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantGilbert Ogetii
      • declaration_date130-03-2021
      • declaration_principal_investigatorProf Mansoor Saleh
      • declaration_date230-03-2021
      • placebo_presentNo
      • study_objectives<p>\n <u>Primary Objective</u></p>\n<p>\n The primary objective of this study is to assess disease activity during treatment with ocrelizumab over 48 weeks in minorities represented by Black or African Americans with RMS (AAwMS) and Hispanic/Latinos with RMS (HAwMS).</p>\n<p>\n <u>Secondary Objectives</u></p>\n<p>\n The secondary objectives of this study are to evaluate other clinical measures of effectiveness, and biomarkers of disease activity and neuronal damage in serum, before and during treatment with ocrelizumab</p>\n<p>\n <u>Exploratory Objectives</u></p>\n<p>\n The exploratory objectives of this study are to evaluate additional immune, ancestral, genomic, and other exploratory markers of disease and their correlations with disease severity and progression, including patient reported outcomes (PROs), before and during treatment with ocrelizumab.</p>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p 1ex=\"\" color:=\"\" font-size:=\"\" helvetica=\"\" line-height:=\"\" margin:=\"\" sans=\"\" source=\"\" style=\"box-sizing: border-box; font-family: \">\n Inclusion Criteria:</p>\n<ul font-size:=\"\" helvetica=\"\" margin-bottom:=\"\" sans=\"\" source=\"\" style=\"box-sizing: border-box; margin-top: 1ex; margin-left: 0px; padding-left: 24px; color: rgb(0, 0, 0); font-family: \">\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Diagnosis of RMS with Expanded Disability Status Scale (EDSS) 0-5.5 at enrollment</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Participants who self-identify as Black or African American or Hispanic/Latino American</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Treatment-naïve or initiating first or second switch from receiving treatment with certain disease modifying therapies (DMTs) including interferon or glatiramer acetate or dimethyl fumarate (DMF); or siponimod; or fingolimod; or diroximel fumarate; or teriflunomide; or ozanimod; or natalizumab</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use acceptable contraceptive methods during the treatment period and for 6 months after the final dose of ocrelizumab</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Neurologically stable for at least 30 days prior to randomization and baseline assessments</li>\n</ul>\n
      • principal_exclusion_criteria<p 0ex=\"\" 0px=\"\" color:=\"\" font-size:=\"\" helvetica=\"\" line-height:=\"\" margin:=\"\" sans=\"\" source=\"\" style=\"box-sizing: border-box; font-family: \">\n Exclusion Criteria:</p>\n<ul font-size:=\"\" helvetica=\"\" margin-bottom:=\"\" sans=\"\" source=\"\" style=\"box-sizing: border-box; margin-top: 1ex; margin-left: 0px; padding-left: 24px; color: rgb(0, 0, 0); font-family: \">\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Diagnosis of secondary progressive MS without relapses for at least 1 year (nonactive or inactive SPMS)</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Primary Progressive Multiple Sclerosis (PPMS)</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Participants with contraindication to gadolinium based contrast agent for MRI and participants who cannot tolerate MRI procedure</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Infection Related</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Cancer Related</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Pregnant or lactating, or intending to become pregnant during the study</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Other Medical Conditions</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Known presence or history of other neurologic disorders</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Vaccinations: Receipt of a live vaccine, or attenuated, or inactivated / component vaccine within 6 weeks prior to first administration of ocrelizumab</li>\n <li style=\"box-sizing: border-box; line-height: 1.6; margin-bottom: 4px; margin-top: 0.7ex;\">\n Laboratory: abnormalities or findings at screening</li>\n</ul>\n
      • primary_end_points<p>\n <strong>Primary Efficacy Endpoint: </strong>The primary efficacy endpoint will be the proportion of patients who are free of any protocol-defined events during a 48-week study.</p>\n<p>\n  </p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety0
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others1
      • scope_others_specifyBiomarkers
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use1
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<p>\n  </p>\n<p>\n The site is fully staffed with specifically research-trained as well as clinical care staff. </p>\n<p>\n The site is able to cater to both emergency, critical care as well as intensive care in terms of facilities and trained staff. The site had a feasibility visit performed by the Sponsor in January 2020 and was qualified as a site that could successfully undertake an interventional clinical trial in Kenya. The site successfully completed an Industry sponsored COVID-19 clinical trial and was inspected by the Pharmacy and Poisons Board in Dec2020 – no major or critical finding.</p>\n<p>\n The PI will have two sub-Investigators assisting her. In addition, there are the following research-trained staff members on hand: </p>\n<ol>\n <li>\n Principle Investigator - Prof. Mansoor Saleh, MD – Professor of Medicine & Pathology Unit</li>\n <li>\n Co-Invetigatigator – Dr Dilraj Sokhi, MD - Neurologist</li>\n <li>\n Co-investigator – Dr Juzar Hooker, MD - Neurologist   </li>\n <li>\n Study Coordinator - Joyce Marete, RN & Aisleen Shamshudin (pharmacist)</li>\n <li>\n Regulatory Coordinator - Stacey Gondi </li>\n <li>\n Research Pharmacist & Drug Shipment - Aisleen Shamshudin (registered pharmacist)</li>\n <li>\n Pharmacy Technician & Drug Shipment - Nancy Owiti </li>\n <li>\n Data Manager - Grace Kirathe </li>\n <li>\n Research Program Manager - Noureen Karimi </li>\n <li>\n Research Patient Navigator - Innocent Abayo </li>\n <li>\n Contracts Coordinator - Innocent Abayo </li>\n <li>\n Payments and Budget - Noureen Karimi </li>\n</ol>\n<p>\n  </p>\n
      • other_details_explanation<p>\n Not Applicable</p>\n
      • other_details_regulatory_notapproved<p>\n None</p>\n<p>\n  </p>\n
      • other_details_regulatory_approved<p>\n US Food and Drug Administration - Approval date 21-Mar-2020</p>\n
      • other_details_regulatory_rejected<p>\n Not Applicable - None</p>\n
      • other_details_regulatory_halted<p>\n Not Applicable</p>\n
      • estimated_duration2 years
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaAga Khan University, Nairobi
      • single_site_physical_address3rd Parklands Avenue, Nairobi-Kenya
      • single_site_contact_personProf Mansoor Saleh
      • single_site_telephone+254 709 93 1500
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states2
      • number_of_sites
      • multi_country_listUnited States of America (USA) and Kenya
      • data_monitoring_committeeNo
      • total_enrolment_per_site10
      • total_participants_worldwide150
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsNo
      • subjects_vulnerable_populationsNo
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameNot Applicable
      • investigator1_middle_name
      • investigator1_family_nameNot Applicable
      • investigator1_qualificationNot Applicable
      • investigator1_professional_addressNot Applicable
      • investigator1_telephoneNot Applicable
      • investigator1_emailmansoor.saleh@aku.edu
      • organisations_transferred_Yes
      • number_participants10
      • notification<p>\n This a first of a kind clinical trial in Africa (and Kenya in particular) as blacks and ethnic minorities are underreprented in multiple sclerosis clincial trials (<span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\"><span style=\"font-variant-numeric: normal; font-variant-east-asian: normal;\">Together </span><span style=\"font-variant-numeric: normal; font-variant-east-asian: normal;\">minorities </span><span style=\"font-variant-numeric: normal; font-variant-east-asian: normal;\">represent approximately one-third of </span><span style=\"font-variant-numeric: normal; font-variant-east-asian: normal;\">the multiple sclerosis (MS) </span><span style=\"font-variant-numeric: normal; font-variant-east-asian: normal;\">population </span><span style=\"font-variant-numeric: normal; font-variant-east-asian: normal;\">but </span><span style=\"font-variant-numeric: normal; font-variant-east-asian: normal;\">their representation in major clinical trials for MS in less than 5%</span><span style=\"font-variant-numeric: normal; font-variant-east-asian: normal;\">-</span><span style=\"font-variant-numeric: normal; font-variant-east-asian: normal;\">10% of all patients</span>). Therefore, this trial will not only give an opportunity for Kenya MS patients to participate in a therapeutic clinical trial but also open the window for the conduct of other therapeutic clinical trials in neuroscience, in Kenya.</span></span></p>\n<p>\n  </p>\n
      • approval_date08-06-2021
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted30-03-2021
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe application has been approved by the experts
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2024-10-31 13:47:38
      • created2021-02-26 14:32:15
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id627
        • application_id980
        • given_nameMansoor
        • middle_name
        • family_nameSaleh
        • qualificationMD, Professor of Medicine & Pathology
        • professional_addressAga Khan University, AKU Cancer Center 3rd Parklands Avenue, Nairobi-Kenya
        • telephone+254 709 93 1500
        • emailmansoor.saleh@aku.edu
        • created2021-03-02 16:38:33
        • modified2021-03-30 19:48:06
    • SiteDetail(array)
      • 0(array)
        • id860
        • application_id980
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2021-03-02 16:38:33
        • modified2021-03-30 19:48:06
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id483
        • application_id980
        • sponsorGenentech, Inc/Roche Kanya Ltd
        • sponsor_typeIndustry
        • contact_personGilbert Ogetii
        • addressRoche Kenya Limited The Atrium, 6th Floor Chaka Road, off Lenana Road P.O. Box 44212-00100 Nairobi, Kenya
        • telephone_number +254 780 441 913
        • fax_number
        • cell_number +254 780 441 913
        • email_addressGilbert.Ogetii@roche.com
        • created2021-03-02 16:38:33
        • modified2021-03-30 19:48:06
  • 4(array)
    • Application(array)
      • id1113
      • user_id693
      • trial_status_id1
      • abstract_of_study<div>\n <strong>Introduction</strong></div>\n<div>\n  </div>\n<div>\n Sickle cell disease is one of the most commonly inherited blood disorders in the world characterized by vaso-occlusive crises, anemia, stroke and multiple organ damage. Vaso-occlusive crises are the most common presentation of sickle cell disease. Vaso-occlusive crises are caused by activation of the endothelial cells, neutrophils, monocytes and platelets by the sickled red blood cells. The activation of these cells leads to their expression of the p-selectin molecule promoting the aggregation and adhesion of these cells to one another and to the endothelial cells leading to clot formation and blockage of the microvascular channels.</div>\n<div>\n  </div>\n<div>\n There is only one known cure of sickle cell disease, which is a hematopoietic stem cell transplant (HSCT). Unfortunately, this intervention is not easily accessible to most patients due to its cost and unavailability in the country. Most patients with sickle cell disease are therefore mainly on supportive treatment. These reasons inform the need for more affordable and accessible treatments.</div>\n<div>\n  </div>\n<div>\n The study participants will have completed a study of inclacumab (originating study) and will receive inclacumab intravenous infusion in this open-label study. They will receive the intravenous treatment every 12 weeks. The mechanism of action of inclacumab is to prevent the action of p-selectin molecule, which reduces adhesion of molecules and leads to a reduction in the episodes of vaso-occlusive crises. The study aims to assess the safety of long-term administration of inclacumab in participants with SCD that have completed an inclacumab clinical trial. During the study period, participants can receive standard of care treatment except for crizanlizumab.</div>\n<div>\n  </div>\n<div>\n <strong>Methodology</strong></div>\n<div>\n  </div>\n<div>\n <strong>Study setting</strong></div>\n<div>\n The study will be carried out in up to 150 global clinical sites with a sample size of 520 participants. There will be approximately 5 sites in Kenya. We have three study sites in different parts of Nairobi, one in Siaya and the last one in Eldoret.</div>\n<div>\n  </div>\n<div>\n <strong>Study design</strong></div>\n<div>\n This study is an open-label extension study to evaluate the safety of long-term treatment with inclacumab in participants with SCD. The study will be available to eligible participants who were enrolled in a prior GBT-Sponsored inclacumab clinical study (originating study). Eligible participants, who continue to receive clinical benefit that outweighs risk, will receive inclacumab every 12 weeks until the participant has access to inclacumab from an alternative source. Given the long half-life of inclacumab (terminal half-life of 21 to 28 days) at the dose to be evaluated in this study, the majority of participants receiving active study drug are expected to maintain target concentrations as required throughout the study period.</div>\n<div>\n  </div>\n<div>\n <strong>INTRODUCTION & JUSTIFICATION</strong></div>\n<div>\n  </div>\n<div>\n Sickle cell disease is one of the most commonly inherited blood disorders worldwide (Sj et al., 2017). It is estimated that approximately 300,000 children are born with sickle cell disease in the world annually, 75% of whom are from Sub-Saharan Africa (Makani et al., 2013). As there is no systematic neonatal screening program in most public and private facilities, there is no national prevalence data. However, it is estimated that 4% of children born in Western Kenya have sickle cell disease(Wanjiku et al., 2019). The study is being conducted in Kenya due to the high incidence of sickle cell disease in the country.</div>\n<div>\n  </div>\n<div>\n Sickle cell disease (SCD) is an autosomal recessive disease characterized by chronic haemolysis, inflammation and vaso-occlusion presenting as recurrent pain episodes (variously termed sickle cell-related pain crises or VOCs), multi-organ dysfunction, and early death (Kato, 2018).</div>\n<div>\n Vaso-occlusion in SCD is driven by a series of complex and often redundant receptor–ligand interactions involved in the adhesion of circulating cells to the damaged</div>\n<div>\n endothelium and exposed sub-endothelium. Extensive research demonstrates that P-selectin mediated cellular interactions with sickled red blood cells (RBCs), leukocytes and platelets play a crucial role in the pathophysiology of vaso-occlusion in SCD. Blocking P-selectin-mediated cellular interactions reduces vaso-occlusion in animal models. Taken together, these data led to the hypothesis that blocking P-selectin could reduce the risk of VOCs in SCD patients.</div>\n<div>\n Results from a randomized, placebo-controlled Phase 2b trial of crizanlizumab, a humanized monoclonal antibody in SCD, bolstered the hypothesis that blocking the</div>\n<div>\n interaction of P-selectin with its receptors could prevent vaso-occlusion and VOCs (Ataga, 2017). In summary, there is a high unmet need for treatment options in SCD and there is a scientific rationale, supported by clinical data, that p-selectin inhibition has the potential to reduce the risk for acute vaso-occlusions.</div>\n<div>\n  </div>\n<div>\n <strong>JUSTIFICATION/RATIONALE</strong></div>\n<div>\n  </div>\n<div>\n Allogeneic HSCT remains the only curative therapy for sickle cell disease. It is however unavailable for most patients due to its high cost and it being available only in high income countries. It is also associated with various transplant complications (Kassim and Sharma 2017). Three therapies, hydroxyurea (HU [DROXIA®, 2017]; (also known as hydroxycarbamide), L-glutamine (ENDARI, 2017) and crizanlizumab (ADAKVEO®, 2019), have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to reduce VOCs in patients with SCD (Charache, 1995; Niihara, 2018; Ataga, 2017). The effectiveness of HU is impaired by low compliance rates and frequent discontinuations in treatment (Shah, 2019) while L-glutamine provides a modest 25% reduction in annual VOC rates (Niihara, 2018).</div>\n<div>\n  </div>\n<div>\n Crizanlizumab is a monoclonal antibody directed against human P-Selectin and is administered as an infusion every 4 weeks whereas inclacumab is to be administered every 12 weeks. The 4-week administration of crizanlizumab is a potential barrier to continued adherence to lifelong therapy because patients need to travel more frequently to an infusion centre to receive treatment. This regimen extracts a higher cost on patient and caregiver productivity and frequent intravenous infusions generally attract extra costs to the patient. (Saini, 2009; Richter, 2003). It has also been shown that less frequent dosing results in better adherence to medication (Saini, 2009; Richter, 2003).</div>\n<div>\n  </div>\n<div>\n Inclacumab has a similar mechanism of action as crizanlizumab. Previous studies on inhibition of p-selectin through crizanlizumab, have demonstrated it to be efficacious and safe for use in SCD patients. Additionally, the dose selected is 30mg/kg every 12 weeks and from previous studies, population PK simulations project that the inclacumab dose regimen of 30 mg/kg Q12W will maintain concentrations above 10 μg/mL throughout the study period in the majority of participants, thereby maximizing the pharmacology required for effective reduction of VOC in the SCD population. The 12-week dosing for inclacumab offers a potential benefit over the 4-week dosing of crizanlizumab and this could increase patient adherence to treatment, reduce the costs of patient and caregiver productivity, leading to a reduction in the overall health costs. Treatments with stable standard of care are allowed except for crizanlizumab because it has a similar mechanism of action as the study drug and would confound the interpretation of this data.</div>\n<div>\n  </div>\n<div>\n In summary, despite the recent availability of new options to treat VOCs, an unmet medical need exists to further reduce the frequency of VOCs while reducing patient burden and enhancing patient adherence to therapy.</div>\n<div>\n  </div>\n<div>\n <strong>NULL HYPOTHESIS</strong></div>\n<div>\n  </div>\n<div>\n There is no null hypothesis.</div>\n<div>\n  </div>\n<div>\n <strong>OBJECTIVES</strong></div>\n<div>\n <strong>Primary objective</strong></div>\n<div>\n  </div>\n<div>\n 1. To evaluate the long-term safety of every 12-week dosing of inclacumab in participants with SCD that have completed a prior inclacumab clinical trial.</div>\n<div>\n  </div>\n<div>\n <strong>Additional objectives</strong></div>\n<div>\n 2.To evaluate the incidence of VOCs, hospitalizations, missed work/school days, RBC transfusions, and quality of life (QoL) with long-term use of inclacumab.</div>\n<div>\n  </div>\n<div>\n <strong>STUDY DESIGN</strong></div>\n<div>\n  </div>\n<div>\n This study is a multicenter,global,open-label extention,designed to assess the safety of long-term treatment with inclacumab in participants with SCD.</div>\n<div>\n  </div>\n<div>\n Participants must have completed participation in their originating clinical study and must meet the entry criteria for this study to be eligible for enrolment. Eligible</div>\n<div>\n participants will receive Inclacumab 30 mg/kg administered IV Q12W; if they continue to receive clinical benefit that outweighs the risk, until the participant has access to inclacumab from an alternative source (e.g., through commercialization or a managed-access program).</div>\n<div>\n  </div>\n<div>\n All participants will undergo safety and outcome assessments at Baseline (Day 1), Week 6, and every 12 weeks thereafter. Visits to the clinical site for infusion of study drug will occur at Baseline (Day 1) and every 12 weeks (Weeks 12, 24, 36, 48, etc.).</div>\n<div>\n  </div>\n<div>\n Despite this being an open-label study, Investigators, study site staff, the Sponsor’s study staff, the Sponsor’s clinical CRO, and study participants will remain blinded to the randomized treatment assignments, as applicable, from the originating GBT-Sponsored inclacumab study. During the study, access to participants’ treatment assignment from the originating study will be limited to DMC members and service providers supporting DMC reviews, including the independent Data Coordinating Centre, until the database from the originating study is locked and primary endpoint analysis is complete. If a need arises for unblinding of the originating GBT-Sponsored inclacumab study, the instruction for unblinding as outlined in the originating study protocol will be followed.</div>\n<div>\n  </div>\n<div>\n A Data Monitoring Committee (DMC) will regularly review the totality of accumulated safety data from all ongoing inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent participants. DMC review will continue until the originating studies have been completed and the randomization assignments are unblinded. Details will be provided in the DMC Charter.</div>\n
      • study_title<div>\n An Open-Label Extension Study to Evaluate the Long-Term Safety of Inclacumab Administered to Participants with Sickle Cell Disease Who Have Participated in an Inclacumab Clinical Trial</div>\n
      • laymans_summary<div>\n Sickle cell disease is an inherited blood disorder that causes frequent pain episodes, and multiple organ complications. Currently, there is only one known cure for sickle cell disease which is a bone marrow transplant that is inaccessible for most Kenyans. However, currently most patients are usually on treatments that help control the disease e.g. hydroxyurea and folic acid, or prevent infections e.g. palludrine and Penicillin V, or manage symptoms as they arise e.g. painkillers for pain episodes and blood transfusion for anemia. There is a need for new treatments that help improve the patients’ quality of life.</div>\n<div>\n  </div>\n<div>\n Pain episodes are mainly caused by the blockage of blood flow to various parts of the body. One of the causes of this blockage includes formation of clots in the blood vessels. A molecule called p-selectin; produced by our bodies contributes to formation of this clots. GBT has developed a drug called inclacumab that prevents the function of p-selectin leading to a reduction in the formation of clots bringing about an overall decrease in pain episodes. The main aim of this study is to assess whether inclacumab is safe for use and if it reduces the number of vaso occlusive crises in patients with sickle cell disease when administered long-term.</div>\n<div>\n  </div>\n<div>\n A total of 520 participants will be enrolled across 150 clinical sites globally. There will be about 5 sites in Kenya. 3 sites are in Nairobi 1 in Siaya and another one in Eldoret .The sites will enrol this participants following their participation in and receipt of inclacumab in another GBT-sponsored inclacumab clinical study.</div>\n<div>\n  </div>\n<div>\n Participation in the study is voluntary and those enrolled have the possibility of benefiting from the study. If the drug proves to be efficacious there may be a reduction in the number of pain episodes. Additionally, participants will receive education on the disease. Participation in the study may also benefit health care workers and the local community who are actively involved with sickle cell disease management by providing more information on the treatment of the disease.</div>\n<div>\n There are potential risks associated with participation in the study and are mainly related to the side effects of the investigational product including but not limited to diarrhoea, vomiting, tiredness, nasal congestion, common cold symptoms and pain in the mouth and throat. Participants will be monitored for any side effects or sickness and if unwell treatment will be provided.</div>\n
      • short_titleAn Open label Inclacumab study
      • protocol_noECCT/22/02/01
      • version_noOriginal (V1.0) Protocol
      • date_of_protocol30-03-2021
      • study_drugOpen Label inclacumab - Prof Ogutu
      • disease_conditionSickle Cell Disease
      • product_type_biologicals1
      • product_type_proteins1
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorNo
      • comparator_nameN/A
      • comparator_registeredN/A
      • comparator_countriesN/A
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressPPDSubmissionsMembers.SM@ppd.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantMillicent Aketch
      • declaration_date123-02-2022
      • declaration_principal_investigatorDr. Videlis Nduba
      • declaration_date223-02-2022
      • placebo_presentNo
      • study_objectives<div>\n <strong>Main Objective</strong></div>\n<div>\n The primary objective of this study is to:</div>\n<div>\n 1. evaluate the long-term safety of every 12 week dosing of inclacumab in participants with sickle cell disease (SCD) that have</div>\n<div>\n completed a prior inclacumab clinical trial.</div>\n<div>\n <strong>The secondary Objective</strong></div>\n<div>\n Additional objectives are to:</div>\n<div>\n 1.Evaluate the incidence of vaso-occlusive crises (VOCs), hospitalizations, missed work/school days, red blood cell (RBC)</div>\n<div>\n transfusions, and quality of life (QoL) with long-term use of inclacumab</div>\n
      • principal_inclusion_criteria<div>\n 1. Male or female participant with SCD who participated and received study drug in a GBT-Sponsored inclacumab clinical</div>\n<div>\n study.</div>\n<div>\n 2. Participant has completed the originating inclacumab study within 30 days prior to the Day 1 Visit. Participants who</div>\n<div>\n discontinued study drug in the originating study due to a non-study drug-related adverse event (AE), but who remained on</div>\n<div>\n study, may be eligible for treatment in this study provided the AE does not pose a risk for treatment with inclacumab.</div>\n<div>\n 3. Female participants of childbearing potential are required to have a negative urine pregnancy test prior to dosing on Day 1.</div>\n<div>\n Note: Female participants who become childbearing during the study must be willing to have a negative urine pregnancy test</div>\n<div>\n to remain in the study.</div>\n<div>\n 4. If sexually active, female participants of childbearing potential must use highly effective methods of contraception until</div>\n<div>\n 165 days after the last dose of study drug. If sexually active, male participants must use barrier methods of contraception</div>\n<div>\n until 165 days after the last dose of study drug.</div>\n<div>\n 5. Participant has provided written informed consent/assent. For underage participants, both the consent of the participant's</div>\n<div>\n legal representative or legal guardian and the participant's assent (where applicable) must be obtained based on local</div>\n<div>\n requirement</div>\n
      • principal_exclusion_criteria<div>\n 1. Female participant who is breastfeeding or pregnant.</div>\n<div>\n 2. Participant had an infusion-related reaction (IRR) in the originating inclacumab clinical study.</div>\n<div>\n 3. Participant withdrew consent from the originating inclacumab clinical study.</div>\n<div>\n 4. Participant was lost to follow-up from the originating inclacumab clinical study.</div>\n<div>\n 5. Participant has any medical, psychological, safety, or behavioral conditions that, in the opinion of the Investigator, may</div>\n<div>\n confound safety interpretation, interfere with compliance, or preclude informed consent.</div>\n
      • primary_end_points<p>\n not applicable</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<div>\n <strong>International Cancer Institute-Eldoret</strong></div>\n<div>\n  </div>\n<div>\n The Investigator (PI) has adequate staff and have the necessary time,capacity and availability to conduct the study, including site management, collection, processing and shipment of lab samples. Below is the list of the staff at the site:</div>\n<div>\n  </div>\n<div>\n - Dr Fredrick Chite -PI - Joyce Chizi Kiti- Medical officer - Mercy Cherop-Biostatistician - Hildah Kaziga Chavera- Medical Officer -</div>\n<div>\n Collins Saina- Pharmacist - David Wambasi-Nurse - Stephen Karuru-Data manager - George Gitau Thumbi-Laboratory Technologist</div>\n<div>\n  </div>\n<div>\n The site is in a spacious compound and has 5 building. The main clinic buildings, the Pharmacy, laboratory, an office for the study Coordinator and additional personnel (essential documents are stored in a locked cabinet in this office). The main administrative building has individual work space, the Investigators office, a reception area, ablution blocks and individual works space cabins. The site has an access-controlled pharmacy, with shelving for storage of IP and non-IP products. There are consultation rooms, a nursing station with emergency equipment which also serves as a reception area and a procedure room.</div>\n<div>\n  </div>\n<div>\n The clinic is fully equipped to handle emergencies and the site has a 5-bed additional bed capacity that can be used as a temporary inpatient facility. The clinic also has a counselling room which will be used for the consenting process. Each consultation room is equipped with a desk, computer which is video enabled, a lamp, an examination couch, a trolley, a wooden lockable cabinet for supplies, equipment required to perform examinations e.g. sphygmomanometer, stethoscopes and  several other scopes, blood collection tools e.g tourniquets. The site will outsource Xray services and laboratory services that require an accredited laboratory to Lancet laboratories. The site has a high-speed internet.</div>\n<div>\n  </div>\n<div>\n <strong>Strathmore University Medical Centre (SUMC) Site</strong></div>\n<div>\n  </div>\n<div>\n The SUMC is designed for clinical trials and has a full clinical laboratory with bioanalytical capability. The Centre is managed by Strathmore University and the CREATES consortium. The Centre also has a dental unit.</div>\n<div>\n  </div>\n<div>\n The medical centre is staffed by 2 pediatricians, 2 physicians, 1 medical officer, 1 clinical officer, 4 dental surgeons, 3 psychologists, 1 pharmacist, 1 visiting psychiatrist, 1 physician assistant, 4 nurses and 4 laboratory technologists. The facility supports healthcare to university students and staff and also general public. The centre currently runs a SCD clinic every Tuesday.</div>\n<div>\n  </div>\n<div>\n Location The Sickle Cell study will be conducted at SUMC; recruitment will occur at the clinic. SUMC is located at Strathmore University in Madaraka Estate of Nairobi west, Nairobi County. SUMC will be staffed by qualified research personnel from KEMRI and SUMC. The site has a pharmacy, treatment area, clinical assessment area, data entry area, internal quality control and registration area and space where monitoring can be done. SUMC currently runs a SCD clinic with more than 200 patients on follow up comprising of both adults and children.</div>\n<div>\n  </div>\n<div>\n Provision of medical care SUMC is an outpatient facility with a 2-bed holding unit and a separate emergency resuscitation area. The centre serves as a clinical trials facility for both paediatric and adult studies. The participants who will require inpatient care will be admitted to Coptic Hospital Ngong Road as SUMC already has an existing working arrangement. As for  the Sickle cell disease, there is a database in place that has over 200 patients and we hope to base our recruitment on this list.</div>\n<div>\n The SUMC is also linked to other private, government, non-governmental and county health facilities, in Nairobi County that take care of patients with SCD. For the care of sickle cell patients, the SCD clinic will work closely with the study team.</div>\n<div>\n  </div>\n<div>\n <strong>Kisumu/Siaya Site</strong></div>\n<div>\n  </div>\n<div>\n Site activities are located in Kisumu/Siaya and Nairobi Counties. Kisumu hosts the main IP storage site, administrative offices of the PI and co-investigators, procurement and Human Resource functions are housed at the KEMRI Kisian Campus. Recruitment, follow-up of study participants will occur in Siaya.</div>\n<div>\n  </div>\n<div>\n KEMRI has a modern research annex at the Siaya county hospital with capacity to conduct phase I to Phase III studies. After community mobilization, screening and enrollment, IP dispensation will occur at the Siaya Clinical Research Annexe.</div>\n<div>\n  </div>\n<div>\n Site investigators responsible for day to day running of the project include: Medical Officer 2, Pharmacist 1, Pharm tech 2,</div>\n<div>\n Nurses 5, Quality Assurance Officer 2, Quality Control 1, Clinical Officer 2, Community Interviewers 4.</div>\n<div>\n  </div>\n<div>\n <strong>KEMRI/CRDR clinical research Site</strong></div>\n<div>\n  </div>\n<div>\n Site activities will take place within the KEMRI/CRDR clinical research annex. This facility has several clinical rooms available for consenting, nursing procedures, clinical exams and dosing. There are also additional facilities that include an inpatient ward, staff work areas and a monitoring space, a pharmacy, laboratory and kitchen for preparing participant meals.</div>\n<div>\n  </div>\n<div>\n Site staff include the principal investigator, 4 medical officers, 2 pharmacists, 1 pharmtech, 5 nurses, 5 quality assurance</div>\n<div>\n officers, 3 clinical officers and 6 community health workers.</div>\n<div>\n  </div>\n<div>\n <strong>Gertrude’s Children’s Hospital Site:</strong></div>\n<div>\n  </div>\n<div>\n Gertrude’s Children’s Hospital (GCH) is one of the largest hospital in East and Central Africa dedicated exclusively to the care of children. For over 60 years, the hospital has provided high standards of paediatric care for children from birth to 21 years of age. The hospital is accredited by the Joint Commission International Accreditation and Safe Care, Netherlands following audits of the hospital facilities.</div>\n<div>\n  </div>\n<div>\n GCH is a non-profit organization, chartered with the responsibility of provision of health services, fostering good health, carrying out research and teaching healthcare professionals. Based in Muthaiga, Nairobi, and spread out to various outpatient clinics all over Nairobi and in several other Counties, the hospital attends to over 300,000 children as outpatients and admits over 6,000 patients on average per year.</div>\n<div>\n  </div>\n<div>\n The over 100-bed hospital offers comprehensive paediatric medical services and there are 21 specialist clinics that cover almost every aspect of paediatric healthcare from haematology, chest conditions, cardiology, dermatology, otorhinolaryngology, endocrinology, oncology and HIV/AIDS. Primary care services are also offered including a Well Baby and Immunization clinic.</div>\n<div>\n  </div>\n<div>\n The laboratory is equipped with modern equipment and offers diagnostic laboratory testing in all areas of pathology and is headed by a pathologist supported by several other pathologists, laboratory manager and qualified medical laboratory technologists. The hospital laboratory and pharmacy cater for both children and adults. The laboratory is accredited by Kenya Accreditation Service as a medical testing laboratory (ISO15189:2012). Qualified pharmacists manage the hospital pharmacy.</div>\n<div>\n GCH has an up-to-date paediatric imaging facility that is managed by a team of radiologists and qualified radiographers. Most of the processes at the hospital are fully computerized and supported by a well-integrate Information Technology Department. The main hospital in Muthaiga is open 24/7 and offers 24-hour laboratory and pharmacy coverage. The Accident and Emergency Department is well equipped to deal with all forms of paediatric emergencies and has a crash cart and crash</div>\n<div>\n team on call, 24 hours a day. There are registered nurses, medical officers and specialists specifically trained in Emergency Triage Assessment and Treatment. The Team is fully trained to handle emergencies, including but not limited to airway obstruction and other breathing problems; circulatory impairment or shock; severely altered central nervous system function (coma or convulsive seizures); and severe dehydration which require urgent appropriate care to prevent death. The Hospital</div>\n<div>\n runs an Institute of Child Health and Research based at the Muthaiga site which is approved by the Nursing Council of Kenya. The school offers courses in paediatric endocrinology, paediatric phlebotomy, emergency paediatric medicine and several specialised paediatric nursing courses. The Hospital has an Ethics Review Committee (ERC) that acts independently from the appointing authority, hosting institution, researchers, sponsors and any other stakeholders in its review and decision-making processes. The ERC is accredited by the National Commission for Science and Technology and Innovation (NACOSTI), an institution mandated to advise the Government on policies and matters relating to the scientific and technological activities and research required for the proper development of the country. The population served by the hospital is cosmopolitan and English and Kiswahili are the predominantly spoken languages.</div>\n<div>\n  </div>\n<div>\n <strong>Site Study Staff Details.</strong></div>\n<div>\n  </div>\n<div>\n The site has a multidisciplinary study team that comprises specialists and professionals in many fields of medicine including;</div>\n<div>\n medical officers, paediatricians, haematologists, oncologists, pathologists, nurses, pharmacists, medical laboratory technologists. The Team has members who have been trained on the job as study coordinators. The team members are experienced in clinical trials and have all been trained in Good Clinical Practice and most have successfully participated in several other clinical trials.</div>\n<div>\n  </div>\n<div>\n <strong>Site personnel roles and responsibilities</strong></div>\n<div>\n  </div>\n<div>\n <strong>Principal Investigator </strong>• Prof Jessie Githanga A qualified haematologist/clinical pathologist, registered by the Kenya Medical Practitioners and Dentists Council (KMPDC). She will be responsible for the overall conduct of the trial at the study site, budgetary negotiations, administrative actions and communication between Institutional Review Boards, and the sponsor and oversight of patient care. She will oversee the recruitment of the subjects and directly supervise study staff.</div>\n<div>\n  </div>\n<div>\n <strong>Co-Investigator/main coordinator</strong> • Dr. Doreen Karimi Mutua A qualified paediatrician, with subspecialty training in paediatric haemato-oncology working at GCH and registered by the KMPDC. Dr Mutua will be responsible for clinical care provision of the patients, assist in supervision of study staff and will also participate in study recruitment. Dr Mutua supports PI and has roles that may be delegated such as ethical and sponsor communication and may be delegated related roles.</div>\n<div>\n  </div>\n<div>\n <strong>Study Coordinator : </strong>• Dr Joy Githua A qualified medical officer, registered by the KMPDC working at GCH. She will be the main coordinator for the study and will be responsible for day to day management of trial aspects including participant recruitment, follows up, safety monitoring, data entry and maintaining the site files and other study records and may be delegated related roles.</div>\n<div>\n  </div>\n<div>\n <strong>Study Pharmacist and assistant:</strong></div>\n<div>\n Dr Samuel Madere (pharmacist) • Crecencia Nekesa Makokha (pharmaceutical technologist) Qualified pharmacist, registered by the Pharmacy and Poison’s Board (PPB), will be delegated roles of the IP storage and related duties, dilution of IP and dispensing, processing of import permit for IP and may be delegated related roles. He will be assisted by a pharmaceutical technologist.</div>\n<div>\n  </div>\n<div>\n <strong>Study nurses</strong>: • Hannah Wanjiku (assistant study coordinator) • Felicity Kamundi • Jane Nduati A registered nurse, registered by the Nursing Council of Kenya, will be responsible for co-ordinating the patient visits, taking patent vital signs and patient training. The assistant study coordinator will in addition be the assistant study coordinator.</div>\n<div>\n  </div>\n<div>\n <strong>Laboratory Manager: </strong>Peninah Chege: Laboratory manager registered by the Kenya Medical Laboratory Technologists and Technicians Board (KMLTTB) will coordinate laboratory functions, process the import permits for laboratory items, equipment and may be delegated related roles. Laboratory technologist/phlebotomist • Charles Muia (technologist) • Herman  Akumu(technologist) • Joseph Langat (phlebotomist) Trained laboratory technologists registered by the KMLTTB and trained in Good Clinical Practice (GCP) and phlebotomist who will obtain specimens from study participants. The technologists will perform any local laboratory testing where necessary and package specimens for shipping to Central or other local labs.</div>\n<div>\n  </div>\n<div>\n <strong>Quality Assurance Officer •</strong> Winnie Abuto Quality Assurance Officer Nurse registered by the Nursing Council of Kenya, and GCP trained. She will be tasked with ensuring that study documents are quality controlled so that they are Attributable, Legible, Contemporaneous, Original, and Accurate (ALCOA) in accordance GCP guidelines. She will ensure that staff are alerted to changes in standard operating procedures (SOPs) as necessary.</div>\n<div>\n  </div>\n<div>\n <strong>Administrative assistant </strong>• Truphena Otinyo The Administrative assistant will coordinate and maintain the records of</div>\n<div>\n communications with the ERC, assist the main coordinator in patient visit coordination. She may be delegated related roles.</div>\n
      • other_details_explanation<p>\n N/A, trial is being conducted in USA</p>\n
      • other_details_regulatory_notapproved<table border=\"1\" cellpadding=\"1\" cellspacing=\"1\" style=\"width:500px;\">\n <tbody>\n <tr>\n <td>\n Country </td>\n <td>\n date submited </td>\n <td>\n status </td>\n </tr>\n <tr>\n <td>\n France</td>\n <td>\n 20 Sep2021</td>\n <td>\n pending </td>\n </tr>\n <tr>\n <td>\n Kenya</td>\n <td>\n 24 Sep  2021</td>\n <td>\n pending </td>\n </tr>\n <tr>\n <td>\n Nigeria</td>\n <td>\n 25 May 2021</td>\n <td>\n pending </td>\n </tr>\n <tr>\n <td>\n Ghana</td>\n <td>\n 27 Aug 2021</td>\n <td>\n pending </td>\n </tr>\n <tr>\n <td>\n Tanzania</td>\n <td>\n 27 Aug 2021</td>\n <td>\n pending </td>\n </tr>\n <tr>\n <td>\n N/A</td>\n <td>\n  </td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n N/A</td>\n <td>\n  </td>\n <td>\n  </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_regulatory_approved<p>\n  </p>\n<p>\n  </p>\n<table border=\"1\" cellpadding=\"1\" cellspacing=\"1\" style=\"width:500px;\">\n <tbody>\n <tr>\n <td>\n country approved </td>\n <td>\n date aproved </td>\n <td>\n number of site </td>\n </tr>\n <tr>\n <td>\n Germany </td>\n <td>\n 10 Nov 2021</td>\n <td>\n 1</td>\n </tr>\n <tr>\n <td>\n Italy </td>\n <td>\n 04 Aug 2021</td>\n <td>\n 3</td>\n </tr>\n <tr>\n <td>\n Brazil </td>\n <td>\n 29 Jun2021</td>\n <td>\n 6</td>\n </tr>\n <tr>\n <td>\n Colombia</td>\n <td>\n 29 Nov 2021</td>\n <td>\n 3</td>\n </tr>\n <tr>\n <td>\n Egypt </td>\n <td>\n 01 Sep 2021</td>\n <td>\n 8</td>\n </tr>\n <tr>\n <td>\n saudi Arabia</td>\n <td>\n 08 Dec 2021</td>\n <td>\n 2</td>\n </tr>\n <tr>\n <td>\n Turkey </td>\n <td>\n 26 Dec 2021</td>\n <td>\n 4</td>\n </tr>\n </tbody>\n</table>\n<p>\n  United Kingdom                                  27 Oct 2021                          3 sites </p>\n<p>\n unites states of America                       11 Dec 2020                       25 sites </p>\n<p>\n Zambia                                                   11 Jan 2022                        3 sites </p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n The regulatory authority has not halted the conduct of the study in any country.</p>\n
      • estimated_duration7 years 2 months day
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states17
      • number_of_sites5
      • multi_country_listColombia, Egypt, France ,Germany, Ghana, Italy ,Kenya, Lebanon ,Nigeria, Oman ,Saudi Arabia, Tanzania ,United Republic of Turkey, United Kingdom, United States ,Zambia
      • data_monitoring_committeeYes
      • total_enrolment_per_siteIt is competitive enrollment world wide. Participants who were enrolled in GBT2104-131 and GBT2104-132 will be given a change to join the open label study if they consent.
      • total_participants_worldwide520
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyadolescents from 12years to 17 years however they will assent to be in the study and their parents/legal representative will\nconsent for them to join the study
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameVidelis
      • investigator1_middle_nameN
      • investigator1_family_nameNduba
      • investigator1_qualificationMedical Doctor
      • investigator1_professional_addressKEMRI-CRDR , Kenyatta National Hospital
      • investigator1_telephone+254724522474
      • investigator1_emailvnduba@gmail.com
      • organisations_transferred_Yes
      • number_participantsThe sample size is approximately 520 participants and is based on the combined sample sizes from the originating studies.\n
      • notification<p>\n List of Competent Authority </p>\n
      • approval_date16-05-2022
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted24-03-2022
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments have been addressed adequately
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-04-30 11:33:36
      • created2022-02-01 08:31:14
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id787
        • application_id1113
        • given_nameBernhards
        • middle_nameRagama
        • family_nameOgutu
        • qualificationMedical Doctor
        • professional_addressStrathmore University Medical Centre
        • telephone +254 733812613
        • emailogutu6@gmail.com
        • created2022-02-01 08:37:49
        • modified2022-03-24 21:35:24
      • 1(array)
        • id788
        • application_id1113
        • given_nameFredrick
        • middle_nameAsirwa
        • family_nameChite
        • qualificationInternal Medicine Physician and Medical Oncologist & Hematologist
        • professional_addressDivision of Hematology and OncologyInternational Cancer Institute (ICI) P.O. Box 8088 – 30100, Eldoret – Kenya
        • telephone+254700522149,
        • emailchiteasirwa@gmail.com and chite@intercancer.com
        • created2022-02-03 10:57:02
        • modified2022-03-24 21:35:24
      • 2(array)
        • id789
        • application_id1113
        • given_nameVidelis
        • middle_nameN
        • family_namenduba
        • qualificationmedical Doctor
        • professional_addressKEMRI-CRDR , Kenyata National Hospital
        • telephone+254724522474
        • emailvnduba@gmail.com
        • created2022-02-03 10:57:02
        • modified2022-03-24 21:35:24
      • 3(array)
        • id790
        • application_id1113
        • given_nameProf Jessie
        • middle_nameN
        • family_nameGithanga
        • qualificationhaematologist/clinical pathologist
        • professional_addressGertrude’s Children’s Hospital, 34 Muthaiga Road,
        • telephone+254721245721
        • emailjgithanga3@gmail.com
        • created2022-02-03 10:59:44
        • modified2022-03-24 21:35:24
    • SiteDetail(array)
      • 0(array)
        • id1230
        • application_id1113
        • county_id47
        • site_nameStrathmore University Medical Centre
        • physical_addressStrathmore University Medical Centre ,Ole Sangale Rd
        • contact_details +254733813613
        • contact_personDr Bernhards Ogutu
        • site_capacity(null)
        • misc(null)
        • created2022-02-01 08:37:49
        • modified2022-03-24 21:35:24
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 1(array)
        • id1236
        • application_id1113
        • county_id27
        • site_nameInternational Cancer Institute (ICI)-Eldorate
        • physical_addressInternational Cancer Institute, Nandi Road, Block 8/553
        • contact_detailsTel:+254700522149, P.O. Box 8088 – 30100, Eldoret – Kenya,
        • contact_personProf. Fredrick Chite Asirwa
        • site_capacity(null)
        • misc(null)
        • created2022-02-03 10:47:10
        • modified2022-03-24 21:35:24
        • County(array)
          • id27
          • county_nameUasin Gishu
          • created2012-06-15 10:25:15
          • modified2012-06-15 10:25:15
      • 2(array)
        • id1237
        • application_id1113
        • county_id47
        • site_nameKEMRI/CRDR
        • physical_addressKenyatta National Hospital Off Hospital Road, CRDR.
        • contact_detailsTel:+254790484654, P.O Box 47855-00100
        • contact_personProf. Videlis Nduba
        • site_capacity(null)
        • misc(null)
        • created2022-02-03 10:48:35
        • modified2022-03-24 21:35:24
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 3(array)
        • id1238
        • application_id1113
        • county_id41
        • site_nameKEMRI Siaya Clinical Research Annex
        • physical_addressKEMRI Clinical research Annex,Siaya County Hospital
        • contact_detailsTel: +254722205901, P.O Box 144-40600,Siaya
        • contact_personProf. Videlis Nduba
        • site_capacity(null)
        • misc(null)
        • created2022-02-03 10:48:35
        • modified2022-03-24 21:35:24
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 4(array)
        • id1239
        • application_id1113
        • county_id47
        • site_nameGertrude’s Children’s Hospital.
        • physical_addressGertrude’s Children’s Hospital-Muthaiga
        • contact_detailsTel:+254 721245721,34 Muthaiga Road,
        • contact_personProf.Jessie Githanga
        • site_capacity(null)
        • misc(null)
        • created2022-02-03 10:49:30
        • modified2022-03-24 21:35:24
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 5(array)
        • id1240
        • application_id1113
        • county_id47
        • site_nameStrathmore University Medical Centre
        • physical_addressStrathmore University Medical Centre ,Ole Sangale Rd
        • contact_detailsTel: +254733813613
        • contact_personDr Bernhards Ogutu
        • site_capacity(null)
        • misc(null)
        • created2022-02-03 10:55:27
        • modified2022-03-24 21:35:24
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
    • Sponsor(array)
      • 0(array)
        • id574
        • application_id1113
        • sponsorGlobal Blood Therapeutics, Inc.
        • sponsor_typeIndustry
        • contact_personKalyan Obalampalli
        • address 181 Oyster Point Blvd.South San Francisco CA 94080 United States
        • telephone_number001 916 284 0777
        • fax_numberN/A
        • cell_number001 916 284 0777
        • email_addresskobalampalli@gbt.com
        • created2022-02-01 08:37:49
        • modified2022-03-24 21:35:24
• page_options(array)
  • 55
  • 1010
• redir
• $request->data(array)
  • Application(array)
    • approved1
• $this->validationErrors(array)
  • Permission(empty)
  • Aro(empty)
  • Aco(empty)
  • Application(empty)
  • User(empty)
  • TrialStatus(empty)
  • InvestigatorContact(empty)
  • Sponsor(empty)
  • SiteDetail(empty)
  • County(empty)
• Loaded Helpers(array)
  • 0Html
  • 1Form
  • 2Session
  • 3Text
  • 4Number
  • 5SimpleGraph
  • 6Paginator
  • 7DebugTimer
  • 8Toolbar
  • 9HtmlToolbar

App Constants

CakePHP Constants

PHP Environment

Included Files

Include Paths

• 0/var/www/html/ctr/app/Plugin/Media/Lib/mm/src
• 1/var/www/html/ctr/lib
• 3/usr/share/php
• 4-> /var/www/html/ctr/lib/Cake/

Included Files

• core(array)
  • Behavior(array)
    • 0CORE/Model/Behavior/TreeBehavior.php
    • 1CORE/Model/Behavior/ContainableBehavior.php
    • 2CORE/Model/Behavior/AclBehavior.php
  • Cache(array)
    • 0CORE/Cache/Cache.php
    • 1CORE/Cache/Engine/FileEngine.php
    • 2CORE/Cache/CacheEngine.php
  • Component(array)
    • 0CORE/Controller/Component/AclComponent.php
    • 1CORE/Controller/Component/Acl/DbAcl.php
    • 2CORE/Controller/Component/Acl/AclInterface.php
    • 3CORE/Controller/Component/AuthComponent.php
    • 4CORE/Controller/Component/RequestHandlerComponent.php
    • 5CORE/Controller/Component/SessionComponent.php
    • 6CORE/Controller/Component/PaginatorComponent.php
  • Config(array)
    • 0CORE/Config/routes.php
    • 1CORE/Config/config.php
  • Controller(array)
    • 0CORE/Controller/Controller.php
    • 1CORE/Controller/ComponentCollection.php
    • 2CORE/Controller/Component.php
  • Datasource(array)
    • 0CORE/Model/Datasource/CakeSession.php
    • 1CORE/Model/Datasource/Database/Mysql.php
    • 2CORE/Model/Datasource/DboSource.php
    • 3CORE/Model/Datasource/DataSource.php
  • Error(array)
    • 0CORE/Error/exceptions.php
    • 1CORE/Error/ErrorHandler.php
  • I18n(array)
    • 0CORE/I18n/I18n.php
    • 1CORE/I18n/L10n.php
  • Log(array)
    • 0CORE/Log/CakeLog.php
    • 1CORE/Log/LogEngineCollection.php
    • 2CORE/Log/Engine/FileLog.php
    • 3CORE/Log/Engine/BaseLog.php
    • 4CORE/Log/CakeLogInterface.php
  • Model(array)
    • 0CORE/Model/ConnectionManager.php
    • 1CORE/Model/Permission.php
    • 2CORE/Model/Model.php
    • 3CORE/Model/BehaviorCollection.php
    • 4CORE/Model/Aro.php
    • 5CORE/Model/AclNode.php
    • 6CORE/Model/Aco.php
    • 7CORE/Model/ModelBehavior.php
  • Network(array)
    • 0CORE/Network/CakeRequest.php
    • 1CORE/Network/CakeResponse.php
  • Other(array)
    • 0CORE/bootstrap.php
    • 1CORE/basics.php
    • 2CORE/Core/App.php
    • 3CORE/Core/Configure.php
    • 4CORE/Core/CakePlugin.php
    • 5CORE/Event/CakeEventListener.php
    • 6CORE/Event/CakeEvent.php
    • 7CORE/Event/CakeEventManager.php
    • 8CORE/Core/Object.php
  • Routing(array)
    • 0CORE/Routing/Dispatcher.php
    • 1CORE/Routing/Filter/AssetDispatcher.php
    • 2CORE/Routing/DispatcherFilter.php
    • 3CORE/Routing/Filter/CacheDispatcher.php
    • 4CORE/Routing/Router.php
    • 5CORE/Routing/Route/CakeRoute.php
    • 6CORE/Routing/Route/PluginShortRoute.php
  • Utility(array)
    • 0CORE/Utility/Hash.php
    • 1CORE/Utility/Inflector.php
    • 2CORE/Utility/ObjectCollection.php
    • 3CORE/Utility/Debugger.php
    • 4CORE/Utility/String.php
    • 5CORE/Utility/ClassRegistry.php
    • 6CORE/Utility/Set.php
    • 7CORE/Utility/Sanitize.php
  • View(array)
    • 0CORE/View/HelperCollection.php
• app(array)
  • Behavior(array)
    • 0APP/Model/Behavior/SoftDeleteBehavior.php
  • Config(array)
    • 0APP/Config/core.php
    • 1APP/Config/bootstrap.php
    • 2APP/Config/routes.php
    • 3APP/Config/database.php
  • Controller(array)
    • 0APP/Controller/ApplicationsController.php
    • 1APP/Controller/AppController.php
  • Model(array)
    • 0APP/Model/AppModel.php
    • 1APP/Model/Application.php
    • 2APP/Model/User.php
    • 3APP/Model/TrialStatus.php
    • 4APP/Model/InvestigatorContact.php
    • 5APP/Model/Sponsor.php
    • 6APP/Model/SiteDetail.php
    • 7APP/Model/County.php
  • Other(array)
    • 0APP/webroot/index.php
• plugins(array)
  • CakePdf(array)
    • Config(array)
      • 0CakePdf/Config/bootstrap.php
      • 1CakePdf/Config/routes.php
  • CakeResque(array)
    • Config(array)
      • 0CakeResque/Config/bootstrap.php
    • Plugin(array)
      • 0CakeResque/Lib/CakeResque.php
      • 1CakeResque/vendor/kamisama/php-resque-ex/lib/Resque.php
      • 2CakeResque/vendor/kamisama/php-resque-ex/lib/Resque/Event.php
      • 3CakeResque/vendor/kamisama/php-resque-ex/lib/Resque/Exception.php
  • DebugKit(array)
    • Component(array)
      • 0DebugKit/Controller/Component/ToolbarComponent.php
    • Plugin(array)
      • 0DebugKit/Lib/DebugMemory.php
      • 1DebugKit/Lib/Panel/HistoryPanel.php
      • 2DebugKit/Lib/DebugPanel.php
      • 3DebugKit/Lib/Panel/SessionPanel.php
      • 4DebugKit/Lib/Panel/RequestPanel.php
      • 5DebugKit/Lib/Panel/SqlLogPanel.php
      • 6DebugKit/Lib/Panel/TimerPanel.php
      • 7DebugKit/Lib/Panel/LogPanel.php
      • 8DebugKit/Lib/Log/Engine/DebugKitLog.php
      • 9DebugKit/Lib/Panel/VariablesPanel.php
      • 10DebugKit/Lib/Panel/EnvironmentPanel.php
      • 11DebugKit/Lib/Panel/IncludePanel.php
      • 12DebugKit/Lib/DebugTimer.php
  • Media(array)
    • Config(array)
      • 0Media/Config/bootstrap.php
    • Plugin(array)
      • 0Media/Lib/mm/src/Mime/Type.php
      • 1Media/Lib/mm/src/Mime/Type/Magic/Adapter/Fileinfo.php
      • 2Media/Lib/mm/src/Mime/Type/Magic/Adapter.php
      • 3Media/Lib/mm/src/Mime/Type/Glob/Adapter/Memory.php
      • 4Media/Lib/mm/src/Mime/Type/Glob/Adapter.php
      • 5Media/Lib/mm/src/Media/Process.php
      • 6Media/Lib/mm/src/Media/Info.php
  • Search(array)
    • Component(array)
      • 0Search/Controller/Component/PrgComponent.php
    • Behavior(array)
      • 0Search/Model/Behavior/SearchableBehavior.php
  • Shim(array)
    • Config(array)
      • 0Shim/Config/bootstrap.php
  • Tools(array)
    • Config(array)
      • 0Tools/Config/bootstrap.php