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• trial_statuses(array)
  • 1Recruiting
  • 2Not yet recruiting
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  • 7Analysing
  • 8Writing-up
  • 9Application withdrawn
  • 10Ongoing Closeout Phase
• applications(array)
  • 0(array)
    • Application(array)
      • id654
      • user_id32
      • trial_status_id5
      • abstract_of_study<div style=\"text-align: justify;\">\n In 2012, the WHO Strategic Advisory Group of Experts (SAGE) on immunizations made a recommendation for influenza vaccination of pregnant women. This was based upon compelling evidence of substantial risk of severe disease in this group and the safety and effectiveness of seasonal influenza vaccine in preventing disease in pregnant women as well as their young infants, in whom disease burden is also high. Sub-Saharan Africa has a high prevalence of HIV and malaria, the presence of which among expectant mothers can reduce response to influenza vaccination, and therefore affect transfer of vaccine-induced antibodies to their newborn babies. There is no documention on the effect of malaria parasitemia on influenza vaccination in pregnant women and their newborns. Few studies have shown reduced immunogenicity of influenza vaccine and associated antibody transfer among pregnant women with HIV, however the studies were done late in the course of pregnancy. We propose to conduct an influenza vaccine demonstration project, using an Inactivated Influenza Vaccine (IIV) already licensed in Kenya to vaccinate pregnant women in a high HIV prevalence and malaria-endemic setting in western Kenya. Documentation of vaccine-induced antibody transfer from vaccinated mothers to their babies is essential and key to informing the Kenya Ministry of Health on maternal immunization policy and strategy for these high-risk groups. Western Kenya is a resource-limited setting with high burden of influenza disease among infants. Vaccinating pregnant women for better outcomes in both mother and infant would therefore be a cost effective strategy in preventing influenza disease in two high-risk groups. Data from this study will also help inform influenza vaccine deployment in other countries with similar HIV and malaria profiles. If adopted by the government, maternal influenza immunization could be an important public health strategy in resource constrained settings to protect infants <6 months, not eligible for influenza vaccination themselves, and their mothers from influenza disease and associated complications.</div>\n<div>\n  </div>\n
      • study_title<p>\n Impact of HIV Infection and Malaria Parasitemia on Immunogenicity of Inactivated Influenza Vaccine in Pregnant Women and on Mother-to-Child Vaccine-induced Antibody Transfer</p>\n
      • laymans_summary<p>\n Studies have shown that influenza can be severe among pregnant women and newborn babies. Influenza vaccination during pregnancy can protect pregnant women. Also, women vaccinated against influenza during pregnancy can pass on protective antibodies to their babies who are too young (<6 months of age) to be directly vaccinated. Influenza vaccination has been offered to pregnant women around the world for many years and data show the vaccine to be safe, for the mother and their unborn babies. Based on evidence from such studies, the advisory group of experts on immunization from the WHO recommended influenza vaccination to pregnant women. Sub-Saharan Africa has a high percentage of the population suffering from HIV and malaria; these diseases may affect how pregnant women respond to influenza vaccine and therefore affect the amount of protection transfered to their newborn babies. We propose to carry out a demonstration project using an influenza vaccine licensed in Kenya to vaccinate pregnant women in a setting of western Kenya with high rates of HIV among the population and malaria presence throughout the year. Results from this study will inform the Ministry of Health on policy and startegies for vaccinating mothers to protect these two high-risk groups. These results will also be applicable to other countries with similar HIV and malaria burden and may inform their policies on vaccination of pregnant women.</p>\n
      • short_titleMaternal Influenza Vaccine Study
      • protocol_noECCT/18/04/02
      • version_no1.1
      • date_of_protocol03-11-2017
      • study_drugInactivated Influenza Vaccine
      • disease_conditionInfluenza
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals1
      • 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
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresstonysangke@gmail.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_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_date103-05-2018
      • declaration_principal_investigatorNancy Otieno
      • declaration_date203-05-2018
      • placebo_presentNo
      • study_objectives<div>\n Primary Objectives</div>\n<ol>\n <li>\n To evaluate the immunogenicity of IIV in HIV-infected pregnant women and women with peripheral malaria parasitemia at the time of vaccination.</li>\n <li>\n To evaluate the level of vaccine-induced influenza antibody transfer to infants of HIV-infected and uninfected pregnant women who receive IIV early in pregnancy.</li>\n <li>\n To evaluate the level of vaccine-induced influenza antibody transfer to infants of mothers who had peripheral malaria parasitemia by Rapid Diagnostic Test for malaria at the time of influenza vaccination during pregnancy.</li>\n</ol>\n<div>\n  </div>\n<div>\n Secondary Objectives</div>\n<ol>\n <li>\n To evaluate the impact of HIV infection and peripheral malaria parasitemia on the duration of influenza vaccine-induced antibodies transferred to infant.</li>\n</ol>\n
      • principal_inclusion_criteria<ol>\n <li>\n Pregnancy confirmed by rapid urine pregnancy test for hCG or ultrasound</li>\n <li>\n Should have a singleton current pregnancy</li>\n <li>\n ≤20 weeks’ gestation by ultrasound, fundal height, or within 4 weeks of quickening</li>\n <li>\n Consents to HIV testing and counseling as required</li>\n <li>\n Does not plan to relocate out of the study area or population-based surveillance site in the next 15 months and agrees to all follow-up visits and study procedures.</li>\n <li>\n Provides informed consent by signature or thumb print</li>\n <li>\n Not currently enrolled in another intervention study</li>\n <li>\n Must be willing to deliver in the labor ward of the study hospital</li>\n <li>\n No history of chronic illness requiring multiple hospitalizations or prolonged medical therapy (except HIV on HAART)</li>\n</ol>\n
      • principal_exclusion_criteria<ol>\n <li>\n History of allergic reaction to any component of the study vaccine (e.g allergy to eggs or chicken products)</li>\n <li>\n Planning to relocate out in the 15 months following enrollment</li>\n <li>\n Received immunoglobulin or blood products within 45 days of study entry</li>\n <li>\n Used immunosuppressive medication within 45 days of study entry (inhaled and topical corticosteroids permitted)</li>\n <li>\n Multiple pregnancy (twins, triplets, etc.)</li>\n <li>\n Current enrollment in another interventional study</li>\n <li>\n Gestational age >20 weeks by last menstrual period or fundal height</li>\n <li>\n Hemoglobin <7.0 g/dL</li>\n <li>\n Influenza vaccination in previous 12 months</li>\n <li>\n Unable to give informed consent (for example due to mental disability).</li>\n <li>\n Acutely ill with temperature ≥37.5°C Axillary/38°C Oral on the day of vaccination (will be deferred and can be enrolled after treatment and fever is resolved).</li>\n</ol>\n
      • primary_end_points<ol>\n <li>\n To evaluate the immunogenicity of IIV in HIV-infected pregnant women and women with peripheral malaria parasitemia at the time of vaccination.</li>\n <li>\n To evaluate the level of vaccine-induced influenza antibody transfer to infants of HIV-infected and uninfected pregnant women who receive IIV early in pregnancy.</li>\n <li>\n To evaluate the level of vaccine-induced influenza antibody transfer to infants of mothers who had peripheral malaria parasitemia by Rapid Diagnostic Test for malaria at the time of influenza vaccination during pregnancy.</li>\n</ol>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy0
      • scope_safety0
      • 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_confirmatory0
      • trial_therapeutic_use1
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<div style=\"text-align: justify;\">\n <div>\n The study is to be conducted in Siaya County at two study sites namely Siaya County Referral Hospital (SCRH)and Bondo Sub-county Referral Hospital (BSRH). These are among the largest hospitals in the county with adequate equipment and structures. Siaya County Referral hospital has a Clinical Research Centre(CRC) and this is where the study will be conducted. The study personnel that will handle the study participants are well trained professionally and all of them have undergone intensive Good Clinical Practice(GCP) training. Most of the study staffs have participated in other previous clinical trials and therefore have the expertise and experience of the same.</div>\n <div>\n  </div>\n <div>\n The study is be headed by Dr. Sandra Shaves who is a medical doctor and Nancy Otieno both of which have vast experience in research in human subjects, they are the Principal Investigators, among the Coinvestigator there is Michael Otieno who is also the study coordinator, Michael is a clinical officer with a lot experience of about 8 years in clinical trials, he has worked in Rotateq Vaccine clinical trial and Malaria vaccine clinical trials, the study doctor is Dr. Allan Dungani who is also participating in Malaria vaccine clinical trial as study doctor. Dr. Tony Sang is the study pharmacist. Dr. Sang is well experienced in handling the clinical trials with more than 10 years on the same. He has participated in more than 3 vaccine clinical trials and many drug trials. The study has 10 nurses, 3 clinicians, 6 lab technologists, 3 quality assurance officers, data manager and analysts, and 10 field technicians.</div>\n <div>\n  </div>\n <div>\n The laboratory department where the samples will be handled and processed before shipment for further analysis and even stored has undergone the ISO certification. The lab staffs have all undergone the good clinical and laboratory practice training (GCLP), the lab staffs have as well participated in previous clinical trials</div>\n <div>\n  </div>\n <div>\n The clinical staffs that will be directly involved in handling the study participants have adequate skills to manage and handle any eventuality that may arise in the course of the duration of the study. Adequate preparation has been made in terms of equipment and other supplies required for the study All the staffs have undergone the protocol training and are well conversant with the study design and procedures.</div>\n</div>\n<p>\n  </p>\n
      • other_details_explanation<p>\n The trial is to be conducted in Kenya due to the high prevalence of HIV and malaria.</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<ol>\n <li>\n KEMRI Scientific & Ethics Review Unit approved this protocol as per letter dated XXXXXXX</li>\n</ol>\n
      • other_details_regulatory_rejected
      • other_details_regulatory_halted
      • estimated_duration2.5 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_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites2
      • multi_country_list
      • data_monitoring_committeeNo
      • total_enrolment_per_siteSiaya - 156\nBondo - 156
      • total_participants_worldwide312
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentYes
      • population_above_18Yes
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male0
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenYes
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameNancy
      • investigator1_middle_name
      • investigator1_family_nameOtieno
      • investigator1_qualificationMA, PhDc
      • investigator1_professional_addressKEMRI-CGHR, Kisumu, Kenya
      • investigator1_telephone+254 720 661 245
      • investigator1_emailnotieno@gmail.com
      • organisations_transferred_No
      • number_participants312
      • notification
      • approval_date04-06-2018
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted08-05-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2024-01-31 09:04:07
      • created2018-02-22 10:14:08
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id413
        • application_id654
        • given_nameSandra
        • middle_nameS
        • family_nameChaves
        • qualificationMD, MSc
        • professional_addressUS Centers for Disease Control and Prevention (CDC), Nairobi, Kenya
        • telephone+254 20 2867 000
        • emailSChaves@cdc.gov
        • created2018-02-22 10:16:45
        • modified2020-05-08 11:23:15
    • SiteDetail(array)
      • 0(array)
        • id530
        • application_id654
        • county_id41
        • site_nameSiaya County Referral Hospital
        • physical_addressSiaya Town
        • contact_detailsP.O. Box 144-60400
        • contact_personNancy Otieno
        • site_capacity(null)
        • misc(null)
        • created2018-02-22 10:16:45
        • modified2020-05-08 11:23:15
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 1(array)
        • id531
        • application_id654
        • county_id41
        • site_nameBondo Sub-County Hospital
        • physical_addressBondo Town
        • contact_detailsP.O Box 595-40601
        • contact_personNancy Otieno
        • site_capacity(null)
        • misc(null)
        • created2018-02-22 11:59:52
        • modified2020-05-08 11:23:15
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
    • Sponsor(array)
      • 0(array)
        • id330
        • application_id654
        • sponsorUS Centers for Disease Control and Prevention, Influenza Division
        • sponsor_typeResearch Institution
        • contact_personSandra S Chaves
        • addressUS Centers for Disease Control and Prevention (CDC), Nairobi, Kenya
        • telephone_number+254 710 602 748
        • fax_number
        • cell_number+254 20 2867 000
        • email_addressschaves@cdc.gov
        • created2018-02-22 10:16:45
        • modified2020-05-08 11:23:15
  • 1(array)
    • Application(array)
      • id637
      • user_id77
      • trial_status_id3
      • abstract_of_study<p>\n The trial will be a Phase 2a, Crossover Trial Evaluating the Safety of and Adherence to a Vaginal Matrix Ring Containing Dapivirine (DPV) and Oral Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) in an Adolescent and Young Adult Female Population.The trial will enrol approximately 300  healthy, HIV-uninfected, sexually active adolescent and young adult females aged 16 - 21 years old (inclusive), who will be followedfor a period of 73 weeks. Participants will be randomized (1:1) to one of two sequences of a vaginal ring (VR) containing 25mg of DPV to be inserted monthly for 24 weeks and 200 mg FTC/300 mg TDF oral tablets taken daily for 24 weeks. After completing the randomized sequence of two study product use periods, participants will then select between the two study products to use in the final 24 weeks of the trial. Participants will be able to choose either or neither study product every 4 weeks during the third product use period. The primary objectives are to evaluate the safety of and adherence to the DPV VR and oral FTC/TDF among adolescent and young women while the secondary objective are to evaluate the acceptability of each product, compare adherance to the product of the participant’s choosing (final phase of the study)  and product preference</p>\n
      • study_title<p align=\"center\">\n <strong>MTN 034</strong></p>\n<p align=\"center\">\n <strong>A Phase 2a Crossover Trial Evaluating the Safety of and Adherence to a Vaginal Matrix Ring Containing Dapivirine and Oral Emtricitabine/Tenofovir Disoproxil Fumarate in an Adolescent and Young Adult Female Population</strong></p>\n
      • laymans_summary(null)
      • short_titleMTN 034
      • protocol_noECCT/17/11/01
      • version_no1.0
      • date_of_protocol02-02-2017
      • study_drug Dapivirine and Oral Emtricitabine/Tenofovir Disoproxil Fumarate
      • disease_conditionHIV
      • product_type_biologicals1
      • product_type_proteins1
      • product_type_immunologicals1
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameDapivirine - not in market
      • product_type_medical_device_name
      • comparator(null)
      • comparator_name(null)
      • comparator_registered(null)
      • comparator_countries(null)
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresseayuo@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_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd(null)
      • applicant_prev_data(null)
      • applicant_stability_data(null)
      • applicant_analysis_cert(null)
      • applicant_pictorial_sample(null)
      • applicant_gcp_training(null)
      • applicant_dsmb_charter(null)
      • applicant_detailed_budget(null)
      • applicant_indemnity_pi(null)
      • applicant_practice_license(null)
      • applicant_registration_ctr(null)
      • applicant_pan_african(null)
      • applicant_hard_copies(null)
      • applicant_signed_checklist(null)
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantBeatrice Nyagol
      • declaration_date117-11-2017
      • declaration_principal_investigatorDr. David Schnabel
      • declaration_date217-11-2017
      • placebo_presentNo
      • study_objectives(null)
      • principal_inclusion_criteria<p>\n Females must meet all of the following criteria to be eligible for inclusion in the study:</p>\n<p style=\"margin-left:.25in;\">\n 1)      Age 16 through 21 years (inclusive) at Enrollment, verified per site standard operating procedures (SOPs).1)      Able and willing to provide informed consent, and if under the legal age of consent be able to provide informed assent and obtain parental or guardian permission/consent, to be screened for and to enroll in MTN-034/IPM 045 (as specified in site SOP).</p>\n<p style=\"margin-left:.25in;\">\n 2)      Able and willing to provide adequate locator information, as defined in site SOPs.</p>\n<p style=\"margin-left:.25in;\">\n 3)      Able and willing to comply with all study procedural requirements.</p>\n<p style=\"margin-left:.25in;\">\n 4)      Per participant report at Screening, post-menarche.</p>\n<p style=\"margin-left:.25in;\">\n 5)      HIV-uninfected based on testing performed at Screening and Enrollment (per protocol algorithms in Appendix II and III).</p>\n<p style=\"margin-left:.25in;\">\n 6)      Per participant report at Screening, history of at least one episode of sexual intercourse in participant’s lifetime.</p>\n<p style=\"margin-left:.25in;\">\n 7)      Negative pregnancy test at Screening and Enrollment. </p>\n
      • principal_exclusion_criteria<p>\n Females who meet any of the following criteria will be excluded from the study:</p>\n<p style=\"margin-left:.25in;\">\n 1.      Per participant report at Screening and Enrollment, intends to do any of the following during the study participation period:</p>\n<p style=\"margin-left:.75in;\">\n 1.1.            become pregnant.</p>\n<p style=\"margin-left:.75in;\">\n 1.2.  access and/or use oral PrEP outside the context of study participation.</p>\n<p style=\"margin-left:.75in;\">\n 1.3.  relocate away from the study site.</p>\n<p style=\"margin-left:.75in;\">\n 1.4.  travel away from the study site for a time period that would interfere with product resupply and study participation.</p>\n<p style=\"margin-left:.25in;\">\n 2.      At Screening or Enrollment, has a positive HIV test.</p>\n<p style=\"margin-left:.25in;\">\n 3.      Diagnosed with UTI, PID, STI or reproductive tract infection (RTI) requiring treatment per WHO guidelines at Screening or Enrollment. 1.      Participant report and/or clinical evidence of any of the following:</p>\n<p style=\"margin-left:.75in;\">\n <strong>a.      </strong>Known adverse reaction to any of the study products (ever).</p>\n<p style=\"margin-left:.75in;\">\n <strong>b.      </strong>Known adverse reaction to latex and polyurethane (ever).</p>\n<p style=\"margin-left:.75in;\">\n <strong>c.       </strong>Symptoms suggestive of acute HIV infection at Screening or Enrollment.</p>\n<p style=\"margin-left:.75in;\">\n <strong>d.      </strong>Non-therapeutic injection drug use in the 12 months prior to Enrollment.</p>\n<p style=\"margin-left:.75in;\">\n <strong>e.      </strong>Use of HIV PEP and/or PrEP within the 3 months prior to Enrollment.</p>\n<p style=\"margin-left:.75in;\">\n <strong>f.        </strong>Currently breastfeeding.</p>\n<p style=\"margin-left:.75in;\">\n <strong>g.      </strong>Last pregnancy outcome within 8 weeks or less of Enrollment.</p>\n<p style=\"margin-left:.75in;\">\n <strong>h.      </strong>Participation in any other research study involving drugs, medical devices, vaginal products or vaccines within 60 days of Enrollment. (Refer to Co-enrollment Guidelines in primary/main protocol Section 5.4, page 47)</p>\n<p style=\"margin-left:.75in;\">\n <strong>i.        </strong>At Enrollment, as determined by the IoR/designee, has any significant uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease.</p>\n<p>\n  </p>\n<p style=\"margin-left:.25in;\">\n 2.      Has any of the following laboratory abnormalities at Screening Visit:</p>\n<p style=\"margin-left:.75in;\">\n <strong>a.      </strong>Positive for hepatitis B surface antigen (HBsAG).</p>\n<p style=\"margin-left:.75in;\">\n <strong>b.      </strong>Hemoglobin Grade 2 or higher.*</p>\n<p style=\"margin-left:.75in;\">\n <strong>c.       </strong>Calculated creatinine clearance less than 60 mL/min by the Schwartz Equation.</p>\n<p>\n  </p>\n<p>\n <em>Note: Otherwise eligible participants with an exclusionary test may be re-tested during the screening process; re-testing procedure details can be found in the MTN-034/IPM 045 Study Specific Procedures (SSP) Manual. If improvement to a non-exclusionary grade or resolution is documented within 70 days of providing informed assent/consent for screening, the participant may be enrolled. </em></p>\n<p>\n  </p>\n<p style=\"margin-left:.25in;\">\n 3.      Has any other condition that, in the opinion of the IoR/designee, would preclude informed assent/consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives. </p>\n
      • primary_end_points<p>\n 1.       Safety</p>\n<p>\n Grade 2 or higher adverse events (AEs) as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014 and/or Addendum 1 (Female Genital Grading Table for Use in Microbicide Studies [Dated November 2007])</p>\n<p>\n 2.       Adherence</p>\n<p>\n          i.            Detectable drug levels in blood</p>\n<p>\n Residual drug levels in returned</p>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • 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_other1
      • trial_other_specifyThis study is a multi-center phase II, prospective, two-arm, randomized, open-label study to evaluate the safety of and adherence to a silicone elastomer vaginal matrix ring containing DPV and oral FTC/TDF in an adolescent and young adult female population within MTN CRSs around the world, including sites in Kenya, Zimbabwe,Uganda and South Africa.
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n DR. Eunice OUMA - study doctor</p>\n<p>\n Dr. Victor Mudhune - Pharamacist</p>\n<p>\n Beatrice Nyagol - study coordinator</p>\n<p>\n David Schnabel - site leader</p>\n
      • other_details_explanation<p>\n it is being conducted in Both</p>\n
      • other_details_regulatory_notapproved<p>\n None</p>\n
      • other_details_regulatory_approved<p>\n Kenya - Kisumu CRS  date of approval - 8th Nov 2017</p>\n<p>\n Uganda - one site</p>\n<p>\n Zimbabwe - one site</p>\n<p>\n South Africa - two sites</p>\n<p>\n Information on the sites are confidential and because the sites are autonomous they do not wish to share their information.</p>\n
      • other_details_regulatory_rejected
      • other_details_regulatory_halted
      • estimated_duration3 years
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindNo
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overYes
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorto evaluate the safety of
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKISUMU CRS
      • single_site_physical_addressOFF KAKAMEGA RD. JOOTRH HOSPITAL GROUNDS
      • single_site_contact_personDR. MUMBI MAKANGA
      • single_site_telephone254-700-752822
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states4
      • number_of_sites
      • multi_country_listKENYA, UGANDA, TANZANIA AND ZIMBABWE
      • data_monitoring_committeeYes
      • total_enrolment_per_site60 women
      • total_participants_worldwide300
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentYes
      • population_above_18Yes
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male0
      • 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_nameESTHER
      • investigator1_middle_nameMUMBI
      • investigator1_family_nameMAKANGA
      • investigator1_qualificationMPH
      • investigator1_professional_addressMEDICAL DOCTOR
      • investigator1_telephone+254 -700-752822
      • investigator1_emailmkanga@kemricdc.org
      • organisations_transferred_No
      • number_participants60 women
      • notification
      • approval_date08-02-2018
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted17-11-2017
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-06-30 14:51:44
      • created2017-11-16 14:52:18
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id407
        • application_id637
        • given_nameESTHER
        • middle_nameMUMBI
        • family_nameMAKANGA
        • qualificationMPH
        • professional_addressMEDICAL DOCTOR
        • telephone+254-700-752822
        • emailmkanga@kemricdc.org
        • created2017-11-16 15:00:31
        • modified2017-11-17 12:31:44
    • SiteDetail(array)
      • 0(array)
        • id517
        • application_id637
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2017-11-16 15:00:31
        • modified2017-11-17 12:31:44
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id325
        • application_id637
        • sponsorNIH DAIDS
        • sponsor_type(null)
        • contact_personConnie Celum, MD,MPH
        • addressUW -ICRC
        • telephone_number206-520-3824
        • fax_number
        • cell_number206-520-3824
        • email_addressccelum@U.washington.edu
        • created2017-11-16 15:00:31
        • modified2017-11-17 12:31:44
  • 2(array)
    • Application(array)
      • id633
      • user_id799
      • trial_status_id5
      • abstract_of_study<p>\n Antimicrobial resistance (AMR) has become a major issue in global health. Despite progress in the reduction of under 5 mortality rates in recent decades, the proportion of neonatal deaths occurring within this age group has increased, with almost one quarter of all neonatal deaths occurring due to serious bacterial infection. Common bacteria causing neonatal sepsis are now exhibiting widespread resistance to several classes of antibiotics. There is an urgent need to discover new, effective treatments and re-evaluate existing therapeutic agents to treat infections potentially caused by multi-drug resistant (MDR) pathogens. Gram-negative bacteria (GNB) predominate as the cause of neonatal sepsis, and are increasingly associated with high rates of resistance to the currently recommended WHO empirical therapy regimen of ampicillin/penicillin and gentamicin. There is therefore a need to develop an updated empiric regimen with improved efficacy in the context of increasing MDR sepsis in neonates. New antimicrobials under development will be expensive once licensed, and there are currently virtually no planned trials to assess their efficacy in neonates in low- and middle-income countries (LMICs).</p>\n<p>\n One potential strategy is utilising an existing off-patent (and therefore affordable) antibiotic available in intravenous and oral formulations – fosfomycin. Fosfomycin has a wide spectrum of activity against Gram-positive and Gram-negative bacteria causing neonatal sepsis. It is mainly used for resistant urinary tract infections in adults, but has licenced neonatal and paediatric doses in Europe (though dosing regimens vary between countries). Both oral and IV formulations are available. A large clinical trial to assess the efficacy of a fosfomycin plus an aminoglycoside combination (compared to the current WHO recommended ampicillin and gentamicin) is anticipated, including sites in Kenya. The ultimate aim is for fosfomycin to be included in the WHO Essential Medicines List for children (EMLc) and be available for use in developing countries, where rates of resistance to ampicillin and gentamicin have been estimated at over 40%. The first steps before this trial are to clarify the pharmacokinetics (PK) and safety profile of fosfomycin in neonates, as well as generating further information regarding local patterns of bacterial susceptibility to fosfomycin. The aim of this study is to fulfil both these steps. Fosfomycin (IV and oral) PK will be investigated among 60 babies admitted to hospital and being treated for presumed sepsis; administered alongside the standard antibiotics. Another 60 babies receiving standard treatment only (without PK sampling) will be monitored in the same way to compare adverse events. In the laboratory at CGMR-C, previoiusly archived bacterial isolates will be tested for their sensitivity to fosfomycin.</p>\n
      • study_title<p>\n Intravenous and Oral Fosfomycin in Hospitalised Neonates with Clinical Sepsis: an open-label safety and pharmacokinetics study</p>\n
      • laymans_summary<p>\n Among babies presenting with signs of serious infection, or who develop these signs whilst in hospital, bacterial resistance to the antibiotics that are normally used is increasing. This means that babies with infections may be at a higher risk of dying. In Africa, alternative antibiotics are often expensive and may themselves cause the bacteria to become resistant. Therefore, new treatment strategies are needed. Fosfomycin is a potentially inexpensive antibiotic that is licenced for use in children in Europe and may be useful to resource-poor countries. It has a good safety profile in children and is expected to be effective against infections that do not respond to the currently used antibiotics. However, more information is needed to inform how fosfomycin should be used in babies in Kenya.</p>\n<p>\n We wanted to find out what doses of fosfomycin would be most suitable for sick newborns in Kenya in order to optimise its use in an effective and safe way. We also wanted to find out how well local bacteria that have been previously found (and stored) from patients at Kilifi County Hospital are able to be killed by fosfomycin.</p>\n<p>\n The study took place in Kilifi County Hospital, Kilifi, Kenya.</p>\n<p>\n The study measuring the levels of antibiotics in newborn babies, included 120 babies admitted to the hospital with presumed infection. Sixty-one (61) of these babies were given fosfomycin in addition to standard treatment and drug levels measured; the other 59 received standard treatment only.</p>\n<p>\n We asked parents and guardians of all babies aged 28 days or less who were admitted to Kilifi County Hospital with signs of infection to participate, unless they were being transferred from another hospital, already received other antibiotics by injection, were very sick or premature, or had abnormally high salt (sodium) levels in their blood.</p>\n<p>\n After providing information and answering any questions, informed consent was requested from the child’s parent or guardian. A doctor or study clinical officer examined the baby and took the usual admission investigations, then prescribed the two antibiotics that are currently recommended by the WHO for the treatment of presumed infection in babies (ampicillin and gentamicin).</p>\n<p>\n Half of the babies were selected randomly to receive intravenous fosfomycin as well as the standard antibiotics. The nurse or clinical officer then took two blood samples to check fosfomycin levels. After a minimum of four doses of intravenous (IV) fosfomycin (over 48 hours), when their condition improved and they were tolerating feeds by mouth, the baby was then changed on to oral fosfomycin. A further two blood samples were collected after the first oral dose of fosfomycin, including one to check the kidney and liver function and level of salts in the blood (which is currently a routine investigation). Each of these blood samples was approximately 0.5ml, giving a total for this research of  approximately 2.5ml (half a teaspoon) for checking the drug levels, and a further 1ml (a quarter of a teaspoon) for checking the level of salts in their blood.</p>\n<p>\n For all babies, a blood test was taken (which is normally part of routine care) at around 48 hours to check the blood count, kidney and liver function and level of salts in the blood. If a baby had a lumbar puncture as part of their normal treatment (if their doctor was concerned about an infection in their brain), the fosfomycin level in the fluid surrounding their brain was also checked.</p>\n<p>\n The babies were closely followed by the study team, working together with the hospital staff to provide the best care available in the hospital. On day 7, any babies who remained as inpatients had a blood test to check blood count, kidney and liver function and level of salts in the blood (and 0.5ml drawn for fosfomycin levels in the group receiving this antibiotic). Breastfeeding and health counselling was given according to national guidelines. All babies were followed up in the outpatients’ clinic 28 days after their presentation to hospital and parents/guardians could also phone the study team directly on a study-specific mobile phone, or bring the baby to the ward prior to that review, in case of health concerns.</p>\n<p>\n Additional staff (clinical officers and nurses) were recruited to undertake study duties and assist in general care on the ward, adding to the staff available. Training was enhanced for all paediatric ward staff on the treatment of babies presenting with infections, and on the prevention of infections within the hospitals. We also made available additional antibiotics as needed, if a baby continued to have signs of infection despite treatment or remained unwell. Drawing a blood sample carried the potential risks of bruising to the vein or infection, and careful training on procedures was done to help prevent these. There was a small risk of the baby having high levels of salt (sodium) in their blood due to the salt content of the fosfomycin injection. Improved monitoring of kidney function and blood salt levels was done to offset these risks.</p>\n<p>\n This study done is leading up to a large clinical trial assessing how effective fosfomycin is to treat babies with infections, and if it is effective, will support efforts to make fosfomycin available at low cost for Kenya and other countries.  This will help babies to be more effectively treated when bacteria are resistant to the currently used antibiotics.</p>\n<p>\n  </p>\n
      • short_titleNeo-Fosfo
      • protocol_noECCT/17/10/01
      • version_noV1.1
      • date_of_protocol23-08-2017
      • study_drugFosfomycin (Fosfocina and Fomicyt)
      • disease_conditionNeonatal Sepsis
      • 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_nameFosfomycin
      • product_type_medical_device_name
      • comparator(null)
      • comparator_name(null)
      • comparator_registered(null)
      • comparator_countries(null)
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressecorreia@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_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd(null)
      • applicant_prev_data(null)
      • applicant_stability_data(null)
      • applicant_analysis_cert(null)
      • applicant_pictorial_sample(null)
      • applicant_gcp_training(null)
      • applicant_dsmb_charter(null)
      • applicant_detailed_budget(null)
      • applicant_indemnity_pi(null)
      • applicant_practice_license(null)
      • applicant_registration_ctr(null)
      • applicant_pan_african(null)
      • applicant_hard_copies(null)
      • applicant_signed_checklist(null)
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantDr Monique Wasunna
      • declaration_date103-10-2017
      • declaration_principal_investigatorProf James Berkely
      • declaration_date203-10-2017
      • placebo_presentNo
      • study_objectives(null)
      • principal_inclusion_criteria<p>\n Criteria for inclusion of subjects (for pharmacokinetics):</p>\n<p>\n Neonates defined as:</p>\n<p>\n • Age 0 to 28 days inclusive</p>\n<p>\n • Weight >1500g</p>\n<p>\n • Born (an estimated) >34 weeks gestation (calculated as per the Ballard Maturational Assessment)</p>\n<p>\n • Admitted to hospital and eligible to receive IV antibiotics, according to national guidelines</p>\n<p>\n All neonates presenting to Kilifi County Hospital meeting the above criteria will be screened for inclusion in a systematic recruitment process</p>\n
      • principal_exclusion_criteria<p>\n Criteria for exclusion of subjects:</p>\n<p>\n • Baseline sodium level > 150mmol/L</p>\n<p>\n • Baseline creatinine >150 micromol/L</p>\n<p>\n • Presenting with severe (grade 3) Hypoxic Ischaemic Encephalopathy (HIE), defined as per Sarnat and Sarnat44 as a stuporous, flaccid infant (with or without seizure activity) with suppressed brainstem and autonomic functions and absent reflexes</p>\n<p>\n • Requiring cardiopulmonary resuscitation on admission</p>\n<p>\n • Jaundice requiring exchange transfusion</p>\n<p>\n • Admitted as a transfer after an overnight inpatient stay at another hospital</p>\n<p>\n • Known allergy or contraindication to fosfomycin</p>\n<p>\n • A specific clinical indicatio</p>\n
      • primary_end_points<p>\n Estimation of the pharmacokinetic disposition and absorption parameters of IV and oral fosfomycin in neonates with clinical sepsis with sufficient precision such that a dose schedule can be recommended for a future efficacy trial.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy0
      • 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_other1
      • trial_other_specifyPharmacokinetic and Pharmacodynamic (safety)
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n KEMRI-Kilifi WTRP is a multi disciplinary research facility with over 600 employees engaged in the facility at Kilify, including clinical officers, nursing staff, research officers, laboratory scientists and field workers.</p>\n<p>\n The clinical facilities include a functional High Dependency Unit. For neonates (our study population), this includes the provision  of emergency medical facilities, incubator care, oxygen and saturation monitoring, phototherapy for jaundice, parenteral medication administration and feeding support. The site is staffed by 2 medical officers at all times and 8 nursing staff including a clinical nurse specialist (also a study investigator).</p>\n<p>\n The study will be coordinated by a number of local investigators:</p>\n<p>\n Professor Jay Berkley, Professor of Paediatric Infectious Disease, FRCPCH FMedSci</p>\n<p>\n Dr Christina Obiero: Clinical Research Officer (MBChB), Clinical Research Fellow</p>\n<p>\n Dr Phoebe Williams: MBBS (Hons), MSc, Dip. Paeds</p>\n<p>\n Dr Neema Mturi: Paediatrician (MBChB)</p>\n<p>\n Dr Claire Gordon: Clinical Microbiologist MBBS PhD</p>\n<p>\n Dr Martin Ongas: Research Fellow, BSc Analytical Sciences</p>\n<p>\n Mr Johnstone Thitiri: Clinical Trials Coordinator, BSc, MSc</p>\n<p>\n Ms Sheila Murunga: Clinical Trial Data Manager, BSc Apllied Statistics</p>\n<p>\n Ms Mwananvua Boga: Clinical Nurse, Consultant in Intensive Care Medicine, RN, MSc</p>\n<p>\n Mr Joseph Waichungo: Microbiology Research Scientist, BSc, MSc</p>\n
      • other_details_explanation<p>\n Neonatal sepsis has a high risk of morbidity and mortality. The current WHO and national guidelines recommend antibiotics to which resistance is reported in neonatal populations, although the available data is limited. Research on alternative empirical regimens for neonatal sepsis which are affordable, safe and cost-effective, with a step-down oral option, is needed. AMR is an issue of global public health concern and is one of the WHO’s global health prority areas. Understanding the benefits, risks, MIC capacity and PK of fosfomycin will influence global policy on the case management of neonates with sepsis in Kenya and international settings.</p>\n
      • other_details_regulatory_notapproved<p>\n None</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 None</p>\n
      • estimated_duration6 months
      • 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_comparatorampicillin and gentamycin
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherYes
      • design_controlled_medicinal_specifyAmpicillin, Gentamicin
      • single_site_member_stateYes
      • location_of_areaKEMRI-WTRP
      • single_site_physical_addressKEMRI CGMR-Coast, PO Box 230-80108, Kilifi, Kenya
      • single_site_contact_personDr Phoebe Williams
      • single_site_telephone+254 740 310 773
      • multiple_sites_member_stateNo
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_siteNA single site
      • total_participants_worldwideNA single site
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornYes
      • population_newbornYes
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18No
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • 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_specifyNeonates
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameJames
      • investigator1_middle_nameA
      • investigator1_family_nameBerkley
      • investigator1_qualificationFRCPCH FMedSci
      • investigator1_professional_addressKEMRI CGMR-Coast PO Box 230-80108, Kilifi, Kenya
      • investigator1_telephone+254 720 867 011
      • investigator1_emailjberkley@kemri-wellcome.org
      • organisations_transferred_Yes
      • number_participants120
      • notification
      • approval_date18-12-2017
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted05-10-2017
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<div>\n Objectives:</div>\n<div>\n The primary objective was to improve the understanding of the pharmacokinetics (PK) and safety of fosfomycin amongst newborns aged ≤28 days hospitalised with clinically diagnosed sepsis and provide detailed information regarding the antimicrobial susceptibility of local invasive bacteria to fosfomycin:</div>\n<div>\n • To estimate the PK disposition parameters of intravenous (IV) and oral (PO) fosfomycin in neonates.</div>\n<div>\n • To assess the safety of fosfomycin, particularly with regard to possible elevation of sodium after 48 hours of IV fosfomycin administration in neonates.</div>\n<div>\n • To estimate the PO bioavailability (F) of fosfomycin in neonates.</div>\n<div>\n • To generate preliminary data on the safety of PO fosfomycin in neonates.</div>\n<div>\n • To generate a recommended dosing schedule for future IV and PO fosfomycin efficacy trials.</div>\n<div>\n • To collect information regarding the tolerability of PO fosfomycin.</div>\n<div>\n The secondary objective was to gain information regarding susceptibility patterns of local bacterial species to fosfomycin.</div>\n<div>\n <div>\n  </div>\n <div>\n Methodology:</div>\n <div>\n A randomised controlled trial evaluating the safety and PK of IV and PO fosfomycin (in particular sodium levels and adverse events [AEs]) compared to the standard of care (SOC) antibiotics (ampicillin/gentamicin) among neonates admitted to a rural hospital in Kenya and eligible for IV antibiotics under current Kenya national guidelines.</div>\n <div>\n  </div>\n <div>\n <div>\n Number of Subjects (planned and analysed):</div>\n <div>\n Planned: 120, Analysed: 120</div>\n <div>\n  </div>\n <div>\n <div>\n Diagnosis and Main Criteria for Inclusion: Parents and guardians of all babies aged 28 days or less who were admitted to Kilifi County Hospital with signs of infection were asked to consent for their child to participate, unless they were being transferred from another hospital, already received other antibiotics by injection, were very sick or premature, or had abnormally high salt (sodium) levels in their blood.</div>\n <div>\n Criteria for inclusion of subjects (for pharmacokinetics):</div>\n <div>\n Neonates were defined as:</div>\n <div>\n • Age 0 to 28 days inclusive.</div>\n <div>\n • Weight >1500 g.</div>\n <div>\n • Born (an estimated) >34 weeks gestation (calculated as per the Ballard Maturational</div>\n <div>\n Assessment).</div>\n <div>\n • Admitted to hospital and eligible to receive IV antibiotics, according to national guidelines.</div>\n </div>\n <div>\n  </div>\n <div>\n <div>\n Test Product:</div>\n <div>\n Fosfomycin or SOC (ampicillin + gentamicin)</div>\n <div>\n  </div>\n <div>\n <div>\n Dose and Mode of Administration:</div>\n <div>\n 120 subjects were randomised 1:1 to SOC antibiotics plus up to 7 -days of fosfomycin (n=61); or SOC (n=59) antibiotics only (ampicillin 50 mg/kg twice daily and gentamicin 3 mg/kg for babies <2 kg or 5 mg/kg for babies >2 kg once daily for 7 days, as per Kenyan guidelines).</div>\n </div>\n <div>\n  </div>\n <div>\n <div>\n Duration of Treatment:</div>\n <div>\n IV fosfomycin was given for at least 48 hours together with SOC (ampicillin + gentamicin) then changed to PO fosfomycin, once the baby was able to tolerate oral medication to complete a total of 7 days of fosfomycin (or until the baby was discharged).</div>\n <div>\n  </div>\n <div>\n <div>\n Criteria for Evaluation:</div>\n <div>\n Efficacy:</div>\n <div>\n Not applicable. All neonates enrolled received SOC antibiotics, so there were no efficacy concerns /analysis. Children were monitored closely for toxicity and the study drug stopped in individual cases if warranted medically.</div>\n <div>\n Safety:</div>\n <div>\n Safety was assessed based on the following variables:</div>\n <div>\n • AEs and serious adverse events (SAEs).</div>\n <div>\n • Haematology and serum chemistry including sodium.</div>\n <div>\n • Physical examination.</div>\n <div>\n • Vital signs.</div>\n <div>\n  </div>\n <div>\n <div>\n Statistical Methods:</div>\n <div>\n • PK modelling and dosing simulations were undertaken by non-linear mixed-effects modelling using NONMEM® software.</div>\n <div>\n • Shift tables were used to present changes in biological parameters between baseline and Day 2 and baseline and Day 7 (if available).</div>\n <div>\n • Software analysis was done using STATA version 15.1.</div>\n <div>\n  </div>\n <div>\n <div>\n Pharmacokinetic Results:</div>\n <div>\n A 3 compartment population PK model was developed using the IV, PO and cerebrospinal fluid (CSF) PK data. Weight, post menstrual age (PMA), postnatal age on clearance, and CSF protein on CSF uptake were identified as covariates during model development.</div>\n <div>\n  </div>\n <div>\n Safety Results:</div>\n <div>\n Overall, the AEs recorded during the study were all considered unrelated to fosfomycin or SOC. AEs (any grade) were less frequent in the SOC + fosfo group. There were 7 unrelated deaths (4 in the SOC + fosfo group) due to disease progression or underlying conditions. Two subjects (1 in the SOC and 1 in the SOC + fosfo group) experienced 3 SAEs (neonatal meningitis, patent foramen ovale and worsening of sepsis) that resulted in study discontinuation.</div>\n <div>\n No significant abnormalities were recorded from clinical laboratory parameters or vital signs throughout the study for both treatment groups. There was no clinically significant difference between the 2 treatment groups with regard to plasma sodium or potassium levels, liver function or renal function at 3 time points (baseline, Day 2 or Day7).</div>\n <div>\n  </div>\n <div>\n Conclusions:</div>\n <div>\n The 3-compartment population PK model adequately described the observed plasma and CSF exposure, which enables estimation of all model parameters with reasonable levels of precision. Weight, PMA, postnatal age on clearance, and CSF protein on CSF uptake were identified as covariates during model development.</div>\n <div>\n Based on safety results, IV and PO fosfomycin at study dose levels could be considered as well tolerated in neonates.</div>\n </div>\n </div>\n <div>\n  </div>\n </div>\n <div>\n  </div>\n </div>\n </div>\n </div>\n</div>\n<p>\n  </p>\n
      • implication_results<p>\n This clinical trial provides a significant step towards improving treatment regimens for neonatal sepsis. Adding IV and oral fosfomycin to the currently recommended WHO first line antibiotics was not associated with an increased frequency of adverse events. Specifically, IV fosfomycin did not affect plasma sodium at the dose evaluated (100mg/kg twice daily). A small reduction in plasma potassium at day 2 is unlikely to be of clinical significance. This dose is consistent with the range of doses recommended by the EMA. Oral fosfomycin was well-tolerated without evidence of osmotic diarrhoea compared to standard of care.</p>\n<p>\n Our main pharmacokinetic finding was that in, in common with other antimicrobial agents, postnatal age was a key covariate in describing changes in the clearance of fosfomycin, this effect was distinct from gestational age and weight effects. For neonates aged >7 days it is likely that higher IV doses than 100mg/kg used in our study are required to promote bactericidal activity, whereas bacteriostasis could be achieved (<strong>Figure 3</strong>). Resistance suppression could only be achieved with the most sensitive of organisms (MIC <0.5mg/L).</p>\n<p>\n Both these findings point to a need to use fosfomycin in combination with another antimicrobial. Whilst our data do not suggest safety concerns at this higher dose, monitoring electrolytes where this is possible may be helpful in confirming this. This higher dose is also consistent with the recently revised EMA dosing recommendations for fosfomycin for infants and neonates. The presence of fosfomycin-inactivating enzymes in transferrable plasmids also necessitates the use of fosfomycin as a combination to reduce the spread of Fosfomycin resistance. Our estimates are based on limited <em>in vitro </em>pharmacodynamic data and initial studies evaluating fosfomycin in combination with other antibiotics including beta lactams and aminoglycosides using hollow fibre infection model have demonstrated that antimicrobial combinations could delay the emergence of resistance.45,46 Further clinical trials to evaluate the use of such combinations in neonatal sepsis in the LMIC setting incorporating fosfomycin are also under development.</p>\n<p>\n To our knowledge this is the first study to enable model-based estimation of fosfomycin oral bioavailability using a crossover design in neonates, a key factor in properly managing any oral step-down therapy. This study showed that even at higher per kg doses fosfomycin absorption occurs to a greater extent and at a faster rate in neonates than in healthy adult receiving the equivalent (calcium) salt form.49 While only a small amount of CSF data was collected, it has provided good evidence that fosfomycin can cross the meninges in neonates, achieving appreciable concentrations in the CSF. The intention however is to collect further data before making conclusions regarding fosfomycin dosing for meningitis.</p>\n<p>\n In light of fosfomycin’s favourable susceptibility profile against community and hospital acquired organisms,this trial provides the basis on which to evaluate the efficacy and cost-effectiveness of fosfomycin within combination therapy in multiple clinical settings compared to current standard of care either as part of an empiric regimen in hospitalized neonates at high risk of sepsis due to multidrug resistant bacteria or as part of a combination regimen to treat microbiologically-confirmed carbapenem resistant infections.</p>\n<p>\n Our trial has limitations; single-centre recruitment and exclusion of the most unwell neonates at enrolment was judged important given the very limited prior information in neonates but may limit generalisability. Strengths of this trial include a low loss to follow-up rate, standardised observation and the high proportion of PK samples collected with robust timing and dosing information – a logistically challenging exercise in any setting.</p>\n<p>\n Increasing AMR in a population who may die rapidly as a result of inadequate antimicrobial coverage is of concern given the shortage of new antibiotics in the pipeline. Fosfomycin offers potential as part of an affordable regimen with ease of administration (over a short infusion) and a simple twice daily dosing schedule.</p>\n<p>\n  </p>\n
      • quantity_imported828 bottles
      • quantity_dispensed422 bottles
      • quantity_destroyed828 bottles- 422 bottles used and 406 bottles unused
      • quantity_exported0
      • balance_site0
      • final_date0000-00-00
      • modified2023-09-21 12:29:31
      • created2017-09-18 12:41:37
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    • InvestigatorContact(array)
      • 0(array)
        • id406
        • application_id633
        • given_nameJames
        • middle_nameA
        • family_nameBerkley
        • qualificationFRCPCH FMedSci
        • professional_addressKEMRI CGMR-Coast PO Box 230-80108, Kilifi, Kenya
        • telephone+254 720 867 011
        • emailjberkley@kemri-wellcome.org
        • created2017-09-19 15:03:51
        • modified2017-10-05 15:42:44
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        • id516
        • application_id633
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        • created2017-09-19 15:03:51
        • modified2017-10-05 15:42:44
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id324
        • application_id633
        • sponsorDrugs for Neglected Diseases initiative (DNDi)
        • sponsor_type(null)
        • contact_personDr Monique Wasunna
        • addressTetezi Towers, 3rd Floor, George Padmore Rd, Kilimani, PO BOX 21936-00505, Nairobi, Kenya
        • telephone_number+254 20 3995000
        • fax_number
        • cell_number+254 20 3995022
        • email_addressmwasunna@dndi.org
        • created2017-09-19 15:03:51
        • modified2017-10-05 15:42:44
  • 3(array)
    • Application(array)
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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=\"\" 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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
      • balance_site512
      • final_date0000-00-00
      • modified2025-02-28 14:30:36
      • created2017-09-14 15:53:31
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id401
        • application_id632
        • given_nameAaron
        • middle_name
        • family_nameSamuels
        • qualificationMD
        • professional_addressP.O. Box 1578, Kisumu, 40100
        • telephone+254 724 255 633
        • emailamsamuels@cdc.gov
        • created2017-09-14 16:04:14
        • modified2020-03-16 15:05:40
      • 1(array)
        • id402
        • application_id632
        • given_nameSimon
        • middle_name
        • family_nameKariuki
        • qualificationPhD
        • professional_addressP.O. Box 1578, Kisumu, 40100
        • telephone+254 725 389 246
        • emailskariuki@kemricdc.org
        • created2017-09-14 16:08:27
        • modified2020-03-16 15:05:40
    • SiteDetail(array)
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        • county_id41
        • site_nameSiaya County Referral hospital
        • physical_addressSiaya Town
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:04:14
        • modified2020-03-16 15:05:40
        • County(array)
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          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 1(array)
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        • site_nameNgiya Health Center
        • physical_addressSouth East Alego
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
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          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 2(array)
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        • county_id41
        • site_nameKogelo Health Center
        • physical_addressNyangoma Kogelo
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
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          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 3(array)
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        • site_nameTingwangi
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        • contact_detailsTel: 0729 295 803
        • contact_personTel: 0729 295 803
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
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          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 4(array)
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        • site_nameMulaha
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        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
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          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 5(array)
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        • site_nameNyathengo
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        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
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        • County(array)
          • id41
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          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 6(array)
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        • site_nameBal Olengo
        • physical_addressAlego Usonga
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
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        • County(array)
          • id41
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          • created2012-06-15 10:26:56
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    • Sponsor(array)
      • 0(array)
        • id323
        • application_id632
        • sponsorGlaxoSmithKline Biologicals
        • sponsor_typeIndustry
        • contact_person
        • addressRue de l’Institut 89, 1330 Rixensart, Belgium
        • telephone_number+32 2 656 81 11
        • fax_number
        • cell_number+32 2 656 81 11
        • email_addressinfo@gskbio.com
        • created2017-09-14 16:04:14
        • modified2020-03-16 15:05:40
  • 4(array)
    • Application(array)
      • id625
      • user_id77
      • trial_status_id3
      • abstract_of_study<p style=\"margin-left:1.5in;\">\n This is a phase II, prospective, open-label study to measure the effects of early antiretroviral therapy (ART) on the establishment of HIV-1 reservoir and HIV-1-specific immunity.  Participants with acute HIV-1 infection (AHI) will have an enrollment visit that will include the immediate initiation of ART. The primary endpoint is cell-associated HIV-1 DNA (CAHD) in 5 million blood-derived CD4+ T-cells assayed by quantitative PCR (qPCR) at week 48.</p>\n<p style=\"margin-left:1.5in;\">\n  </p>\n<p style=\"margin-left:1.5in;\">\n Participants who demonstrate no detectable CAHD in 5 million blood-derived CD4+ T- cells at week 48 and a comparative subset of participants who have detectable CAHD will be offered and consented for optional leukapheresis or large volume blood collection, cerebrospinal fluid collection via lumbar puncture, and gut biopsy via flexible sigmoidoscopy. Participants may agree to one or more of these optional procedures, which will be performed at any time from week 60 to week 72 in willing participants.</p>\n<p>\n  </p>\n<p style=\"margin-left:1.5in;\">\n The Fiebig stage-classification system will be used to characterize the progression from HIV-1 exposure to HIV-1 seroconversion at the time of ART initiation. Plasma and serum samples will be collected at the time of ART initiation and the results of the Fiebig stage at ART initiation will be available within 12 weeks. In this study, the Fiebig I-V stages of interest will be simplified into three study groups (based on HIV-1 antibody diagnostic profile at the time of ART initiation) as described below.</p>\n<p>\n  </p>\n<p style=\"margin-left:2.25in;\">\n Group 1:    Fiebig I/II (non-reactive HIV-1 antibody)</p>\n<p style=\"margin-left:2.25in;\">\n Group 2:    Fiebig III/IV (reactive HIV-1 antibody and negative or indeterminate results on the Western blot or Geenius HIV-1/HIV-2)</p>\n<p style=\"margin-left:2.25in;\">\n Group 3:    Fiebig V (reactive HIV-1 antibody and positive Western blot or Geenius HIV-1/HIV-2 without p31 band)</p>\n<p style=\"margin-left:157.5pt;\">\n  </p>\n<p style=\"margin-left:1.5in;\">\n It is possible that a small number of participants will be determined to be in Fiebig VI (positive Western blot or Geenius HIV-1/HIV-2 with p31 band) based on analysis of the entry samples even though these participants are not specifically targeted for enrollment in this study. Participants who are determined to be in Fiebig VI will be followed until study week 24, allowing ample time for them to pursue alternative sources for ART.</p>\n<p style=\"margin-left:1.5in;\">\n  </p>\n<p style=\"margin-left:1.5in;\">\n The Clinical Management Committee of the A5354 protocol team will review the Fiebig staging and primary endpoint determinations and ensure that these results are communicated to the site, as described in the study’s Manual of Procedures.</p>\n<p>\n  </p>\n<p style=\"margin-left:1.5in;\">\n <u>DURATION</u>                 Up to 72 weeks</p>\n<p>\n  </p>\n<p style=\"margin-left:1.5in;\">\n <u>SAMPLE SIZE</u>            A total of 150 participants will be enrolled (50 in each study group). Up to 25 eligible participants will be asked to consent to each optional procedure.</p>\n<p>\n  </p>\n<p style=\"margin-left:1.5in;\">\n <u>POPULATION</u>            Men and women 18 years and older with AHI.</p>\n<p style=\"margin-left:1.5in;\">\n  </p>\n<p style=\"margin-left:1.5in;\">\n NOTE: Pregnant and breastfeeding women may enroll in the study.</p>\n<p>\n  </p>\n<p style=\"margin-left:1.5in;\">\n <u>REGIMEN</u>                   The antiretroviral (ARV) regimen provided through the study is the single tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF). Other non-study-provided ARV regimens will be allowed for participants who are pregnant, breastfeeding, or unable/unwilling to take EVG/COBI/FTC/TAF, or for participants whose local health care/primary care provider prefers starting a different initial ARV regimen.</p>\n
      • study_title<p align=\"center\">\n <strong>A</strong><strong>5354</strong></p>\n<p align=\"center\">\n  </p>\n<p>\n <strong>Effect of Antiretroviral Treatment Initiated During Acute HIV-1 Infection on Measures of HIV-1 Persistence and on HIV-1-Specific Immune Responses</strong></p>\n
      • laymans_summary(null)
      • short_titleA5354
      • protocol_noECCT/17/09/04
      • version_no1.0
      • date_of_protocol19-04-2016
      • study_drugelvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF).
      • disease_conditionHIV
      • product_type_biologicals1
      • product_type_proteins1
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones1
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparator(null)
      • comparator_name(null)
      • comparator_registered(null)
      • comparator_countries(null)
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresseayuo@kemricdc.org
      • applicant_covering_letter1
      • applicant_protocol1
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      • 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
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      • applicant_addendum0
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      • applicant_complete_form(null)
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      • applicant_pictorial_sample(null)
      • applicant_gcp_training(null)
      • applicant_dsmb_charter(null)
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      • applicant_registration_ctr(null)
      • applicant_pan_african(null)
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      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantBrian Baker, P.O BOX 1578 , KISUMU 40100, Kenya
      • declaration_date128-09-2017
      • declaration_principal_investigatorDr. Brian Baker
      • declaration_date228-09-2017
      • placebo_presentNo
      • study_objectives(null)
      • principal_inclusion_criteria<p style=\"margin-left:1.0in;\">\n 4.1.1      Appropriate documentation from medical records of diagnosis of AHI within 7 days prior to enrollment, that includes one of the following:</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:85.5pt;\">\n a)  A detectable HIV-1 RNA within 28 days prior to study entry <u>AND</u> a non-reactive HIV-1 antibody within 7 days prior to entry</p>\n<p style=\"margin-left:1.0in;\">\n <u>OR</u></p>\n<p style=\"margin-left:85.5pt;\">\n b)  A detectable HIV-1 RNA or a reactive HIV-1 antibody within 28 days prior to study entry <u>AND</u> a negative/indeterminate WB or negative/indeterminate Geenius HIV-1/HIV-2 Supplemental Assay within 7 days prior to entry</p>\n<p style=\"margin-left:1.0in;\">\n <u>OR</u></p>\n<p style=\"margin-left:85.5pt;\">\n c)   A documented non-reactive HIV-1 antibody or negative HIV-1 RNA within 90 days prior to study entry<u> AND</u> a documented reactive HIV-1 antibody or positive WB that is negative for p31 band or a <strong>positive</strong> Geenius HIV-1/HIV-2 Supplemental Assay that is negative for p31 band within 7 days prior to entry</p>\n<p style=\"margin-left:1.0in;\">\n <u>OR </u></p>\n<p style=\"margin-left:85.5pt;\">\n d)  ARCHITECT or GSCOMBO S/CO ≥10 within 7 days prior to entry <u>AND</u> a non-reactive HIV-1 antibody within 7 days prior to entry</p>\n<p style=\"margin-left:1.0in;\">\n <u>OR</u></p>\n<p style=\"margin-left:85.5pt;\">\n e)  ARCHITECT or GSCOMBO S/CO ≥1 within 7 days prior to entry <u>AND</u> a non-reactive HIV-1 antibody within 7 days prior to entry AND a known prior S/CO <0.5 within 90 days prior to entry</p>\n<p style=\"margin-left:1.0in;\">\n <u>OR</u></p>\n<p style=\"margin-left:85.5pt;\">\n f)    ARCHITECT or GSCOMBO S/CO >0.5 but <10 within 7 days prior to entry <u>AND</u> a non-reactive HIV-1 antibody within 7 days prior to entry AND detectable HIV-1 RNA within 7 days prior to entry</p>\n<p style=\"margin-left:85.5pt;\">\n  </p>\n<p style=\"margin-left:1.7in;\">\n NOTE A:  HIV-1 RNA result must be reported from an FDA-approved assay.</p>\n<p style=\"margin-left:.5in;\">\n  </p>\n<p style=\"margin-left:1.7in;\">\n NOTE B:  See section 10.5 for additional information on estimated Fiebig group according to each inclusion criterion in section 4.1.1 above. The protocol team will notify the sites if some criteria may no longer be used because accrual is completed in certain Fiebig groups.</p>\n<p style=\"margin-left:1.7in;\">\n  </p>\n<p style=\"margin-left:1.7in;\">\n NOTE C: Specimens for the testing specified in section 4.1.1 above may be collected on the day of study entry provided the testing result is available prior to enrollment.</p>\n<p>\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.1.2    Men and women age ³18 years.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.1.3    Ability and willingness of candidate to provide written informed consent.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.1.4    Ability and willingness to initiate ART at enrollment.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.1.5    Ability and willingness to participate in scheduled study visits for up to 72 weeks.  </p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.1.6    Female candidates of reproductive potential who are not pregnant at the time of enrollment will receive the study-provided EVG/COBI/FTC/TAF <strong>and </strong>must agree not to participate in the conception process (ie, active attempt to become pregnant, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the female candidate must agree to use at least one reliable form of contraceptive while receiving study-provided treatment.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n Female candidates are considered to be of reproductive potential if any of the following conditions apply:</p>\n<p style=\"margin-left:1.25in;\">\n ·       Candidate has experienced menarche.</p>\n<p style=\"margin-left:1.25in;\">\n ·       Candidate has not undergone bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.</p>\n<p style=\"margin-left:1.25in;\">\n ·       Candidate has not experienced menopause, defined as lack of menstruation within the preceding 12 months.</p>\n<p style=\"margin-left:1.5in;\">\n Acceptable contraceptive methods include:</p>\n<p style=\"margin-left:1.0in;\">\n ·       Condoms (male or female) with or without a spermicidal agent</p>\n<p style=\"margin-left:1.0in;\">\n ·       Diaphragm or cervical cap with spermicide</p>\n<p style=\"margin-left:2.5in;\">\n ·       Intrauterine device</p>\n<p style=\"margin-left:1.0in;\">\n ·       Hormonal contraceptive</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n Female candidates who are not of reproductive potential or whose male partner(s) has documented azoospermia are not required to use contraceptives. Any statement of self-reported sterility or that of her partner must be entered in the source documents. </p>\n<p>\n  </p>\n<p style=\"margin-left:1.5in;\">\n NOTE: Acceptable documentation of lack of reproductive potential is oral or written documentation from the individual.</p>\n<p style=\"margin-left:1.5in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n Female candidates who are prescribed a non-study-provided ARV regimen should discuss the safety of that regimen during conception and pregnancy with the prescribing physician. Such individuals should follow medical guidance regarding any potential need for contraception while using the non-study-provided ARV regimen.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.5in;\">\n NOTE: Pregnant and breastfeeding women may enroll in the study provided that they meet the eligibility requirements and have access to non-study-provided ARV regimens.</p>\n<p>\n  </p>\n
      • principal_exclusion_criteria<p style=\"margin-left:1.0in;\">\n Positive HIV-1 antibody test ≥90 days prior to study entry.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.2.2    Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.2.3    Any acute, chronic, or recent and clinically significant medical condition that, in the opinion of the site investigator, would interfere with adherence to study requirements or jeopardize the safety or rights of the participant.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.2.4    Receipt of an investigational study agent within 28 days prior to enrollment</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.2.5    Chronic or recurrent use of medications that modify host immune response, eg, oral or parenteral steroids, cancer chemotherapy.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.2.6    AHI diagnosis within 60 days after receiving any investigational ARV or HIV-1 vaccine or immune prophylaxis for HIV-1 infection.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:1.0in;\">\n 4.2.7    Initiation of ARVs for pre- and post-exposure prophylaxis within 60 days prior to the diagnosis of AHI.</p>\n<p style=\"margin-left:1.0in;\">\n  </p>\n<p style=\"margin-left:112.5pt;\">\n NOTE: The rationale for this exclusion is to minimize the chance for resistance among individuals who initiate pre-exposure prophylaxis during undiagnosed AHI and subsequently experience viremia.</p>\n<p style=\"margin-left:112.5pt;\">\n  </p>\n
      • primary_end_points<p style=\"margin-left:.5in;\">\n The primary endpoint is CAHD in 5 million blood-derived CD4+ T-cells assayed by qPCR at week 48. Only participants who have not met criteria for permanent study discontinuation, have not missed more than 6 consecutive days of ART and have HIV-1 RNA <50 copies/mL at week 48 will have their primary outcome measure evaluated. If adequate sample and analyzable data are not available from the week 48 visit, week 49 will be used instead.  </p>\n<p style=\"margin-left:112.5pt;\">\n  </p>\n
      • scope_diagnosis1
      • scope_prophylaxis1
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • 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_study1
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Brian Baker - MD</p>\n<p>\n Eunice Ouma MD</p>\n<p>\n Victor Mudhune - Pharmacist</p>\n<p>\n Francis Angira - study Coordinator</p>\n<p>\n Bob Chen - Technical ADvisor</p>\n
      • other_details_explanation<p>\n The study is conducted in the sponsor's country and has most sites.</p>\n
      • other_details_regulatory_notapproved<p>\n None</p>\n
      • other_details_regulatory_approved<p>\n KEMRI- SERU - July 5th 2017</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n None</p>\n
      • estimated_duration72 weeks
      • design_controlled_randomisedNo
      • 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_comparatorelvitegravir/cobicistat/e
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKISUMU CRS
      • single_site_physical_addressOff kisumu - kakamega road
      • single_site_contact_personFrancis Angira
      • single_site_telephone0722834973
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states14
      • number_of_sites
      • multi_country_listKenya, South Africa, Zimbabwe, Malawi,USA,Brazil,Uganda
      • data_monitoring_committeeYes
      • 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_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenYes
      • subjects_nursing_womenYes
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyThe study will be dealing with acute HIV and will be providing ART as indicated to different arms as indicated in the protocol.
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameBrian
      • investigator1_middle_name
      • investigator1_family_nameBaker
      • investigator1_qualificationmedical Doctor
      • investigator1_professional_addressMD
      • investigator1_telephone0728608671
      • investigator1_emailbabker@cdc.gov
      • organisations_transferred_No
      • number_participants10
      • notification
      • approval_date21-03-2018
      • submitted1
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      • deleted_date(null)
      • deactivated0
      • date_submitted28-09-2017
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      • initial_date_submitted(null)
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      • admin_stopped_reason(null)
      • approved2
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      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-06-30 14:51:14
      • created2017-08-24 11:40:15
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id400
        • application_id625
        • given_nameBrian
        • middle_name
        • family_nameBaker
        • qualificationMD
        • professional_addressKEMRI CDC JOOTRH Grounds - box 1578 - Kisumu
        • telephone0728608671
        • emailbbaker@cdc.gov
        • created2017-08-24 11:57:17
        • modified2017-09-28 16:12:34
    • SiteDetail(array)
      • 0(array)
        • id508
        • application_id625
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2017-08-24 11:57:17
        • modified2017-09-28 16:12:34
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id322
        • application_id625
        • sponsorThe National Institute of Allergy and Infectious Diseases
        • sponsor_type(null)
        • contact_person
        • addressUS Military HIV Research Program 6720-A Rockledge Drive, Suite 400 Bethesda, MD 20817
        • telephone_number301-500-3949
        • fax_number
        • cell_number301-500-3949
        • email_addressjananworanich@hivresearch.org
        • created2017-08-24 11:57:17
        • modified2017-09-28 16:12:34
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