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      • id814
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      • abstract_of_study<p>\n In the era of anti-malaria drug resistance and resistance to insecticide treated bed nets, there is an urgent need for a highly efficacious vaccine. We plan to evaluate the immunogenicity and efficacy of candidate malaria vaccines incorporating the sporozoite antigen R21 (<em>P. falciparum</em> circumsporozoite protein co-expressed with hepatitis B antigen) administered as protein-in-adjvuvant with the Matrix M and viral-vectored vaccines expressing the liver antigen TRAP (<em>P. falciparum</em> multiple epitope thrombospondin adhesion protein, ME-TRAP expressed in Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara administered in a heterologous prime-boost regimen). There is evidence of safety and immunogenicity utilising these two vaccines. We plan to conduct a phase IIb trial in malaria-exposed individuals to assess the immunogenicity and efficacy of the two vaccines in the context of controlled human malaria infection<em>. P. falciparum</em> sporozoite challenge, PfSPZ Challenge.</p>\n<p>\n Healthy adults aged between 18-45 years will be recruited to participate in the study after a process of information giving and sensitisation about the study. Those that provide informed consent to participate in the study will be screened to ensure they are in good health based on clinical assessment and laboratory results. Each participant will have blood tests undertaken, and physical and clinical examination to ensure suitability prior to vaccination and PfSPZ Challenge. A total of 64 participants will be enrolled for challenge and divided into four groups as follows: 20 participants to receive R21/Matrix M (R21/MM) with intradermal PfSPZ Challenge; 20 participants to receive viral-vectored ME-TRAP with intradermal PfSPZ Challenge; 10 participants to receive R21/MM with direct venous inoculation PfSPZ Challenge; and 14 participants comprising of the control group with intradermal PfSPZ Challenge. Blood tests and clinical assessments will be conducted to screen out participants with health conditions that may impact participation in the study.</p>\n<p>\n Blood samples will be taken at screening and a day prior to vaccine and PfSPZ Challenge enrolment. Blood will also be taken prior to each vaccination as well as after PfSPZ Challenge administration until diagnosis with malaria, endpoint. A set threshold for malaria diagnosis will be met and once this is achieved, participants will be treated with the recommended anti-malaria drug treatment. Blood samples to assess immunogenicity will be taken prior to vaccination, and throughout the study to assess vaccine-induced immune responses. Efficacy will be assessed in relation to the control group with serial quantitative polymerase chain reaction (PCR) monitoring of parasitaemia during PfSPZ Challenge. A day before PfSPZ Challenge, participants will be enrolled residents at Pwani University where they will be monitored daily up to a period of 25 days depending on when they are diagnosed with malaria. There will be follow-up after exit from residence for up to 90 days after PfSPZ Challenge.</p>\n
      • study_title<p>\n Safety, immunogenicity, and efficacy of R21/Matrix M (R21/MM) and ChAd63/MVA-ME-TRAP in the context of controlled human malaria infection: A Phase IIb Trial in Kenyan Adults.</p>\n
      • laymans_summary<div>\n Lay Title: A study to determine if candidate malaria vaccines are safe, effective, and induce immunity among Kenyan adults.</div>\n<div>\n What is the problem/background? Malaria deaths have fallen with the advent of new drug combinations and widespread use of insecticide treated bed nets, but the hope of malaria eradication is threatened by emerging resistance to these drugs and insecticides. RTS,S, is the only malaria vaccine in advanced clinical development albeit with low efficacy. It is being evaluated for use in an infant vaccine schedule recommended by WHO, while determining the significance of any safety concerns. However, with RTS,S only a small proportion of the vaccine is made up of the malaria parasite protein. We have developed a malaria vaccine candidate, R21, which is also based on the same protein in RTS,S. The majority of RTS,S is composed of the Hepatitis B surface protein which may interfere with the immune response in infants; whereas R21 has very little of this protein on its surface. R21 also induces a good immune response and there is a good case for further clinical development of this vaccine.</div>\n<div>\n What questions are we trying to answer? We plan to evaluate whether the malaria vaccine candidates R21 administered with Matrix M (MM) and ChAd63/MVA-ME-TRAP, are safe and effective in a Controlled Human Malaria Infection (CHMI) and induce good vaccine responses in healthy Kenyan adults (aged 18-45 years). We plan to investigate the immune responses following vaccination and CHMI.</div>\n<div>\n Where is the study taking place, how many people does it involve and how are they selected? The study is taking place in Kilifi County (Ngerenya) as well as at KEMRI-CGMRC where we will recruit and screen healthy adult volunteers. A total number of 64 eligible volunteers will be required after assessment of eligibility at the screening visit to be enrolled for the vaccine efficacy study. This will be done after a programme of sensitization and information giving about the study.</div>\n<div>\n What does the study involve for those who are in it? The following procedures are involved for those who volunteer to participate in the study. Blood samples will be taken at screening, a day prior to vaccine enrolment, prior to each vaccination, and post vaccination, a day before malaria infection, during infection and after infection treatment.</div>\n<div>\n Screening Procedures: For individuals who are screened for potential participation, 8ml of blood will be drawn at the screening visit for serology; haematology; biochemistry and malaria testing. Medical history will also be obtained and a clinical assessment including a check of the functioning of the heart to exclude any significant heart problems. Those that pass screening will be invited to attend a pre-enrolment visit. At the enrolment visit, all eligible volunteers will be re-assessed and a blood sample of 37ml taken for haematology, biochemistry, malaria testing, and immunology.</div>\n<div>\n Vaccine Enrolment and Vaccination Procedures: On the day of enrolment, a total of 64 eligible volunteers will be randomised into one of 4 groups as follows: group 1, receiving R21/MM (N=20); group 2 receiving ChAd63/MVA-ME-TRAP (N=20); group 3, receiving R21/Matrix M (N=10); and group 4 receiving no vaccine (control group). The R21/MM vaccine will be administered as a three-dose regimen at intervals of 28 days (days 0, 28 and 56) whilst the ChAd63/MVA-ME-TRAP will be administered as a prime-boost regimen at days 0 and 56. At each vaccination visit (except for day 0), a blood sample of 33ml will be taken from each of the volunteers. All volunteers in the vaccination groups (groups 1 to 3). Two weeks after each vaccine administration, a blood sample will be taken from each volunteer (30ml or 34ml after the final vaccination). Repeat blood samples may be taken to verify abnormal results. If volunteers are found to have malaria 2 weeks after the final vaccination (day 70), they will be given anti-malarial monotherapy and a blood sample taken post-treatment to test for malaria (4ml). A blood sample from the volunteers in the control group will also be collected at (day 70) for the purposes of checking for malaria and treatment initiated if found positive with a post-treatment sample taken to ensure malaria infection has been cleared.</div>\n<div>\n Malaria Infection Procedures: A clinical assessment will be repeated a day before infection including collection of a urine sample and measurement of weight and height. At this visit, volunteers will be enrolled as residents at Pwani University under medical supervision for up to 25days depending on when they are diagnosed with malaria. This will also include volunteers from the control group who did not go through the vaccination procedures (group 4, N=14). The malaria infection will be given either via the intradermal route-into the skin (groups 1, 2, and 4) or via direct venous injection (into the blood stream) (group 3) of PfSPZ Challenge, which leads to a blood-stage malaria infection after 6.5 days of incubation in the liver. Blood samples will also be taken: a day before the malaria infection (57mls); day five after infection (32mls); twice daily every day from day seven after infection up to the time that signs and symptoms of malaria are detected and malaria treatment initiated and completed (usually between seven to twenty-four days, 238ml); and on days thirty-five and ninety after infection (35ml at each of these time points). A total of 308ml of blood per volunteer will be drawn during this period. Observed treatment for malaria will be administered on the day of diagnosis or after twenty-one days for those who do not develop an infection.</div>\n<div>\n What are the benefits and risks/costs of the study for those involved? Participants may benefit from receipt of the vaccine if it demonstrates that the efficacy in a Kenyan population is favourable and the vaccine is safe. Participants will also have close oversight and treatment support from the study team although this will primarily be for risk monitoring. There will also be wider benefit in the field of malaria vaccine research in building on data available on safety, efficacy and immune responses to R21/MM and ChAd63/MVA ME-TRAP. Controlled human malaria infection challenge via the intradermal route and direct venous injection has been conducted in seventy-eight and one hundred and eighty-four individuals respectively and has been safe and well-tolerated. The first ever controlled malaria infection study in Kenya by intramuscular injection was safely conducted in Nairobi with twenty-eight individuals. We have since conducted a controlled malaria infection study in Kenya by direct venous injection in another one hundred and sixty-one individuals in Kilifi. The risks relate to the possibility of developing an allergic reaction upon administration of the malaria infection. In addition, participants may develop signs and symptoms of malaria after infection which are unpleasant and may develop some side effects to the drugs used to treat the infection. During malaria infection, volunteers are required to be resident in a guest-house for safety monitoring and reduce the risk of acquiring field malaria infections. This is a considerable cost to the volunteers on their time but is a requirement for the study to be successful. There are no direct benefits to individuals participating in this study other than information about their health. There might be a perception of benefit from receipt of a vaccine, clinical assessment and laboratory screening.</div>\n<div>\n How will the study benefit society? Controlled human malaria infection provides a way of studying immunity to malaria in a very detailed way that is not possible using natural infections, and we believe that this step is now necessary to inform vaccine design. This study will also evaluate promising malaria vaccine candidates, which will inform the design of a phase III study, contribute further to the area of malaria research and hopefully provide a possible tool to contribute to future eradication.</div>\n<div>\n When does the study start and finish? </div>\n<div>\n The study will start upon receipt of ethical and regulatory approval; data collection, analysis and write up will take place over 2 years.</div>\n
      • short_titleA study to determine if candidate malaria vaccines are safe, effective, and induce immunity among Kenyan adults.
      • protocol_noECCT/19/11/01
      • version_noVersion 1.1
      • date_of_protocol17-05-2019
      • study_drugR21/MM, ChAd/MVA-ME-TRAP PfSPZ Challenge
      • 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
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressregulatory@kemri-wellcome.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)
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      • applicant_prev_data1
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      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantMelissa Kapulu
      • declaration_date104-11-2019
      • declaration_principal_investigatorMelissa Kapulu
      • declaration_date204-11-2019
      • placebo_presentNo
      • study_objectives<div>\n 2.2. Primary objective(s)</div>\n<div>\n 1. To assess the safety and tolerability of adjuvanted R21/MM and heterologous prime- boost regime of ChAd63-MVA ME-TRAP in healthy adult volunteers.</div>\n<div>\n 2. To assess the safety of intradermal sporozoite infection dose in semi-immune healthy adult volunteers.</div>\n<div>\n 3. To assess the efficacy (occurrence of P. falciparum parasitemia, (assessed by qPCR) of adjuvanted R21 and heterologous prime- boost regime of ChAd63-MVA ME-TRAP against malaria sporozoite challenge, in healthy adult volunteers.</div>\n<div>\n <div>\n 2.3. Secondary objective(s)</div>\n <div>\n 1. To assess humoral immunogenicity generated in individuals of adjuvanted R21(R21/MM) and heterologous prime-boost regime of ChAd63-MVA ME-TRAP at different time points.</div>\n <div>\n 2. To assess cell-mediated immunogenicity by IFN-Æ´ ELISPOT generated in individuals of heterologous prime-boost regime of ChAd63-MVA ME-TRAP at different time points.</div>\n <div>\n 3. To assess any differences in efficacy estimates with ID versus DVI challenge in individuals receiving R21/MM by assessing parasite density dynamics by qPCR.</div>\n <div>\n 4. To measure and compare the parasite growth rates and liver to blood inoculum in individuals receiving DVI versus ID sporozoite challenge in relation to naturally acquired immunity.</div>\n <div>\n 2.4. Tertiary objective(s)</div>\n <div>\n To evaluate cell-mediated immunogenicity using flow cytometry with intracellular cytokine staining and other exploratory immunological end points.</div>\n</div>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n • Healthy adults aged 18 to 45 years</p>\n<p>\n • Able and willing (in the Investigator’s opinion) to comply with all study requirements</p>\n<p>\n • Non-pregnant, non-lactating adult female or adult male</p>\n<p>\n • Agreement to refrain from blood donation during the study</p>\n<p>\n • Use of effective method of contraception for the duration of study for female participants. For those with no contraception, they will be referred for contraception at the relevant health facility. For female participants, we will ask them to attend with their family planning records for verification. Effective contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly, in accordance with the product label. Examples of these include: combined oral contraceptives; injectable progestogen; implants of etenogestrel or levonorgestrel; intrauterine device or intrauterine system; male condom combined with a vaginal spermicide (foam, gel, film, cream or suppository); and male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository)</p>\n<p>\n • Provide written informed consent</p>\n<p>\n • Plan to remain resident in the study area for 1 year following first dose of vaccination</p>\n
      • principal_exclusion_criteria<p>\n • Clinically significant congenital abnormalities as judged by the study clinicians</p>\n<p>\n • Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection; asplenia; recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed).</p>\n<p>\n • Sickle cell disease</p>\n<p>\n • Any history of anaphylaxis in relation to vaccination</p>\n<p>\n • Clinically significant laboratory abnormality as judged by the study clinician</p>\n<p>\n • Blood transfusion within one month of enrolment</p>\n<p>\n • Haemoglobin less than 11.3 g/dl for men and less than 10g/dl for in women, where judged to be clinically significant in the opinion of the investigator.</p>\n<p>\n • Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccine candidate</p>\n<p>\n • Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period
</p>\n<p>\n • Seropositive for hepatitis B surface antigen (HBsAg) or hepatitis C (HCV IgG)</p>\n<p>\n • Use of systemic antibiotics with known antimalarial activity within 30 days of administration of PfSPZ Challenge (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones and azithromycin)</p>\n<p>\n • Women only; pregnancy, or an intention to become pregnant a day before challenge i.e. at C-1</p>\n<p>\n • Any significant disease, disorder or situation which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial</p>\n<p>\n • Confirmed parasite positive by PCR a day before challenge i.e. at C-1.</p>\n<p>\n • Exclusion criteria on day of challenge Acute disease, defined as moderate or severe illness with or without fever (temperature >37.5°C)</p>\n
      • primary_end_points<p>\n Safety:</p>\n<p>\n The specific endpoints for safety and reactogenicity will be actively and passively collected data on adverse events. The following parameters will be assessed for all study groups</p>\n<p>\n 1. Occurrence of solicited local reactogenicity signs and symptoms for 7 days following the vaccination</p>\n<p>\n 2. Occurrence of solicited systemic reactogenicity signs and symptoms for 7 days following the vaccination and occurrence of unsolicited adverse events for 28 days following the vaccination</p>\n<p>\n 3. Change from baseline for safety laboratory measures</p>\n<p>\n 4. Occurrence of serious adverse events during the whole study duration including safety with regards to PfSPZ Challenge administration.</p>\n<p>\n Efficacy:</p>\n<p>\n Venous blood samples will be taken at each study visit during the post-CHMI follow-up period as described above for quantitative PCR (qPCR) for P. falciparum nucleic acids which will be processed within 6 hours of collection. A diagnosis of malaria infection will be made and treatment with anti-malarials commenced immediately for a volunteer satisfying one of the following criteria:</p>\n<p>\n 1. The density of infection rises past a threshold of 500 parasites per µl</p>\n<p>\n 2. The volunteer develops symptoms or signs of illness and an immediate blood film examination shows any evidence of detectable malaria parasites</p>\n<p>\n 3. The volunteer reaches day 21 of monitoring, at which point CHMI will be completed The investigators are able to treat any volunteer for malaria regardless of the qPCR result if they are clinically concerned (and have discussed the case with the Chief Investigator), or a volunteer wishes to withdraw from the study.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Medical officer-1<br />\n Clinical officer - 3<br />\n Nurses -2<br />\n Fieldworkers - 6<br />\n Assistant Research Officer - 1 and Research Officer - 1<br />\n Study Coordinator -1<br />\n Pharmacisit-1<br />\n Data Manager-1<br />\n Data Clerk-2<br />\n The inpatient facility is already staffed with 3 clincians, 1 paediatrician and 20 nurses.<br />\n All staff are trained in basic life support and resuscitation facilitaties are available</p>\n
      • other_details_explanation<p>\n Not Applicable</p>\n
      • other_details_regulatory_notapproved<p>\n Not applicable with only PPB providing regulatory oversight and approval.</p>\n
      • other_details_regulatory_approved<p>\n Not applicable.</p>\n
      • other_details_regulatory_rejected<p>\n Not applicable.</p>\n
      • other_details_regulatory_halted<p>\n Not applicable.</p>\n
      • estimated_duration2 years
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindNo
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorChAd63/MVA-ME-TRAP and no
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKEMRI-Wellcome Trust Research Programme (KWTRP) Centre for Geographic Medical Research - Coast (CGMRC), Kilifi, Kenya.
      • single_site_physical_addressKEMRI-Wellcome Trust Research Programme, Off Bofa Road, Kilifi County Hospital, Kilifi, Kenya
      • single_site_contact_personMelissa Kapulu
      • single_site_telephone+254717501319
      • multiple_sites_member_stateNo
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_site64
      • total_participants_worldwide64
      • 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_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameMelissa
      • investigator1_middle_nameChola
      • investigator1_family_nameKapulu
      • investigator1_qualificationBSc MSc DPhil
      • investigator1_professional_addressKEMRI-Wellcome Trust Research Programme, P. O. Box 230, Kilifi, Kenya 80108
      • investigator1_telephone+254709983463
      • investigator1_emailmkapulu@kemri-wellcome.org
      • organisations_transferred_No
      • number_participants64
      • notification
      • approval_date07-08-2021
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted15-12-2021
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonApplication approved by the experts
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      • balance_site(null)
      • final_date(null)
      • modified2024-08-02 17:52:27
      • created2019-07-17 16:47:36
      • total_sites(null)
      • ecitizen_invoice(null)
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        • id504
        • application_id814
        • given_nameMelissa
        • middle_name
        • family_nameKapulu
        • qualificationBSc MSc DPhil
        • professional_addressKEMRI-Wellcome Trust Research Programme, P. O. Box 230, Kilifi, Kenya 80108
        • telephone+254709983463
        • emailmkapulu@kemri-wellcome.org
        • created2019-07-17 16:51:47
        • modified2021-12-15 04:41:06
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        • id663
        • application_id814
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        • created2019-07-17 16:51:47
        • modified2021-12-15 04:41:06
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id394
        • application_id814
        • sponsorUniversity of Oxford
        • sponsor_typeResearch Institution
        • contact_personAdrian Hill (Chief Invetigator)
        • addressUniversity Offices, Wellington Square, Oxford, OX1 2JD, UK
        • telephone_number+44 (0)1865 611418
        • fax_number
        • cell_number+44 (0)1865 611418
        • email_addressadrian.hill@ndm.ox.ac.uk
        • created2019-07-17 16:51:47
        • modified2021-12-15 04:41:06
  • 1(array)
    • Application(array)
      • id436
      • user_id32
      • trial_status_id5
      • abstract_of_study<div>\n Malaria morbidity and mortality have been reduced substantially as malaria control interventions have been scaled up across Africa, including in Kenya. Nonetheless, malaria continues to cause considerable morbidity and mortality, especially in children under 5 years of age living in sub Saharan Africa.  As we aim for a reduction in malaria burden, and towards malaria elimination, it has become clear that new tools to fight malaria are urgently needed. A highly efficacious vaccine would be an important addition to complement current malaria control measures and to contribute to elimination efforts. Among the different vaccine approaches used to prevent malaria infection, whole Plasmodium falciparum sporozoite (PfSPZ) vaccines have shown consistent, high-level protection in a number of phase I clinical trials. </div>\n<div>\n  </div>\n<div>\n The candidate malaria vaccine, PfSPZ Vaccine, consists of aseptic purified, cryopreserved, radiation-attenuated Plasmodium falciparum (Pf) sporozoites, which when given by direct venous inoculation (DVI) to malaria naïve volunteers in the United States was safe, well tolerated and showed dose-dependent, high protection against controlled human malaria infection.  The Kenya Medical Research Institute and the U.S. Centers for Disease Control and Prevention, in collaboration with NIH and Sanaria, propose to conduct a study to measure safety, immunogenicity and efficacy of this novel candidate malaria vaccine when given to infants from 5 to 12 months inclusive.  The study will be conducted in Siaya County in western Kenya. Initially, in Part 1 of the trial, 120 children will be recruited into an age de-escalation and dose escalation study to document safety of the vaccine in three age groups (children aged 5–12 years, children aged 13 – 59 months, and infants aged 5–12 months) and at the following dosages of sporozoites versus placebo: 1.35 x 105, 2.7 x 105, 4.5 x 105, 9.0 x 105 PfSPZ vaccine (only the higher two doses in children aged 5–12 years), given as a single injection by direct venous inoculation (DVI). Part 1, age de-escalation and dose escalation, will begin with administration of 4.5 x 105 PfSPZ in 12 children aged 5–12 years (8 vaccine, 4 placebo), provided to a limited number of participants each day (for example, approximately 3 participants each day on days 1–4).  The PfSPZ Vaccine dose will only be increased to the next level when safety has been assessed in participants of the first group, and earliest at 14 days after the first injection. At this time, the lowest dose (1.35 x 105) will be administered to children age 13-59 months, with doses doubling every two weeks, after assessment of safety signals, until the final dose of 9.0 x 105 PfSPZ is reached. The lowest dose will be administered to infants 5–12 months after this dosage has shown to be safe in 13-59 months-olds, and doses will be doubled every two weeks, after assessment of safety signals, until the dose of 9.0 x 105 PfSPZ is reached. Overall vaccine doses will only be increased if they are assessed as well tolerated and the safety data are acceptable for further evaluation of the vaccine at a higher dose, applicable to all the age groups. All of these proposed doses have been shown to be well tolerated with no serious safety signals in studies in US adults and, in African adults at the two lowest doses.  Therefore, based on the critical importance of dose in mediating protection with this vaccine, the 2 highest dosages found to be well tolerated will be used for the Part 2 of the trial, which will measure safety and efficacy of the PfSPZ vaccine. The highest well tolerated dosage (likely to be 9.0 x 105 PfSPZ) will be administered by DVI 3 times to 104 infants (group 1), and 4 times to 104 infants (group 2); the second highest dosage (likely to be 4.5 x 105 PfSPZ) will be given 3 times to another study arm of 104 infants (group 3) to document a dose response and to understand whether the lower dose is highly efficacious in this age-category.  The rationale for the amount of PfSPZ Vaccine (4.5 x 105  or  9.0 x 105 PfSPZ), number of doses ( 3 or 4) and intervals between doses ( 4 and 8 weeks) is based on data from ongoing studies in US and African adults for conferring durable immunity and protection, and will be further informed by the dose escalation trial. Another group of 104 infants will receive 3 (n=52; group 4) or 4 (n=52; group 5) doses of normal saline (NS) by direct venous injection as placebo. The dosing interval in all 3 dose groups will be 8 weekly (0, 8,16 weeks), while the doses in the 4 dose groups will be given at 0, 4, 8 and 16 weeks. The main objectives of this study are to measure the safety, tolerability and immunogenicity of PfSPZ Vaccine in infants (measured in Part 1 and Part 2 of this trial) and to determine whether PfSPZ Vaccine administered by DVI to infants provides high-level protection (point estimate >60%) against Pf infection during 6 months following the last vaccine dose when compared to a placebo group (Part 2 of the trial).  A secondary objective will be to measure safety tolerability, immunogenicity and efficacy during 12 months follow-up.</div>\n<div>\n  </div>\n
      • study_title<p>\n Safety, Tolerability and Efficacy of PfSPZ Vaccine Administered by Direct Venous Inoculation (DVI) to Healthy Children and Infants 5 Months through 12 Years of Age Living in an Area of High Malaria Transmission in Western Kenya: Age de-escalation and Dose Escalation and a Double Blind, Randomized Placebo-Controlled Trial for Safety and Efficacy</p>\n
      • laymans_summary<div>\n Malaria morbidity and mortality have been reduced substantially as malaria control interventions have been scaled up across Africa, including in Kenya. Nonetheless, malaria continues to cause considerable morbidity and mortality, especially in children under 5 years of age living in sub Saharan Africa.  As we aim for a reduction in malaria burden, and towards malaria elimination, it has become clear that new tools to fight malaria are urgently needed. A highly efficacious vaccine would be an important addition to complement current malaria control measures and to contribute to elimination efforts. Among the different vaccine approaches used to prevent malaria infection, whole Plasmodium falciparum sporozoite (PfSPZ) vaccines have shown consistent, high-level protection in a number of phase I clinical trials. </div>\n<div>\n  </div>\n<div>\n The candidate malaria vaccine, PfSPZ Vaccine, consists of aseptic purified, cryopreserved, radiation-attenuated Plasmodium falciparum (Pf) sporozoites, which when given by direct venous inoculation (DVI) to malaria naïve volunteers in the United States was safe, well tolerated and showed dose-dependent, high protection against controlled human malaria infection.  The Kenya Medical Research Institute and the U.S. Centers for Disease Control and Prevention, in collaboration with NIH and Sanaria, propose to conduct a study to measure safety, immunogenicity and efficacy of this novel candidate malaria vaccine when given to infants from 5 to 12 months inclusive.  The study will be conducted in Siaya County in western Kenya. Initially, in Part 1 of the trial, 120 children will be recruited into an age de-escalation and dose escalation study to document safety of the vaccine in three age groups (children aged 5–12 years, children aged 13 – 59 months, and infants aged 5–12 months) and at the following dosages of sporozoites versus placebo: 1.35 x 105, 2.7 x 105, 4.5 x 105, 9.0 x 105 PfSPZ vaccine (only the higher two doses in children aged 5–12 years), given as a single injection by direct venous inoculation (DVI). Part 1, age de-escalation and dose escalation, will begin with administration of 4.5 x 105 PfSPZ in 12 children aged 5–12 years (8 vaccine, 4 placebo), provided to a limited number of participants each day (for example, approximately 3 participants each day on days 1–4).  The PfSPZ Vaccine dose will only be increased to the next level when safety has been assessed in participants of the first group, and earliest at 14 days after the first injection. At this time, the lowest dose (1.35 x 105) will be administered to children age 13-59 months, with doses doubling every two weeks, after assessment of safety signals, until the final dose of 9.0 x 105 PfSPZ is reached. The lowest dose will be administered to infants 5–12 months after this dosage has shown to be safe in 13-59 months-olds, and doses will be doubled every two weeks, after assessment of safety signals, until the dose of 9.0 x 105 PfSPZ is reached. Overall vaccine doses will only be increased if they are assessed as well tolerated and the safety data are acceptable for further evaluation of the vaccine at a higher dose, applicable to all the age groups. All of these proposed doses have been shown to be well tolerated with no serious safety signals in studies in US adults and, in African adults at the two lowest doses.  Therefore, based on the critical importance of dose in mediating protection with this vaccine, the 2 highest dosages found to be well tolerated will be used for the Part 2 of the trial, which will measure safety and efficacy of the PfSPZ vaccine. The highest well tolerated dosage (likely to be 9.0 x 105 PfSPZ) will be administered by DVI 3 times to 104 infants (group 1), and 4 times to 104 infants (group 2); the second highest dosage (likely to be 4.5 x 105 PfSPZ) will be given 3 times to another study arm of 104 infants (group 3) to document a dose response and to understand whether the lower dose is highly efficacious in this age-category.  The rationale for the amount of PfSPZ Vaccine (4.5 x 105  or  9.0 x 105 PfSPZ), number of doses ( 3 or 4) and intervals between doses ( 4 and 8 weeks) is based on data from ongoing studies in US and African adults for conferring durable immunity and protection, and will be further informed by the dose escalation trial. Another group of 104 infants will receive 3 (n=52; group 4) or 4 (n=52; group 5) doses of normal saline (NS) by direct venous injection as placebo. The dosing interval in all 3 dose groups will be 8 weekly (0, 8,16 weeks), while the doses in the 4 dose groups will be given at 0, 4, 8 and 16 weeks. The main objectives of this study are to measure the safety, tolerability and immunogenicity of PfSPZ Vaccine in infants (measured in Part 1 and Part 2 of this trial) and to determine whether PfSPZ Vaccine administered by DVI to infants provides high-level protection (point estimate >60%) against Pf infection during 6 months following the last vaccine dose when compared to a placebo group (Part 2 of the trial).  A secondary objective will be to measure safety tolerability, immunogenicity and efficacy during 12 months follow-up.</div>\n<div>\n  </div>\n
      • short_titlePfSPZ Malaria Vaccine
      • protocol_noECCT/16/02/05
      • version_no1.0
      • date_of_protocol10-10-2015
      • study_drugPfSPZ Malaria Vaccine
      • 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
      • comparatorNo
      • comparator_name
      • comparator_registered
      • 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_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data0
      • 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_african0
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan0
      • applicant_contractual_agreement0
      • declaration_applicantDr Tony Sang
      • declaration_date112-02-2016
      • declaration_principal_investigatorDr Martina Oneko
      • declaration_date212-02-2016
      • placebo_presentYes
      • study_objectives<div>\n <strong>Primary objectives:</strong></div>\n<div>\n Part 1: Age de-esclation and dose escalation trial in children and infants (5 months -12 years)</div>\n<div>\n Measure the safety, tolerability and immunogenicity of PfSPZ Vaccine administered at escalating dosages by DVI in older children aged 5–12 years (highest two doses only), younger children aged 13-59 months, and infants 5-12M (at vaccination) at doses of 1.35x105, 2.7x105, 4.5x105, 9.0x105 PfSPZ Vaccine given as a single dose.</div>\n<div>\n  </div>\n<div>\n <div>\n Part 2: Safety and efficacy trial in infants (5-12M inclusive) living in an area of high malaria transmission</div>\n <ul>\n <li>\n Primary Objective 1: Safety, Tolerability and Immunogenicity in infants (5-12M inclusive)\n <ul>\n <li>\n Measure the safety, tolerability and immunogenicity of the highest safe and well tolerated dose 666 of PfSPZ Vaccine administered by DVI in 3 or 4 doses to infants 5-12M inclusive of age. Dosage will be determined during the age de-escalation and dose escalation trial (Part 1) based on safety and tolerability.</li>\n </ul>\n </li>\n <li>\n Primary Objective 2: Efficacy in infants (5-12M inclusive)\n <ul>\n <li>\n Determine whether PfSPZ Vaccine administered by DVI to infants 5-12M inclusive of age at the highest safe and well tolerated dose of PfSPZ vaccine provides high-level (point estimate > 60%) protection against naturally acquired Pf infection, measured by blood smear microscopy, during 6 months following the last vaccine dose when compared to a control (placebo) group.</li>\n </ul>\n </li>\n </ul>\n <div>\n <strong>Secondary Objectives:</strong></div>\n <ul>\n <li>\n Secondary Objective 1: Determine safety and efficacy of alternative dosages of PfSPZ Vaccine at 6676 months after last vaccination</li>\n <li>\n Secondary Objective 2: Determine safety and efficacy of each dosage of PfSPZ Vaccine at 12 678 months after last vaccination</li>\n <li>\n Secondary Objective 3: Determine whether PfSPZ Vaccine administered by DVI to infants 5-12M 680 inclusive of age at any of the given doses of PfSPZ Vaccine provides high-level (point estimate > 60%) protection against naturally acquired Pf infection, measured by PCR, during 6 and 12 months following the last vaccine dose when compared to a control (placebo) group.</li>\n <li>\n Secondary Objective 4: Assess the cellular immunity and antibody responses induced by PfSPZ Vaccine</li>\n <li>\n Secondary Objective 5: Determine whether measured immune responses correlate with protection against Pf infection</li>\n <li>\n Secondary Objective 6: Determine the safety, tolerability, efficacy and immunological response provided by the addition of a booster dose 12 months after the primary vaccination series in infants 5M-12M of age on enrolment (dependent on achieving a statistically significant point estimate of at least 60% VE during 6 months follow-up)</li>\n </ul>\n <p>\n <strong>Exploratory Objectives</strong></p>\n <ul>\n <li>\n Objective 1: Determine the efficacy of PfSPZ Vaccine against Pf infection at specific parasite density thresholds (Pf parasite density >400 or >5000 parasites per microliter)</li>\n <li>\n Exploratory Objective 2: Determine the efficacy of PfSPZ Vaccine against malaria hospitalization (defined as hospitalization and Pf parasite density >5000 parasites per microliter or hemoglobin <5g/dl determined to be caused by malaria).</li>\n <li>\n Exploratory Objective 3: Determine whether any of the PfSPZ vaccination schedules has an effect on the prevalence of anemia as measured during the month 6 and month 12 visits</li>\n <li>\n Exploratory Objective 4: Measure allele-specific efficacy and selection of vaccine-resistant Pf genotypes through a genome-wide sieve analysis.</li>\n </ul>\n</div>\n<p>\n  </p>\n
      • principal_inclusion_criteria<ul>\n <li>\n Healthy children 5 months – 12 years (Part 1) and healthy infants 5 -12M inclusive (Part 2) </li>\n <li>\n HIV negative </li>\n <li>\n Able to participate for the duration of the study. </li>\n <li>\n Parents/guardians over the age of 18 years able and willing to provide informed consent/permission. The consent/permission will be in writing.  For adult parents or guardians who are illiterate, an impartial witness can sign the consent/permission form on behalf of the parent and the parent/guardian will provide a thumbprint</li>\n</ul>\n<div>\n  </div>\n
      • principal_exclusion_criteria<ul>\n <li>\n Positive HIV test or breastfeeding infants or children of a known HIV positive mother (per Kenyan guidelines, these HIV exposed breastfeeding children should be on cotrimoxazole)</li>\n <li>\n Refusal of HIV testing</li>\n <li>\n Elevated ALT (liver function test) ≥2x ULN ( ALT >84 U/L)  </li>\n <li>\n Abnormal hematological parameters defined as: hemoglobin < 8 g/dl, WBC <1500 / mm3, neutrophils <750/ mm3, platelet count <75.000/ mm3</li>\n <li>\n Abnormal renal function test with creatinine >0.9 mg/dL</li>\n <li>\n Known sickle cell disease</li>\n <li>\n Current use of systemic immunosuppressant pharmacotherapy</li>\n <li>\n Current significant medical condition (cardiac, hepatic, renal, or hematological) or evidence of any other serious underlying medical condition identified by medical history, physical examination, or laboratory examination</li>\n <li>\n History of a splenectomy</li>\n <li>\n History of neurologic disorder (including seizures, other than uncomplicated febrile seizures)</li>\n <li>\n Known allergy to any component of the vaccine formulation, history of anaphylactic response to mosquito-bites, or known allergy to first or second line anti-malarials used to treat malaria</li>\n <li>\n Plan to participate in another investigational vaccine/drug research during or within 1 month of this study end</li>\n <li>\n Prior participation in a malaria vaccine trial</li>\n <li>\n Participation in the PfSPZ Vaccine Trial Part 1 (for Part 2 only)</li>\n <li>\n History of any other illness or condition which, in the investigator's judgment, may substantially increase the risk associated with the subject’s participation in the protocol or compromise the scientific objectives</li>\n <li>\n Child/orphan in institutional care</li>\n</ul>\n<div>\n  </div>\n
      • primary_end_points<p>\n Incidence of Pf parasitemia with parasite density >0 by thick blood smear</p>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • 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<p>\n The study will be conducted at Siaya County Referral Hospital and Wagai Dispensary. </p>\n<p>\n Staff will include a study pediatrician and PI, a study site coordinator, a regulatory officer, administrative officer, data manager and data clerk, part time statistical support, sufficient clinical staff, including medical officers, clinical officers, nurses, quality assurance officers, community workers, laboratory personnel, including part time laboratory supervisor, and laboratory technicians and technologists, a pharmacist and pharmacist technician.  </p>\n<p>\n PI - Dr Martina Oneko, MD,Pediatrician</p>\n<p>\n PI - Dr Mary Hamel, MD</p>\n<p>\n Study Site Coordinator - Reuben Yego</p>\n<p>\n Pharmacist - Dr Tony Sang, BPharm</p>\n<p>\n Laboratory supervisor - Kephas Otieno, MSc</p>\n<p>\n Administrative officer - Diana Okello, MBA</p>\n<p>\n Data Manager - Wycliffe Odongo</p>\n<p>\n Data clerks</p>\n<p>\n Medical officer - To be hired</p>\n<p>\n Clinical officers</p>\n<p>\n Nurses</p>\n<p>\n Quality Assurance officers</p>\n<p>\n Community workers</p>\n<p>\n Laboratory personnel</p>\n<p>\n Laboratory technicians and technologists</p>\n<p>\n pharmacist technologist</p>\n<p>\n The trial budget also includes sufficient clinical supplies to test for malaria and provide treatment for common childhood diseases in the outpatient setting, ITNs for enrolled children, laboratory supplies for laboratory procedures, including immunological and molecular studies, transport costs, transport reimbursement for enrolled children.  </p>\n<p>\n  </p>\n
      • other_details_explanation<p>\n The proposed PfSPZ Vaccine has shown to be very safe and well tolerated in subjects in the US and Africa. High -level protective efficacy has been demonstrated in malaria naïve adult individuals, and therefore should be evaluated in African infants in an area of intense malaria transmission who continue to experience the highest morbidity and mortality from malaria and have not been exposed to frequent malaria infections.</p>\n
      • other_details_regulatory_notapproved<p>\n None</p>\n
      • other_details_regulatory_approved<p>\n KEMRI Scientific Ethics Review Unit approved the trial on 27-Oct-2015</p>\n<p>\n CDC IRB approved the trial on 10-Nov-2015</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n Not applicable</p>\n
      • estimated_duration3 years
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorNormal saline placebo
      • design_controlled_other_medicinalNo
      • design_controlled_placeboYes
      • 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_countriesNo
      • multiple_member_states
      • number_of_sites2 sites anticipated in Kenya.
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_siteWe will have only one site in Kenya
      • total_participants_worldwide536 participants
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenYes
      • population_adolescentNo
      • population_above_18No
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifywe will enroll children below 12 years. Parental consent will be sought
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameMartina
      • investigator1_middle_name
      • investigator1_family_nameOneko
      • investigator1_qualificationMD, Pediatrician
      • investigator1_professional_addressKEMRI Center for Global Health Research, P.O.Box 1578-40100, Kisumu, Kenya
      • investigator1_telephone+254 717 747279
      • investigator1_emailmoneko@kemricdc.org
      • organisations_transferred_No
      • number_participants120 participants for the age de-escalation component of the study\n416 participants for the main study
      • notification
      • approval_date18-05-2016
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted15-12-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<div style=\"margin-left: 28.35pt;\">\n <p style=\"margin-left: 0.3in;\">\n <strong>Safety, Tolerability and Efficacy of PfSPZ Vaccine Administered by Direct Venous Inoculation (DVI) to Healthy Children and Infants 5 Months through 9 Years of Age Living in an Area of High Malaria Transmission in Western Kenya</strong></p>\n <p>\n <strong>Leadership/Partnership:</strong></p>\n</div>\n<ul>\n <li>\n <strong>Kenya: </strong>Dr. Martina Oneko (site Principal Investigator)</li>\n <li>\n <strong>LSTM: </strong>Prof. Feiko ter Kuile (co-Investigator)</li>\n <li>\n <strong>CDC contact person:</strong> Dr. Laura Steinhardt (Co Principal Investigator), Dr Aaron Samuels (CDC-Kenya)</li>\n</ul>\n<p style=\"margin-left: 0.35in;\">\n <strong>Brief background</strong></p>\n<p>\n Double blind, randomized placebo controlled trial of PfSPZ Vaccine, consisting of cryopreserved, radiation-attenuated Plasmodium falciparum (Pf) sporozoites, which when given by direct venous inoculation showed dose-dependent, high level protection against controlled human malaria infection. The trial is divided into Part 1 – age de-escalation and dose escalation involving children between 5 months and 9 years inclusive, and Part 2, a 4-arm placebo controlled safety and efficacy trial in infants 5 to 12 months of age.</p>\n<p style=\"margin-left: 0.35in;\">\n <strong>Progress report</strong></p>\n<p>\n <strong>Overall Primary objective: </strong>Evaluate the safety, tolerability, immunogenicity and efficacy of PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya by: 1) conducting and completing placebo controlled age de-escalation and dose escalation phase 2 trial in children and infants of 5 months through 9 years of age inclusive to evaluate safety and tolerability of increasing vaccine doses and to determine the safe doses to be used in the Part 2 safety and efficacy trial in infants; and 2) conducting and completing a placebo-controlled phase 2 trial to evaluate the safety, tolerability, immunogenicity, and efficacy against <em>Plasmodium falciparum </em>(Pf) infection of the three highest doses found to be safe in Part 1</p>\n<p>\n <strong>Primary Objective Part 1: </strong><em>Age de-escalation and dose escalation trial in children and infants (5 months – 9 years): </em>Measure the safety, tolerability and immunogenicity of PfSPZ Vaccine administered at escalating dosages by DVI in older children aged 5–9 years (highest three doses only), younger children aged 13–59 months, and infants 5–12M (at vaccination) at doses of 1.35x10⁵, 2.7x10⁵, 4.5x10⁵, 9.0x10⁵ and 1.8 x 10⁶ PfSPZ Vaccine given as a single dose or, for the two highest doses in two doses at 8 week intervals.</p>\n<ol style=\"list-style-type: lower-alpha;\">\n <li>\n <strong>Status</strong>: Data collection and analysis have been concluded. The CSR report is being finalized by the sponsor Sanaria.</li>\n <li>\n <strong>Major findings/accomplishments</strong>:</li>\n</ol>\n<p style=\"margin-left: 17.85pt;\">\n Find below the findings of Part 1 unblinded.</p>\n<p style=\"margin-left: 17.85pt;\">\n <u>Recruitment: </u>Study start was on 4 July, 2016, recruitment ended in November 2016.</p>\n<p style=\"margin-left: 17.85pt;\">\n Total number of consented participants: 282</p>\n<p style=\"margin-left: 17.85pt;\">\n Total number of enrolled participants:  165</p>\n<p style=\"margin-left: 17.85pt;\">\n Total number of screening failures: 117 participants</p>\n<p style=\"margin-left: 17.85pt;\">\n <u>Vaccinations: </u>156 participants, the target sample size, were successfully vaccinated with either 1 or 2 doses of the PfSPZ Vaccine, according to the dosing schedule. An additional 9 participants received an incomplete intravenous vaccination and were subsequently replaced, but followed up for safety. The last vaccination took place on 13 January 2017.</p>\n<p style=\"margin-left: 17.85pt;\">\n <u>Safety: </u>There were no Grade 3 related adverse events (AEs), laboratory abnormalities, or significant electrocardiogram changes post vaccination. Among participants of all ages, 26.8% of vaccine recipients and 35.8% of placebo recipients experienced a solicited AE that was considered related within seven days of immunization. Related systemic AEs were less common in vaccine recipients (10 of 112, or 8.9%) compared to placebo recipients (8 of 53, or 15.1%), solicited local symptoms at the injection site, primarily mild pain and swelling, occurred in 20.5% of vaccine recipients and 22.6% of placebo recipients. There was no obvious dose or age relationship.  Unsolicited AEs in the 28-day period following each vaccination deemed to be possibly or probably related occurred in nine of 112 (8.0%) vaccine recipients and 1 placebo recipient (1.9%); all were mild, resolved, and occurred within 7 days of vaccine/placebo injection. Three serious AEs were related to incident malaria infection. One severe malarial anemia occurred in a child 44 days after receiving her first dose of 9.0x10⁵ PfSPZ and two children in the 13–59-month-old group, both of whom had received one dose of 1.8x10⁶ PfSPZ Vaccine, experienced simple febrile seizures associated with malaria, one 26 days and the other 4 days after vaccination. One 8-year-old boy who received one injection of normal saline placebo developed an abscess on his finger after a capillary blood draw on vaccination day that was therefore considered related to a study procedure but not the study product. All grade 3 events resolved.</p>\n<p style=\"margin-left: 17.85pt;\">\n We had 4 DSMB (Data Safety and Monitoring Board) meetings, the last two on 05 December 2016 and  on 06 March 2017. On 05 December 2016 it was concluded that there were no safety concerns regarding the use of 4.5x10⁵, 9.0x10⁵ and 1.8 x 10⁶ doses of PfSPZ Vaccine in infants and that Part 2 of the study could start with these doses. On 06 March 2017 the results of second vaccinations at the 2 highest doses in infants were reviewed. As there were no safety concerns, we were allowed to continue Part 2 vaccinations, proceeding to vaccination 2 and later to vaccination 3, in the infants.</p>\n<ol style=\"list-style-type: lower-alpha;\">\n <li value=\"3\">\n <strong>Significance of those findings/accomplishments</strong>:</li>\n</ol>\n<p style=\"margin-left: 0.25in;\">\n Conclusion of Part 1 of the trial resulted in proof of safety and tolerability of PfSPZ Vaccine in the protocol specified dose ranges in infants, which allowed us to proceed into the efficacy trial in infants (Part 2).</p>\n<ol style=\"list-style-type: lower-alpha;\">\n <li value=\"4\">\n <strong>Challenges and lessons learned</strong>:</li>\n</ol>\n<ol>\n <li>\n Study start was delayed by about 3 months due to a delay in getting approval from the regulatory authorities and a clinical hold imposed on the sponsor by the FDA in the US.</li>\n</ol>\n<p style=\"margin-left: 0.5in;\">\n We expected about a rate of 25% screening failures and the final screening failure rate was 41%. About 30% of the screening failures were due to consent withdrawals by fathers before vaccination, and in most cases even before screening. The mothers had consented but when they reached home with the consent, fathers did not want their children to participate in the study, mostly because of the associated blood draws.</p>\n<p>\n <strong>Primary objectives Part 2</strong>:  <em>Safety and efficacy trial in infants (5-12M inclusive) living in an area of high malaria transmission: </em>1. Measure the safety, tolerability and immunogenicity of the highest safe and well tolerated dose of PfSPZ Vaccine administered by DVI in 3 doses to infants 5-12M inclusive of age.  Dosage has been determined to be 4.5x10⁵, 9.0x10⁵ and 1.8 x 10⁶ PfSPZ Vaccine during the age de-escalation and dose escalation trial (Part 1) based on safety and tolerability. 2. Determine whether PfSPZ Vaccine administered by DVI to infants 5-12M inclusive of age at a pre-specified well tolerated dose level provides high-level (point estimate <u>></u> 60%) protection against naturally acquired Pf infection, measured by blood smear microscopy, during 6 months following the last vaccine dose when compared to a control (placebo) group. </p>\n<ol style=\"list-style-type: lower-alpha;\">\n <li>\n <strong>Status: </strong> All primary vaccinations have been given as of 15 AUG2017. Twelve months of follow up for safety, immunogenicity and efficacy have been completed for all participants on 15AUG2018. Data lock occurred on 15OCT2018. Data analysis is ongoing. PCR assays to detect malaria are still ongoing at the KEMRI/CDC laboratories in Kisumu. Specific antibody assays and cell assays for assessment of parasite-specific T cell responses are ongoing at laboratories of our collaborators in the United States. Epstein Barr Virus serological assays are ongoing at the University of Massachusetts. Parasite genotyping is ongoing at the University of Maryland.</li>\n <li>\n <strong>Major findings/accomplishments:</strong></li>\n</ol>\n<p style=\"margin-left: 0.25in;\">\n <u>Recruitment:</u> In December 2016, multiple meetings with members of the communities in Siaya and Wagai (our satellite study clinic) took place. We concentrated on the issues we had encountered during Part 1 of the study and explained the blood draws and the vaccination procedure in detail. Study start for part 2 was on 03 January 2017. Consenting of the last participant took place on 10APR2017, and a total of 548 parents of potential participants were consented. Of these, 212 (38.7%) are confirmed screening failures. A total of 337 participants were enrolled and randomized, although one mother withdrew consent after randomization, leaving 336 participants who were vaccinated.</p>\n<p style=\"margin-left: 0.25in;\">\n <u>Vaccinations:</u>  Vaccinations in part 2 started on 23JAN2017, and the last enrolment (i.e. the last vaccination 1) took place on 13 April 2017.  The last vaccination 3 was given on 15AUG2017.</p>\n<p style=\"margin-left: 0.25in;\">\n <u>Safety:</u> Final unblinded safety evaluations showed no related serious adverse events; unrelated serious adverse events occurred in 38/252 (15.1%) of vaccine participants and in 8/84 (9.5%) of those who had received placebo. One child (placebo recipient) died at home due to bee attack. Grade 3 unsolicited adverse events included simple febrile seizures, considered to be adverse events of special interest which did not fulfil SAE criteria and were reported throughout the study period; at least one febrile seizure was reported in 14/252 (5.6%) of vaccinees compared to 4/84 (4.8%) of placebo recipients. Unsolicited adverse events which were considered possibly or probably related occurred in 15/252 (6%) of vaccine recipients compared to 4/84 (4.8%) of placebo recipients; all were of mild severity. Solicited local adverse events occurred in 11.9% of vaccine recipients and in 16.7% of placebo recipients after a total of 980 vaccinations: 2 participants(0.6%) one a vaccine recipient and the other a placebo recipient had severe swelling at the injection site, and one of those was withdrawn from further vaccination. There was a clear trend that injection site swelling was less common at vaccinations 2 and 3. Overall, 45.6% of vaccine recipients and 45.2% of placebo recipients experienced solicited systemic adverse events like fever, drowsiness, irritability or loss of appetite during the first week post vaccination, but most of these were related to other infections and thus unlikely related to the vaccine. Possibly and probably related solicited systemic reactions were observed in 24/252 (9.5%) of vaccine recipients and in 7/84 (8.3%) of placebo recipients after a total of 980 vaccinations, with one Grade 3 reaction in the placebo group (one spike of fever to 40.1 ⁰Celsius) which was considered possibly related in the absence of another explanation. There was no trend showing that solicited systemic events increased after second or third doses.</p>\n<p style=\"margin-left: 0.25in;\">\n <u>Feasibility:</u> In a total of 980 injections, 95.2% were successful with one needle stick. Children did not cry during 15.8% of injections with vaccine versus 18.2% of injections with placebo.</p>\n<p style=\"margin-left: 0.25in;\">\n <u>Efficacy: </u> The 6 month endpoint of vaccine efficacy (VE) by proportional analysis was 12% by proportional  analysis and 30.1% by survival analysis method in infants who had received 3 doses of 18 x 10⁵PfSPZ. In the 9.0 x 10⁵ PfSPZ group VE was -6.5% by proportional analysis and 3.3% by survival analysis, and in the 4.5 x 10⁵ PfSPZ group proportional analysis showed VE of 0.8% and survival analysis of 13.5%. None of these results were statistically significant. Thus the efficacy needed per protocol to allow for a booster dose was not reached.</p>\n<p style=\"margin-left: 0.25in;\">\n <u>Immunogenicity: </u>The vaccine was immunogenic in all 3 dose groups in terms of circumsporozoite antibody titers 2 weeks after vaccination 3. Those who did not become infected had significantly higher response to PfCSP in the 18x10⁵ and 4.5x10⁵ PfSPZ groups</p>\n<ol style=\"list-style-type: lower-alpha;\">\n <li value=\"3\">\n <strong>Significance of those findings/accomplishments:</strong></li>\n</ol>\n<p style=\"margin-left: 0.25in;\">\n Feasibility of intravenous inoculation by DVI in infants was assessed during all vaccinations. In total, several very experienced injectors managed to vaccinate 95.2% of the infants in Part 2 by 1 direct venous inoculation. This is an improvement compared to Part 1, where only 75% of the infants were vaccinated by 1 single injection. The injector performance improved significantly over time and this finding is important also for other future vaccinations which have to be given to infants via the intravenous route. </p>\n<p style=\"margin-left: 0.25in;\">\n The vaccine was overall safe and well tolerated, but the efficacy did not reach the expected levels while circumsporozoite antibody titers were increased in all dose groups 2 weeks after vaccination 3. Further immunological evaluation and parasite genotyping may provide the answer why the vaccination in infants did not show the same levels of efficacy as in malaria naïve adults. </p>\n<ol style=\"list-style-type: lower-alpha;\">\n <li value=\"4\">\n <strong>Challenges and lessons learned</strong>:</li>\n</ol>\n<p style=\"margin-left: 0.25in;\">\n Recruitment of participants was a challenge. Consent withdrawals before screening contributed in about 50% to the screening failures, mostly by fathers.  The original sample size of 416 participants was not reached, but the previously expected minimum number of 320 participants was exceeded and we enrolled 336 participants. 98.2% of the scheduled follow up visits were completed. We retained 303 children in the study, however only 260 participants remained in the ATP cohort, falling short of our original aim to retain 280 children in the ATP cohort.  46 participants have dropped out of the study for various reasons, including consent withdrawals (14) and migration out of the study area (26).</p>\n<div>\n  </div>\n
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        • telephone_number+1 301-770-3222
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        • email_addresssanaria@sanaria.com
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      • abstract_of_study<p>\n Severe Malaria In African Children: A Research and Trials Consortium (SMAART) was funded in 2018 by a collaboration award in science from the Wellcome Trust. Owing the continued high burden of malaria and poor outcomes of severe malaria, even on the best antimalarial, artesunate, the major objective of SMAART is to conduct better research faster across a collaborative platform to identify interventions to optimise the whole treatment pathway for children with severe malaria, and thus to achieve a step-change in improving their outcomes in the current era.</p>\n<p>\n  </p>\n<p>\n A novel new drug candidate for adjunctive treatment of severe malaria, sevuparin, has been identified that can blocks merozoite invasion, prevent cytoadherence and transiently de-sequesters infected erythrocytes in humans with uncomplicated <em>P. falciparum</em> malaria. If given, in addition to antimalarial treatment, early in the course of admission (<24 hours) this could result in improvements in outcomes from severe malaria for the subgroups at greatest risk and during the period of greatest risk (first day of hospitalisation). Sevuparin has been shown to be safe and well tolerated in adults with only some mild effects on activated partial thromboplastin time (APTT) at higher doses given over longer periods of time (3 days), which are not clinically relevant to the time of greatest risk.</p>\n<p>\n  </p>\n<p>\n In this Phase I trial dose-finding paediatric study, we aim to use only 3 doses given at admission (0 hours), and 8 and 16 hours later, and measure APTT 1 hour after each dose (to assess maximum toxicity based on adult data). The Phase I trial is designed to obtain data on safety, dosing, feasibility and potentially lactate clearance of sevuparin given as an adjuvant therapy in severe malaria in children. We aim to study 20 children admitted to hospital with severe malaria which will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method (CRM), which adapts or informs subsequent doses for each child entering the trial based on the data from previously enrolled children. The maximum tolerated dose (MTD) will be identified based on the dose-toxicity model being updated by each previous patient’s APTT results using standard methods.</p>\n<p>\n  </p>\n<p>\n The results of the Phase I trial will identify the final dosage to be tested in a Phase II trial in terms of both efficacy and safety outcomes. The primary endpoint for the future Phase II trial (lactate clearance) reflects the primary hypothesis that sevuparin improves microcirculatory flow by reversing and preventing parasite sequestration. The Phase I trial will also assess whether this endpoint, lactate clearance, is realistic; thus lactate will be collected along with other test results at baseline 4 hours and 8 hours, as well as other time points.</p>\n<p>\n  </p>\n
      • study_title<p>\n SEVUSMART TRIAL</p>\n<p>\n Sevuparin as a potential adjunctive therapy in children with severe malaria</p>\n
      • laymans_summary<p>\n  </p>\n<p>\n <strong>What is the problem/background? </strong></p>\n<p>\n Even on the best antimalarial treatments (injectable artesunate) many African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (<24hours). One of the bad things that happen in severe malaria is that red blood cells that are infected with malaria parasites that stick to the very deep parts of our blood vessels. This occurs throughout the body and therefore the blood flow is poor tissues which leads to a build-up of body acids (called lactate). Up to the present there have been no treatments available to prevent or reverse stop red cells sticking to the blood vessels when they have malaria parasites in them.</p>\n<p>\n  </p>\n<p>\n The SMAART: Severe Malaria in African children: A Research and Trials consortium have identified one key innovation which could improve this. A novel new drug candidate called sevuparin, has been identified and safely tested in adults with malaria in Thailand. Sevuparin acts by preventing malaria parasites getting into red cells in the first place (this means that the malaria parasite cannot survive); it also prevents red cells with infected with malaria parasites from sticking to the blood vessels and also able to ‘unstick’ red cells with infected with malaria parasites that are already sticking to the blood vessel and causing poor blood flow.</p>\n<p>\n  </p>\n<p>\n Given its potential to be transformative in improving current outcomes from severe malaria, a large group of specialist doctors in severe malaria research and clinical trials suggested that sevuparin should be tested in children with severe malaria. They have all helped to design this clinical trial, which will be conducted on the high dependency ward in Kilifi, Kenya.</p>\n<p>\n  </p>\n<p>\n <strong>What questions are we trying to answer?</strong></p>\n<p>\n <strong>Study design</strong>: Phase I Safety and Dose Finding to assess the optimal dose of sevuparin given as a supportive therapy in severe malaria alongside of the usual antimalarial treatments to determine toxic level, adverse events and to identify the highest dose with an acceptable safety profile</p>\n<p>\n <strong>Study Population:</strong> 20 children hospitalised with severe malaria.</p>\n<p>\n  </p>\n<p>\n <strong>Sample Size:</strong> This is a Phase I trial designed to test safety and Dose Finding Trial of sevuparin as a supportive therapy in severe malaria; there is therefore no formal sample size calculation.</p>\n<p>\n  </p>\n<p>\n <strong>Where is the study taking place, how many people does it involve and how are they selected?</strong></p>\n<p>\n The study will be carried out at Kilifi County Hospital, Kenya and plans to enroll 20 children. Children enrolled in the study will be aged 3 months to 12 years, and presenting to Kilifi County Hospital with severe malaria evidence of malaria (rapid diagnostic test positive or positive malaria slide). The carers of these children will be approached for consent and enrolment in the study. The study drug will be given on the first day of admission only alongside of usual treatments given for children with malaria.</p>\n<p>\n  </p>\n<p>\n <strong>What does the study involve for those who are in it?</strong></p>\n<ul>\n <li>\n Parental information and consent/parental assent (for emergencies when the child is too sick for full consent).</li>\n <li>\n Admission to the high dependency ward at Kilifi County Hospital.</li>\n <li>\n The sevuparin will be given as 3 infusions on the first day at study enrolment (0 hours), 8 and 16 hours following this. All other treatments for severe malaria will follow the usual guidelines</li>\n <li>\n Two groups of 2 participants will receive a dose of 1.5 mg/kg/dose with the plan to escalate to a cohort of 2 participants receiving 3mg/kg/dose and a cohort of 2 participants receiving 6.0 mg/kg/dose. The model will then inform each subsequent patient what dose they would then be assigned (between 1.5 and the maximum dose of 6.0 mg/kg/dose)</li>\n <li>\n All children will have regular (4 hourly clinical and vital sign) monitoring during the period of admission to the high dependency ward and twice daily thereafter until discharge and will be followed up to day 28. Routine blood tests will be done at admission, 8 and 24 hours and at follow up.  Additional samples will be taken to check clotting at 0, 1-hour post sevuparin infusion (i.e. 1, 9 and 17 hours) and lactate (the body acid that builds up in severe malaria) will be check regularly at admission, 4, 8 16 and 24 hours.</li>\n <li>\n The microcirculation, using a small soft probe placed on the gum of a children will be checked three times during admission.</li>\n</ul>\n<p>\n  </p>\n<p>\n <strong>What are the benefits and risks/costs of the study for those involved?</strong></p>\n<p>\n <strong>Benefits:  </strong>Close monitoring of all children on the high dependency unit during admission and follow up to day 28 after discharge. Hospital bills for participants older than 5 years will be covered by the study (covering the costs for standard treatment for severe malaria and related complications).</p>\n<p>\n <strong>Risks: </strong>One potential risk of sevuparin, as it is heparin-like drug is that it increases one of the blood clotting markers. This was seen in the study in Thailand but was short lived (ie only happened for a few hours only) and did not cause any side effects. We are monitoring carefully this blood clotting marker and this will help us make decisions about whether the child receives the next dose and as we are using a continuous reassessment method to monitor toxicity this will inform the dosages for the children enrolled in the trial. </p>\n<p>\n  </p>\n<p>\n <strong>How will the study benefit society?</strong></p>\n<p>\n The study aims to improve the outcome from severe malaria. It will generate robust feasibility and safety data to support a future larger phase II trial with the aim of improving management of a vulnerable population of children and improving outcomes.</p>\n<p>\n  </p>\n<p>\n <strong>When does the study start and finish?   </strong>Once we have received ethical approval.</p>\n<p>\n Enrolment will be over 12-15 months and study will end after 2 years.</p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n
      • short_titleSEVUSMART Trial
      • protocol_noECCT/20/06/05
      • version_no1.2
      • date_of_protocol08-02-2019
      • study_drugSevuparin
      • disease_conditionMalaria
      • product_type_biologicals1
      • product_type_proteins1
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressregulatory@kemri-wellcome.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_countries(null)
      • 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_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantKathryn Maitland
      • declaration_date123-06-2020
      • declaration_principal_investigatorKathryn Maitland
      • declaration_date223-06-2020
      • placebo_presentNo
      • study_objectives<p>\n The primary objective of this trial is to conduct a dose-finding study of intravenous sevuparin given in 3 doses over the first 18 hours from enrolment (within 24h of hospital admission), defining toxicity events as any APTT >2.5 upper limit of normal (ULN) (grade 3 toxicity) 1 hour after each dose to identify the maximum tolerated dose (MTD). The initial dosage (1.5 mg/kg) and the <em>a priori</em> dose-toxicity curve are based upon the results of the adult trial (where a dose of 1.5 mg/kg was associated with minimal risk of toxicity) and experimental evidence of dose-dependent efficacy i.e. inhibition of merozoite invasion and reversal of cytoadherence of infected erythrocytes [36]. Almost all adults enrolled in this trial experienced grade 2 toxicity after one or more sevuparin doses, but APTT rapidly normalized, hence the choice of grade 3 toxicity to define the MTD in this dose-finding trial.</p>\n<p>\n  </p>\n<p>\n The results of this Phase I trial will identify the final dosage selected for a subsequent Phase II that will include both efficacy and safety outcomes. The Phase II trial will be conducted by the SMAART consortium and plans to use change in lactate at 8 hours as its primary endpoint; likely secondary endpoints include neurological sequelae, day-28 and day-180 mortality, length of initial hospitalisation, re-admission to hospital, grade 3/4 and serious adverse events.</p>\n<p>\n  </p>\n<p>\n The primary endpoint for the future Phase II trial reflects the primary hypothesis that sevuparin improves microcirculatory flow by reversing and preventing parasite sequestration. Data collected in the Phase I trial will also assess whether lactate clearance at 8 hours is a realistic and feasible primary endpoint for a subsequent Phase II trial.</p>\n<p>\n  </p>\n<ol>\n <li value=\"1.1\">\n Specific Objectives</li>\n</ol>\n<p>\n To identify the maximum tolerated dose (MTD) of intravenous sevuparin as an adjunctive therapy in children with severe malaria given as three infusions at 0, 8 and 16 hours using the Continual Reassessment Method (CRM) to adapt or inform subsequent doses for each child entering the trial, based on a toxicity event defined as any APTT >2.5 upper limit of normal (ULN) 1 hour after each dose, and updating the dose-toxicity model using the previous patients’ APTT results.</p>\n<p>\n  </p>\n
      • principal_inclusion_criteria<ol>\n <li>\n Aged between 3 months and 12 years admitted to the paediatric wards within the last 24h</li>\n <li>\n Current or recent evidence of <em>P. falciparum</em> malaria (slide or rapid diagnostic test (RDT) positive)</li>\n <li>\n Clinical evidence of severe malaria: impaired consciousness: coma (inability to localize painful stimulus) or prostration (inability to sit unsupported for those above 6 months) or deep breathing</li>\n <li>\n Lactate > 2 mmol/L</li>\n <li>\n Guardian or parent willing and able to provide consent</li>\n</ol>\n<p>\n  </p>\n
      • principal_exclusion_criteria<ol>\n <li>\n Clinical evidence or a history of a bleeding/coagulation disorder</li>\n <li>\n A comorbidity which clinician believes has a significant risk of poor outcome e.g. malignancy, end-stage renal failure, major cardiac condition</li>\n <li>\n Thrombocytopenia (platelet count <25 x10⁹/L).</li>\n</ol>\n<p>\n  </p>\n<p>\n  </p>\n
      • primary_end_points<ul>\n <li>\n APTT>2.5xULN 1h post any sevuparin dose (grade 3 following the CTC)</li>\n</ul>\n<p>\n  </p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology1
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifySafety and dose finding trial.
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Clinicians (5)</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Professor Kathryn Maitland</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Dr. Mainga Hamaluba</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Dr. Nchafatso Obonyo</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Mohammed Bakari</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Emmanuel Omondi</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Nurses</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n We have a pool of 15 nurses in the KEMRI High dependency Unit but we will also have two dedicated trial nurses. All the nurses will be trained on the study protocol and procedures.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Dedicated trial nurses: Mwanamvua Boga and Floice Ombiso (Both are senior paediatric research nurses)</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Trial Coordinator</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Hellen Mnjala</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n The trial willbe conducted in the KEMRI high dependency unit.</p>\n
      • other_details_explanation<p>\n <span font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">The study will be conduected in Kenya in children with malaria as one of the studies under severe malaria consortium to improve outcomes of severe malaria owing to the continued severe malaria burden and poor outcomes.</span></p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n KEMRI - SERU (Scientific Ethics Review Unit) KEMRI/SERU/CGMR-C/127/3744 on 25th Feb 2019.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Imperial College Researcch Ethic Committee (ICREC) Reference number: P71159</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration18 months
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKilifi County Hospital
      • single_site_physical_addressBOX 9Kilifi
      • single_site_contact_personMs Hellen Mnjala
      • single_site_telephone+254731289430
      • multiple_sites_member_stateNo
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_site20
      • total_participants_worldwide20
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenYes
      • 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_situationYes
      • subjects_incapable_consentYes
      • subjects_specifyChildren aged below 12 years.
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameKathryn Maitland
      • investigator1_middle_name
      • investigator1_family_nameMaitland
      • investigator1_qualificationProfessor of Paediatric Tropical Infectious Diseases (MBBS PhD)
      • investigator1_professional_addressBOX 230 KILIFI
      • investigator1_telephone+254733411022
      • investigator1_emailkathryn.maitland@gmail.com
      • organisations_transferred_No
      • number_participants20
      • notification
      • approval_date08-08-2021
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted08-11-2021
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe application has been approved by the experts
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-02-10 10:25:54
      • created2020-06-10 13:40:32
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id559
        • application_id904
        • given_nameKathryn Maitland
        • middle_name
        • family_nameMaitland
        • qualificationProfessor of Paediatric Tropical Infectious Diseases (MBBS PhD)
        • professional_addressBOX 230 KILIFI
        • telephone+254733411022
        • emailkathryn.maitland@gmail.com
        • created2020-06-10 13:44:31
        • modified2021-11-08 11:34:54
    • SiteDetail(array)
      • 0(array)
        • id781
        • application_id904
        • county_id(null)
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        • contact_details
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        • site_capacity(null)
        • misc(null)
        • created2020-06-10 13:44:31
        • modified2021-11-08 11:34:54
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id434
        • application_id904
        • sponsorImperial college london
        • sponsor_typeOthers
        • contact_personJoint Research Compliance Officer
        • addressRoom 221, Medical school building, Norfolk Place, London W21PG
        • telephone_number+44 207 594 1188
        • fax_number
        • cell_number+44 207 594 1188
        • email_addressjro@ic.ac.uk
        • created2020-06-10 13:44:31
        • modified2021-11-08 11:34:54
  • 4(array)
    • Application(array)
      • id1073
      • user_id336
      • trial_status_id1
      • abstract_of_study<p>\n <strong>Introduction</strong>: The primary objective is to evaluate the non-inferiority of a simplified magnesium sulfate regimen [10 g intramuscular (IM) 12 hourly x 2 doses] compared with a standard magnesium sulfate regimen [either 4g intravenous (IV) loading dose, followed by a maintenance dose of 1g/hour until 24 hours (“Zuspan regimen”) or 4g IV plus 10 g IM loading dose, followed by 5 g IM 4 hourly until 24 hours (“Pritchard regimen”)] for the prevention of maternal eclamptic seizure.</p>\n<p>\n  </p>\n<p>\n <strong>Methods  and materials</strong></p>\n<p>\n This will be a phase III, multicountry, multicentre, two-arm, parallel, open-label, active-controlled, randomized, non-inferiority trial.  The study population will be women diagnosed with pre-eclampsia and with a clinical or laboratory indication for magnesium sulfate treatment before giving birth or within 24 hours of giving birth. Eligible, consenting women will be randomized to receive either 10 g of magnesium sulfate IM 12 hourly x 2 doses or a standard IV (Zuspan) or standard IM (Pritchard) magnesium sulfate regimen depending on the standard treatment protocol in the participating hospitals.  Standard IV regimen will be 4g IV as loading dose, followed by IV infusion of 1g per hour for 24 hours whereas standard IM regimen will be administered as 4g IV plus 10 g IM loading dose, followed by 5 g IM every 4 hours for 24 hours. Outcome measurements will be conducted in women and their babies until the time of hospital discharge or transfer to a higher care unit or death. The primary outcome will be the occurrence of maternal eclamptic seizure. <strong>Statistical methods:</strong> In order to demonstrate non-inferiority within a margin of 0.51%, with a power of 80% and with a significance level of 2.5%, a total of 11,596 women (5,798 per group) are needed assuming equal eclampsia prevalence of 0.97% in the standard treatment group and the simplified treatment group. Assuming 3% drop-outs due to exclusion of women after randomization and those who are not protocol-compliant, the estimated sample size will be 11,959 women. The first interim analysis will be conducted for the Data Safety Monitoring Committee (DSMC) to assess safety and futility when 2400 women (1200 per arm) have been recruited. Second interim analysis will be conducted when 6000 women (3000 per arm) have been recruited to assess safety, efficacy, and futility. Final noninferiority analysis will be performed when total sample size of 12000 women is achieved.</p>\n<p>\n  </p>\n<p>\n <strong>Utility </strong></p>\n<p>\n Lack of resources to administer IV medication and provide supportive care and/or repeated IM administration of magnesium sulfate may be associated with pain due to the large volume for injection and risk of infection at the injection site. These challenges have turned the attention of health care workers towards seeking and testing alternative dosage regimens for magnesium sulfate. This approach has largely been driven by the intention to improve coverage of a life-saving treatment for women with pre-eclampsia, minimize potential adverse effects, reduce resources that are required for administering the complex standard regimens, and to encourage task sharing among health care providers where necessary</p>\n
      • study_title<p>\n Simplified Treatment for Eclampsia Prevention using Magnesium sulfate:  A phase III, randomized, open label, active controlled, multicountry, multicentre, non-inferiority trial of simplified magnesium sulfate regimen for eclampsia prophylaxis (The STEP-Mag Trial)</p>\n
      • laymans_summary<p>\n <strong>S</strong>implified <strong>T</strong>reatment for <strong>E</strong>clampsia <strong>P</strong>revention using <strong>Mag</strong>nesium sulfate</p>\n
      • short_titleSTEP-Mag Trial
      • protocol_noECCT/22/01/05
      • version_no2.2
      • date_of_protocol23-04-2021
      • study_drugMagnesium Sulphate
      • disease_conditionPreeclampsia
      • 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_nameMagesium Sulphate
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresszahida@qureshi.co.ke
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantUniversity of Nairobi, Faculty of Health Services, Department of Obstetrics and Gynaecology
      • declaration_date125-01-2022
      • declaration_principal_investigatorProf. Zahida Qureshi, Principal Investigator
      • declaration_date225-01-2022
      • placebo_presentNo
      • study_objectives<h3>\n 1.1.1.Primary objective </h3>\n<p>\n The primary objective of this trial is to evaluate non-inferiority of magnesium sulfate 10g IM administered 12 hourly x 2 doses compared with a standard IV (Zuspan) or IM (Pritchard) magnesium sulfate regimen in the prevention of maternal eclamptic seizure.</p>\n<p>\n <strong>Secondary objective</strong></p>\n<p>\n The secondary objective of this trial is to evaluate superiority of magnesium sulfate 10g IM administered 12 hourly x 2 doses compared with a standard IV (Zuspan) or IM (Pritchard) magnesium sulfate regimen in the proportion of women experiencing adverse events indicative of magnesium toxicity.</p>\n<p>\n  </p>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n To be eligible for inclusion into this trial, the women must fulfill <strong><u>all</u></strong> of the following criteria:</p>\n<p>\n  </p>\n<ol>\n <li style=\"text-align: justify;\">\n Be admitted with a diagnosis of pre-eclampsia and with clinical or laboratory indication(s) for magnesium sulfate treatment, as defined by any of the following: two readings of systolic blood pressure ≥160 mm Hg, or diastolic blood pressure ≥110 mm Hg along with ≥2+ proteinuria on urine dipstick; or the presence of symptoms, signs or laboratory findings suggestive of severe disease such as headache, visual disturbances, upper abdominal pain, pulmonary oedema, nausea and vomiting, hyperreflexia or clonus, elevated liver enzymes, raised serum creatinine, or thrombocytopenia. Women with HELLP syndrome, a severe form of pre-eclampsia characterized by <strong>H</strong>aemolysis, <strong>E</strong>levated <strong>L</strong>iver enzymes, and <strong>L</strong>ow <strong>P</strong>latelets (<100 cells/mcl) will be included if there is no clinical contraindication to IM injection.</li>\n <li style=\"text-align: justify;\">\n Have not yet given birth but birth is planned or expected within the next 24 hours, or have given birth within the last 24 hours.</li>\n <li style=\"text-align: justify;\">\n Provide written informed consent before any trial-related procedures are carried out.</li>\n</ol>\n
      • principal_exclusion_criteria<p>\n Women are not eligible if they fulfill <strong><u>any</u></strong> of the following exclusion criteria:</p>\n<p>\n  </p>\n<ol>\n <li style=\"text-align: justify;\">\n Unable or unwilling to give informed consent (because the woman is too distressed or not capable to understand, confirm and give informed consent due to emergency or health condition, or does not wish to be randomized for whatever reason). </li>\n <li style=\"text-align: justify;\">\n Are non-emancipated minors (as per local regulations) without a guardian.</li>\n <li style=\"text-align: justify;\">\n History of hypersensitivity to magnesium sulfate.</li>\n <li style=\"text-align: justify;\">\n Serious cardiovascular disorders (WHO classification III or IV or acute heart failure).</li>\n <li style=\"text-align: justify;\">\n Serious hepatic (encephalopathy or coma) or renal disease.</li>\n <li style=\"text-align: justify;\">\n History of epilepsy.</li>\n <li style=\"text-align: justify;\">\n Myasthenia gravis or any muscular dystrophies.</li>\n <li style=\"text-align: justify;\">\n Coagulopathy.</li>\n <li style=\"text-align: justify;\">\n Have previously received magnesium sulfate for eclampsia prevention in the current pregnancy.</li>\n <li style=\"text-align: justify;\">\n Planned to receive magnesium sulfate regimen other than the regimens specified for the trial on account of other medical indication(s) (e.g. fetal neuroprotection).</li>\n <li style=\"text-align: justify;\">\n Known oliguria (<400mL urine in 24 hours) at the time of admission.</li>\n</ol>\n
      • primary_end_points<p style=\"margin-left:27.0pt;\">\n Maternal eclamptic seizure</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety0
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n <strong>Mama Lucy Hospital</strong> is a level 4 hospital located in the city of Nairobi. It handles over 1000 deliveries per month.</p>\n<p>\n It has a 66 bed maternity ward with 41 nurses, 6 consultant obstetricians/gynaecologists, and 2 Clinical Officers</p>\n<p>\n <strong>Nakuru Level 5 Hospital</strong> is a public level 5 urban hospital in Nakuru, Kenya. It handles over 1000 deliveries per month.</p>\n<p>\n It has an 18 bed maternity ward with 30 midwives, 4 house officers and 2 consultant obstetricians/gynaecologists.</p>\n<p>\n <strong>Naivasha County Referral Hospital Level 5</strong> is a public level 5 urban hospital in Thika, Kenya. It handles approximately 1000 deliveries per month.</p>\n<p>\n It has a 89 bed maternity ward with 17 midwives, 2 house officers and 1 full time consultant obstetricians/gynaecologists. </p>\n
      • other_details_explanation<p>\n <span font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">This is a multi-country trial conducted in five countries, where WHO is the trial sponsor</span></p>\n
      • other_details_regulatory_notapproved<p>\n <em>Other countries are in preparation as well (India, Malawi, Nigeria, South Africa, Uganda)</em></p>\n
      • other_details_regulatory_approved<p>\n None</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration3 years
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindYes
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorStandard intervention
      • design_controlled_other_medicinalNo
      • 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_states5
      • number_of_sites3
      • multi_country_listIndia\nKenya\nNigeria \nMalawi \nUganda
      • data_monitoring_committeeYes
      • total_enrolment_per_siteMama Lucy Hospital-341\nNakuru Level 5- 392\nNaivasha Sub-county hospital-331
      • total_participants_worldwide12000
      • 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_male0
      • subjects_healthyYes
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • 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_nameZahida
      • investigator1_middle_name
      • investigator1_family_nameQureshi
      • investigator1_qualificationAssociate Professor
      • investigator1_professional_addressP.O.BOX 19676-00202, Department of Obstetrics and Gynaecology, University of Nairobi, Kenyatta National Hospital campus, Nairobi, Kenya
      • investigator1_telephone+254733605140
      • investigator1_emailzahida@qureshi.co.ke
      • organisations_transferred_No
      • number_participants1064
      • notification
      • approval_date15-05-2022
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted22-02-2022
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer queries have been addressed
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2023-06-07 16:43:29
      • created2021-10-12 06:47:01
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id737
        • application_id1073
        • given_nameZahida
        • middle_name
        • family_nameQureshi
        • qualificationAssociate Professor
        • professional_addressP.O.BOX 19676-00202, Department of Obstetrics and Gynaecology, University of Nairobi, Kenyatta National Hospital campus, Nairobi, Kenya
        • telephone+254733605140
        • emailzahida@qureshi.co.ke
        • created2021-10-12 06:57:00
        • modified2022-02-22 07:47:28
    • SiteDetail(array)
      • 0(array)
        • id1137
        • application_id1073
        • county_id32
        • site_nameNakuru Level V Hospital
        • physical_addressshow ground road
        • contact_detailsP.O. Box 71-20100
        • contact_personDr. Barassa
        • site_capacity(null)
        • misc(null)
        • created2021-10-12 06:57:00
        • modified2022-02-22 07:47:28
        • County(array)
          • id32
          • county_nameNakuru
          • created2012-06-15 10:25:52
          • modified2012-06-15 10:25:52
      • 1(array)
        • id1138
        • application_id1073
        • county_id47
        • site_nameMama Lucy Kibaki Hospital
        • physical_addressKangundo road
        • contact_detailsP.O. Box 34349-00100
        • contact_personDr. Mutua
        • site_capacity(null)
        • misc(null)
        • created2021-10-12 07:10:44
        • modified2022-02-22 07:47:28
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 2(array)
        • id1139
        • application_id1073
        • county_id32
        • site_nameNaivasha Level IV Hospital
        • physical_addressNaivasha
        • contact_detailsP.O.B ox 141 Naivasha
        • contact_personDr. Chege
        • site_capacity(null)
        • misc(null)
        • created2021-10-12 07:10:44
        • modified2022-02-22 07:47:28
        • County(array)
          • id32
          • county_nameNakuru
          • created2012-06-15 10:25:52
          • modified2012-06-15 10:25:52
    • Sponsor(array)
      • 0(array)
        • id544
        • application_id1073
        • sponsorWHO
        • sponsor_typeResearch Institution
        • contact_person
        • addressGeneva
        • telephone_number+41227912111
        • fax_number
        • cell_number+41227912111
        • email_addresschoud@who.int
        • created2021-10-12 06:57:00
        • modified2022-02-22 07:47:28
• page_options(array)
  • 55
  • 1010
• redir
• $request->data(array)
  • Application(array)
    • approved2
• $this->validationErrors(array)
  • Permission(empty)
  • Aro(empty)
  • Aco(empty)
  • Application(empty)
  • User(empty)
  • TrialStatus(empty)
  • InvestigatorContact(empty)
  • Sponsor(empty)
  • SiteDetail(empty)
  • County(empty)
• Loaded Helpers(array)
  • 0Html
  • 1Form
  • 2Session
  • 3Text
  • 4Number
  • 5SimpleGraph
  • 6Paginator
  • 7DebugTimer
  • 8Toolbar
  • 9HtmlToolbar

App Constants

CakePHP Constants

PHP Environment

Included Files

Include Paths

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

Included Files

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