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  • 1Recruiting
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• applications(array)
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    • Application(array)
      • id993
      • user_id676
      • trial_status_id(null)
      • abstract_of_study<div>\n Background</div>\n<div>\n Tuberculosis (TB) is the leading cause of death in HIV-positive individuals. Underdiagnosis of TB is a principal barrier to combatting the disease. In resource-limited settings, molecular diagnoses such as Xpert MTB/RIF are still not widely available and sputum samples can be difficult to produce, especially for very ill HIV-positive patients.</div>\n<div>\n  </div>\n<div>\n The Fujifilm SILVAMP TB LAM (FujiLAM; Fujifilm, Tokyo, Japan) is a novel (not commercialised) urine107 based point-of-care assay to diagnose TB in HIV-positive patients. A first study using urine frozen samples has reported a higher sensitivity of this test over the currently commercialised Alere Determine TB LAM Ag assay (AlereLAM).</div>\n<div>\n  </div>\n<div>\n At the time of the study preparations, a pandemic caused by a new coronavirus (SARS-CoV-2), is ongoing. Symptoms of coronavirus disease (CoViD-19) are similar to those of TB and people with suppressed immune systems may be particularly vulnerable to this disease.</div>\n<div>\n  </div>\n<div>\n Objectives</div>\n<div>\n The aim of this study is to investigate the diagnostic performance of FujiLAM in ambulatory HIV positive patients from fresh urine samples.</div>\n<div>\n  </div>\n<div>\n Primary objective: To assess the sensitivity of FujiLAM among patients with microbiological confirmed TB in two groups of HIV-positive patients: 1) ambulatory adult HIV-positive patients with signs and symptoms of TB regardless of their CD4 count (Group 1), and 2) ambulatory adult patients with advanced HIV disease and no signs and symptoms of TB (Group 2).</div>\n<div>\n  </div>\n<div>\n Secondary objectives: To assess the sensitivity of FujiLAM and AlereLAM in urine by level of CD4 among patients with microbiologically confirmed TB and among patients with probable TB or microbiologically confirmed TB, the diagnostic performance of algorithms including FujiLAM, the mortality at 6 months according to the FujiLAM result and the feasibility of using the FujiLAM at point-of-care and the test acceptability by test users, clinic managers and patients. To assess the prevalence of CoViD-19 among HIV-positive ambulatory patients with symptoms of TB, to describe the clinical features, the severity and the outcomes of the patients diagnosed with CoViD-19, and the proportion of patients co-infected with CoViD-19 and TB, to assess the proportion of HIV-positive patients exposed to SARS-CoV-2</div>\n<div>\n  </div>\n<div>\n Methods</div>\n<div>\n This prospective diagnostic study, will include two groups of ambulatory adult patients: 1) HIV positive patients with signs and symptoms of TB (Group 1), and 2) patients with advanced HIV disease (CD4 < 200 cells/μL or WHO Stage III/IV) and no signs and symptoms of TB (Group 2). In addition, a mix-methods approach will be used to assess the feasibility and acceptability of the test. Quantitative and qualitative methods using an exploratory design will be used for this purpose.</div>\n<div>\n  </div>\n<div>\n The study will take place in Homa Bay County Hospital in Kenya. This study is part of a multicentric study that includes other sites: the Mbarara Regional Reference Hospital in Uganda, Alto Maé Health Centre in Mozambique, and Eshowe Gateway Clinic (EGC) in Eshowe, KwaZulu-Natal, South Africa.</div>\n<div>\n  </div>\n<div>\n <div>\n Patients will be assessed for signs and symptoms of TB (cough, fever, weight loss, 138 night sweats). HIV139</div>\n <div>\n positive patients with signs and symptoms of TB and fulfilling other eligibility criteria will be invited to participate in the study as Group 1. HIV-positive patients with no signs and symptoms of TB, and with CD4 <200 cells/μL within the month prior to the consultation or in clinical Stage III/IV at the time of the consultation, and fulfilling other eligibility criteria will be invited to participate in the study as Group 2. All eligible patients will be proposed to sign an informed consent. For patients with no signs and symptoms of TB who are on clinical stage I/II and do not have a CD4 result within the month prior to the consultation, CD4 monitoring will be done by the study. In such case, patients will sign an informed consent before screening for eligibility.</div>\n <div>\n  </div>\n <div>\n Patients will receive a clinical exam, FujiLAM and AlereLAM in urine, Xpert MTB/RIF and MTB culture on sputum samples, and chest X-ray. The treating clinician will decide to treat for TB or not according to the clinical exam and the test results available except the Fuji LAM test results. Patients with signs and symptoms of TB not started on TB treatment will be re-assessed at a second consultation no later than 7 days (earlier if laboratory results are available earlier or if the patient requires a consultation earlier). In some cases a third consultation may be needed due to the clinical situation or to the delay in receiving some test results. Patient’s outcomes whether on TB treatment or not, will be assessed at 3 months and 6 months.</div>\n <div>\n  </div>\n <div>\n In addition to the TB investigations, patients with signs and symptoms of TB will be proposed optional CoViD-19 testing using conventional PCR or point-of-care PCR (GeneXpert SARS-CoV-2) at the first consultation and during follow-up if COVID-19 symptoms arise. Patients diagnosed with Covid-19 will be referred to the Homa Bay Ministry of Health Covid-19 centre for their management. All patients (symptomatic and asymptomatic) will be also proposed optional SARS-CoV-2 antibody testing at the first and last consultation.</div>\n <div>\n  </div>\n <div>\n The primary endpoint will be the sensitivity of FujiLAM calculated as the proportion of patients with a positive test result among patients with microbiological confirmed TB.</div>\n <div>\n  </div>\n <div>\n Secondary endpoints will be:</div>\n <div>\n - Sensitivity of FujijLAM and AlereLAM by level of CD4 among patients with microbiologically confirmed TB and among patients with probable TB or microbiologically confirmed TB</div>\n <div>\n - Specificity, positive and negative predictive values of FujiLAM</div>\n <div>\n - Diagnostic performance of algorithms combining AlereLAM or FujiLAM in urine with Xpert MTB/RIF in sputum</div>\n <div>\n - Median time to FujiLAM, AlereLAM and Xpert MTB/RIF test results</div>\n <div>\n - Mortality at 6 months according to the FujiLAM result.</div>\n <div>\n - Feasibility and acceptability of the FujiLAM test at point of care by test users, managers and patients.</div>\n <div>\n - Proportion of TB symptomatic patients diagnosed with CoViD-19 overall, by TB diagnosis, by severity of disease and by outcome.</div>\n <div>\n - Proportion of patients exposed to SARS-CoV-2.</div>\n <div>\n  </div>\n <div>\n A total of 200 HIV-positive patients with signs and symptoms of TB (Group 1) and 250 HIV-positive patients with no signs and symptoms of TB and CD4<200 or in stage III/IV (Group 2) will be recruited in Homa Bay.</div>\n <div>\n  </div>\n <div>\n <div>\n Patients’ informed consent will be obtained before enrolment in the study. The study 180 protocol, the information sheets, the consent forms and any other relevant documents will be submitted for approval to the National Ethics Committees in each country where the study will be conducted and to Médecins Sans Frontières (MSF) Ethics Review Board.</div>\n <div>\n  </div>\n <div>\n Expected results</div>\n <div>\n This research study would be among the first to provide evidence through a prospective study on the performance of FujiLAM, a novel point-of-care test to diagnose TB in HIV-positive patients in programmatic conditions. If the diagnostic performance of this test is proven to be good, the use of the test would allow rapid TB diagnosis and would potentially decrease mortality in HIV-positive patients.</div>\n <div>\n  </div>\n <div>\n The study will also inform WHO and the international scientific community on the diagnostic performance and other implementation aspects of using the test. The study will also provide additional evidence on CoViD-19 among HIV-positive patients.</div>\n </div>\n</div>\n<p>\n  </p>\n
      • study_title<div>\n Diagnostic performance of a novel lipoarabinomannan test (FujiLAM) to detect tuberculosis in HIV-positive patients in Kenya</div>\n
      • laymans_summary<div>\n Tuberculosis (TB) is the leading cause of death among individuals living with HIV. Many cases of TB are missed each year for various reasons including lack of appropriate tools for the diagnosis of tuberculosis in specific populations at risk. This hinders the efforts to combat the disease. A test called the GeneXpert is a standard in the diagnosis of TB in Kenya and many similar settings. The test looks for the genetic material of the bacteria causing tuberculosis and requires individuals with suspected tuberculosis to produce phlegm for testing. While this test shows good performance, it is not always available and some categories of individuals such as HIV patients who are very sick are unable to cough up the phlegm required for testing.</div>\n<div>\n  </div>\n<div>\n The purpose of this study is to assess the performance of a new test called the Fujifilm SILVAMP TB LAM or simply the Fuji-LAM test. The Fuji-LAM test is a test that can be done on urine to look for specific proteins that are produced by the bacteria that causes tuberculosis. This test offers an advantage over the tests that are based on phlegm because most patients can produce urine for testing even when they are very sick. Additionally, this test does not require a complex laboratory set up and it can therefore be used by health workers as they interact with the patient. This study will also look at how the new test compares with an existing test - AlereLAM - that is based on similar technology. Initial laboratory-based studies conducted on frozen urine samples show that the new test has better performance than the existing test. This study is different from the first studies because it is being conducted in real life settings rather than in a laboratory.</div>\n<div>\n  </div>\n<div>\n Tuberculosis shares certain symptoms with the ongoing COVID-19 pandemic and patients who have both diseases may experience worse outcomes. Because it might be difficult to accurately differentiate between early Tuberculosis and COVID19, individuals who agree to participate will be also offered COVID 19 tests to help distinguish between the two diseases and offer those with COVID19 appropriate treatment. This will also help us understand how COVID19 is affecting patients living with HIV and TB.</div>\n<div>\n  </div>\n<div>\n The study will be conducted at the Homa Bay County Hospital in Kenya. Individuals living with HIV with and without signs and symptoms of TB will be invited to take part. Individuals who agree to participate will be seen by the health workers in the study and will provide samples for testing using the FujiLAM test and other standard tests used to investigate individuals for suspected tuberculosis. We are also conducting similar studies in other African countries including Uganda, Mozambique and South Africa. This will enable us to assess the performance of the test in diverse settings.</div>\n<div>\n  </div>\n<div>\n Should the study find that the performance of the Fuji-LAM test is good, it will make recommendations on the use of the test. The use of the test may allow faster identification of TB particularly among persons living with HIV. This faster identification will allow earlier treatment and likely to reduce the deaths that are associated with TB among persons living with HIV.</div>\n
      • short_titleFujiLAM Study
      • protocol_noECCT/21/04/01
      • version_nov2.3
      • date_of_protocol23-09-2020
      • study_drugNot applicable
      • disease_conditionTuberculosis
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device1
      • product_type_chemical_name
      • product_type_medical_device_nameFUJI LAM Test Kit
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresswansiste07@gmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data0
      • applicant_analysis_cert0
      • applicant_pictorial_sample0
      • applicant_gcp_training1
      • applicant_dsmb_charter0
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantDr. Stephen Sitima Wanjala
      • declaration_date129-03-2021
      • declaration_principal_investigatorDr Stephen Sitima Wanjala
      • declaration_date229-03-2021
      • placebo_presentNo
      • study_objectives<p>\n <strong>Objectives</strong></p>\n<p>\n The aim of this study is to investigate the diagnostic performance of FujiLAM in ambulatory HIV290<br />\n positive patients.</p>\n<p>\n <strong>Primary objective</strong><br />\n To assess the sensitivity of FujiLAM among patients with microbiological confirmed TB in two groups of HIV-positive patients: 1) in ambulatory HIV-positive patients with signs and symptoms of TB regardless of their CD4 count (Group 1), and 2) in ambulatory patients with advanced HIV disease (CD4 below 200 cells/μL or WHO stage III/IV) and no signs and symptoms of TB (Group 2).</p>\n<p>\n <strong>Secondary objectives</strong><br />\n â‚‹ To assess the sensitivity of FujiLAM at different levels of CD4 count.<br />\n â‚‹ To assess the sensitivity of AlereLAM in urine and compare the diagnostic sensitivity of FujiLAM with AlereLAM.<br />\n â‚‹ To assess the diagnostic performance in the 24 hours following the first visit, of diagnostic algorithms combining FujiLAM or AlereLAM in urine with Xpert MTB/RIF in sputum.<br />\n â‚‹ To assess the specificity and predictive values of FujiLAM.<br />\n â‚‹ To compare FujiLAM and Xpert in urine results in patients with no sputum sample available.<br />\n â‚‹ To assess the time to FujiLAM, AlereLAM and Xpert MTB/RIF test results.<br />\n â‚‹ To assess the mortality at 6 months according to the FujiLAM result.<br />\n â‚‹ To assess the FujiLAM test inter-reader agreement<br />\n â‚‹ To assess the feasibility of using FujiLAM at point-of-care, and the test acceptability by test users, managers and patients.<br />\n â‚‹ To assess the prevalence of CoViD-19 in HIV-positive ambulatory patients with symptoms of TB, to describe the clinical features, the severity and the outcomes of the patients diagnosed with CoViD-19 and the proportion of patients co-infected with CoViD-19 and TB, to assess the proportion of HIV-positive patients exposed to SARS-CoV-2.</p>\n
      • principal_inclusion_criteria<p>\n Inclusion criteria<br />\n - 15 years of age or older<br />\n - HIV-positive<br />\n <strong>Group 1:</strong> At least one symptom of TB<br />\n <strong>Group 2</strong>: Advanced HIV disease (CD4 count less than 200cell/μl or clinical stage III/IV)<br />\n                AND No signs and symptoms of TB</p>\n<p>\n Signature of the informed consent for both groups</p>\n
      • principal_exclusion_criteria<p>\n Below 15 years</p>\n<p>\n Intake of anti-tuberculosis drugs for more than 5 days in the month prior to the consultation except preventive TB treatment.</p>\n
      • primary_end_points<p>\n Proportion of patients with a positive FujiLAM result among patients with microbiologically confirmed TB in ambulatory HIV-positive patients with signs and symptoms of TB (Group 1) and ambulatory HIV-positive patients with advanced HIV disease and no signs and symptoms of TB (Group 2).</p>\n
      • scope_diagnosis1
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety0
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyDiagnostic Study
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n <tbody>\n <tr>\n <td style=\"width:32px;\">\n <p>\n <strong>No</strong></p>\n </td>\n <td style=\"width:208px;\">\n <p>\n <strong>Name</strong></p>\n </td>\n <td style=\"width:185px;\">\n <p>\n <strong>Qualification</strong></p>\n </td>\n <td style=\"width:164px;\">\n <p>\n <strong>Role/Experience</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 1</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Milcah Akinyi</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n BsN</p>\n <p>\n APGD_CR,MSc HM</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study coordinator</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 2</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Dalmas Ochiel</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Registered clinical Officer</p>\n <p>\n Bsc Public Health</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study clinician</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 3</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Barnabas Ogere</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Registered Clinical Officer</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study clinician</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 4</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Polycarp Oyoo</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Registered Nurse</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study Nurse</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 5</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Eve Dorcas Awino</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Registered Nurse</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study Nurse</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 6</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Irene Akoth</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Laboratory Technologist</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Study lab technician</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 7</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Lucy Nyadoya Were</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Diploma IT</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Data Entry Clerk</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:32px;\">\n <p>\n 8</p>\n </td>\n <td style=\"width:208px;\">\n <p>\n Beryl Akinyi</p>\n </td>\n <td style=\"width:185px;\">\n <p>\n Diploma Social Work & Community Development</p>\n </td>\n <td style=\"width:164px;\">\n <p>\n Community mobiliser / Tracer</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_explanation<p>\n The primary objective of the study is to evaluate the performence of the FujiLAM test in comparison to known alternatives(Alere LAM, Culture). Kenya and the other countries included in the study deemed appropriate because of the high prevalence of HIV and TB with a significant proportion of patients having advanced HIV. Previous studies have shown that LAM based technology is best suited for advanced HIV patients. In light of this, the countries were chosen because, if successfull, the patients who are most likely to benefit from the diagnostic tool being evaluted will come from high HIV/TB burden countries. </p>\n
      • other_details_regulatory_notapproved<p>\n None</p>\n
      • other_details_regulatory_approved<p>\n Medecines Sans Frontieres IRB , October 2019</p>\n
      • other_details_regulatory_rejected<p>\n Not applicable</p>\n
      • other_details_regulatory_halted
      • estimated_duration24 months
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
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      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaHomabay County Teaching and Referral Hospital
      • single_site_physical_addressHomabay Town Kenya
      • single_site_contact_personDr. Stephen Wanjala
      • single_site_telephone0720284862
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states3
      • number_of_sites
      • multi_country_listUganda - Mbarara Teaching and Referral Hospital\nMozambique - Alto Maé Health Centre\nSouth Africa - Eshowe Gateway Clinic, KwaZulu Natal Province
      • data_monitoring_committeeNo
      • total_enrolment_per_site450 patients at Homabay County and Referral Hospital
      • total_participants_worldwide1870
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsNo
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameStephen
      • investigator1_middle_nameSitima
      • investigator1_family_nameWanjala
      • investigator1_qualificationMBChB, MSc Health Economics and Policy, MBA
      • investigator1_professional_addressP. O. Box 21340 - 00100
      • investigator1_telephone0720284862
      • investigator1_emailwansiste07@gmail.com
      • organisations_transferred_No
      • number_participantsA total of 450 patients will be recruited in Homabay Kenya. 200 of these will be HIV-positive patients with signs and symptoms of TB (Group 1) and 250 will be HIV-positive patients with no signs and symptoms of TB and CD4<200 or in stage III/IV (Group 2)
      • notification
      • approval_date04-11-2021
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted12-07-2021
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe application has been approved
      • final_report(null)
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      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
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      • balance_site(null)
      • final_date(null)
      • modified2021-11-04 19:09:19
      • created2021-03-29 15:20:58
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id635
        • application_id993
        • given_nameHelena
        • middle_name
        • family_nameHuerga
        • qualificationMD, MSc, PhD
        • professional_addressEPICENTRE, CLINICAL RESEARCH DEPARTMENT, 14-34 AVENUE JEAN JAURES, 75019, PARIS
        • telephone+32 493 83 78 95
        • emailHelena.HUERGA@epicentre.msf.org
        • created2021-03-29 16:00:08
        • modified2021-07-12 07:44:39
    • SiteDetail(array)
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        • id879
        • application_id993
        • county_id(null)
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        • contact_details
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        • misc(null)
        • created2021-03-29 16:00:08
        • modified2021-07-12 07:44:39
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id490
        • application_id993
        • sponsorMedecins Sans Frontieres /Epicentre
        • sponsor_typeResearch Institution
        • contact_personHelena Huerga
        • addressEPICENTRE, CLINICAL RESEARCH DEPARTMENT, 14-34 AVENUE JEAN JAURES, 75019, PARIS
        • telephone_number+32 493 83 78 95
        • fax_number
        • cell_number+32 493 83 78 95
        • email_addressHelena.HUERGA@epicentre.msf.org
        • created2021-03-29 16:00:08
        • modified2021-07-12 07:44:39
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      • user_id32
      • trial_status_id5
      • abstract_of_study<p>\n Malaria due to <em>Plasmodium falciparum</em> infection is a major cause of human suffering and an economic drain in many parts of sub-Saharan Africa. The current malaria control programs in endemic areas have relied mainly on three key strategies i.e. use of effective artemisinin-based combination therapies (ACTs), insecticide-treated bednets (ITNs) and indoor residual spraying (IRS). Widescale deployment of these control tools has significantly reduced the burden of malaria in endemic areas. However, challenges such as the emergence of parasite resistance to antimalarial drugs and vector resistance to insecticides used in ITNs and IRS calls for additional and novel tools. Historically, vaccines have proven to be one of the most cost-effective means of preventing infectious diseases and saving lives. Therefore, a malaria vaccine could be an important additional tool that could complement the existing malaria control strategies.</p>\n<p>\n <span style=\"font-size: 12px;\">The RTS,S/AS01</span>_E<span style=\"font-size: 12px;\"> is the only vaccine at the most advanced stage of clinical development and the first to be tested in a large phase III clinical trial in children and infants in malaria endemic areas of sub-Saharan Africa. In these phase III studies, the vaccine was shown to be safe, immunogenic and provided moderate protection against malaria. However, vaccine efficacy waned with time and further research is needed to explore alternative vaccination schedules to those tested and other strategies to improve its efficacy. The proposed study will evaluate the efficacy, safety and immunogenicity of RTS,S/AS01</span>_E<span style=\"font-size: 12px;\"> vaccine administered using different schedules from those tested in the phase III trials, with or without fractional doses, early Dose 4 and yearly doses, in children 5-17 months of age in a malaria endemic area of Siaya County, western Kenya. Results from this study will aid in the ongoing evaluation of RTS,S and will be critical in the development of malaria vaccine-based control strategies which, in combination with other interventions, may contribute to the global malaria elimination efforts.</span></p>\n
      • study_title<div>\n Efficacy, safety and immunogenicity study of GSK <span style=\"font-size: 12px;\">Biologicals’ candidate malaria vaccine (SB257049) </span><span style=\"font-size: 12px;\">evaluating schedules with or without fractional doses, </span><span style=\"font-size: 12px;\">early Dose 4 and yearly doses, in children 5-17 months </span><span style=\"font-size: 12px;\">of age.</span></div>\n
      • laymans_summary<div>\n <strong>What was the main purpose of the study?</strong></div>\n<div>\n Malaria is a sickness that one can get from the bite of a mosquito carrying the malaria parasite. Malaria causes high fever, chills and can lead to serious problems. Problems include low blood levels, loss of consciousness and sometimes death. Young children have the biggest risk for getting very sick and dying from malaria.</div>\n<div>\n Vaccination is a means of protection against a disease. A vaccine increases body’s ability to fight off a particular infection. A malaria vaccine has been developed to protect children against malaria.</div>\n<div>\n The aim of this study was to find out how well the malaria vaccine (RTS,S/AS01E- which will be referred as RTS,S in this document) worked against malaria (vaccine efficacy) when given in different doses and at various schedules. The researchers were also interested in knowing if the vaccine continued to be well tolerated in children at those doses and schedules.</div>\n<div>\n  </div>\n<div>\n <strong>When and where did the study take place?</strong></div>\n<div>\n A total of 1500 children from Kenya and Ghana participated in this study (750 Kenya, 750 Ghana)</div>\n<div>\n  </div>\n<div>\n <div>\n <strong>Who took part in the study?</strong></div>\n <div>\n Studies have a list of requirements for participants who can take part or cannot take part in the study.</div>\n <div>\n The children were included in the study if they:</div>\n <div>\n •Were a boy or a girl, aged 5–17 months.</div>\n <div>\n •Had previously received 3 injections of diphtheria, tetanus, pertussis, and hepatitis B vaccine and at least 3 doses of oral polio vaccine.</div>\n <div>\n •Were healthy, without any history of serious illness.</div>\n <div>\n Children were excluded from the study if they:</div>\n <div>\n • Were under the care of an orphanage.</div>\n <div>\n • Were taking long-term medication which could affect their immune responses or unapproved medicines/ vaccines before the study start.</div>\n <div>\n • Had a history of allergy to the vaccine contents or had a history of serious illness that would make the study vaccine unsafe.</div>\n <div>\n <strong><span lang=\"EN-US\">Which<span style=\"letter-spacing: 0.1pt;\"> </span></span>medicines<span style=\"letter-spacing: -0.2pt;\"> </span>were<span style=\"letter-spacing: -0.2pt;\"> </span>studied?</strong></div>\n <div>\n RTS,S-Malaria vaccine</div>\n <div>\n - In this study, a standard vaccine dose (full dose) and smaller amounts called fractional dose (1/5th of the volume)were tested.</div>\n <div>\n Rabies vaccine</div>\n <div>\n - In this study the rabies vaccine was given as a comparator vaccine.</div>\n <div>\n - Comparator is a non-malaria vaccine, helpful to see the malaria vaccine protects against malaria as compared to the comparator.</div>\n <div>\n <strong>What happened during the study?</strong></div>\n <div>\n This was an open-label study, which means that the study doctors and the parents of the children knew which vaccine was given.</div>\n <div>\n Children were randomly assigned to a group using a computer program to receive one of the malaria vaccine combinations or the rabies comparator vaccine.</div>\n <div>\n Depending on the group, children received 3, 4, 5 or 6 injections of vaccine at various times. The vaccine injections were given in the arm. The details of the groups and vaccination schedules were as shown in the study design below.</div>\n <div>\n <img alt=\"\" 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
      • short_titleMal 094
      • protocol_noECCT/18/01/01
      • version_no1
      • date_of_protocol06-04-2017
      • study_drugMalaria Vaccine RTS,S AS01E
      • disease_conditionMalaria
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines1
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameRabipur (inactivated rabies virus) vaccine
      • comparator_registeredYes
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresstsang@kemricdc.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi0
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantDr Tony Sang
      • declaration_date123-01-2018
      • declaration_principal_investigatorDr Simon Kariuki
      • declaration_date223-01-2018
      • placebo_presentYes
      • study_objectives<div>\n <strong>General Objective</strong></div>\n<ol>\n <li>\n The overall objective of the proposed study is to evaluate the safety, immunogenicity and efficacy of the candidate malaria vaccine RTS,S/AS01E in vaccination schedules with or without fractional doses, early Dose 4 and yearly doses, in children 5-17 months of age living in a malaria endemic area of western Kenya.</li>\n</ol>\n<div>\n  </div>\n<div>\n <strong>Specific Objectives</strong></div>\n<ol>\n <li>\n To evaluate the efficacy of RTS,S/AS01E primary schedule with or without fractional doses, early dose 4 and yearly doses</li>\n <li>\n To assess efficacy against prevalent P. falciparum infections (defined by a positive blood slide) of each RTS,S/AS01E schedule at cross sectional visits</li>\n <li>\n To describe the antibody response to the anti-circumsporozoite protein of P. falciparum (anti-CS) and hepatitis B surface antigen (anti-HBs) in a subset of subjects for each schedule.</li>\n <li>\n To assess the safety of RTS,S/AS01E for each schedule in terms of serious adverse events (SAEs), unsolicited adverse events (AEs) and AEs of specific interest.</li>\n <li>\n To assess the reactogenicity of RTS,S/AS01E in a subset of subjects terms of solicited local and general AEs.</li>\n <li>\n To assess the safety of RTS,S/AS01E in a subset of subjects in terms of biochemistry (alanine aminotransferase [ALT], creatinine) and hematology (hemoglobin, white blood cells [WBC], platelets) parameters.</li>\n <li>\n To describe the anti-CS antibody response in a subset of subjects in terms of avidity.</li>\n</ol>\n
      • principal_inclusion_criteria<div>\n All subjects must satisfy ALL the following criteria at study entry:</div>\n<ul>\n <li>\n Subjects’ parent(s)/LAR(s) who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. return for follow-up visits).</li>\n <li>\n Signed or thumb-printed and witnessed informed consent obtained from the parent(s)/LAR(s) of the subject prior to performance of any study specific procedure. Where parent(s)/LAR(s) are illiterate, the consent form will be countersigned by an independent witness.</li>\n <li>\n A male or female between, and including, five and 17 months of age at the time of the first vaccination.</li>\n <li>\n Healthy subjects as established by medical history and clinical examination before entering into the study.</li>\n <li>\n Previously received three documented doses of diphtheria, tetanus, pertussis, hepatitis B vaccine (DTPHepB), and at least three doses of oral polio vaccine.</li>\n</ul>\n<div>\n  </div>\n
      • principal_exclusion_criteria<ul>\n <li>\n Child in care. Please refer to the glossary of terms for the definition of child in care.</li>\n <li>\n Use of a drug or vaccine that is not approved for that indication (by one of the following regulatory authorities: Food and Drug Administration [FDA; USA] or European Union member state or WHO [with respect to prequalification]) other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day -29 to Day 0), or planned use during the study period.</li>\n <li>\n Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.</li>\n <li>\n Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone ( 0.5 mg/kg/day (for pediatric subjects) or equivalent. Inhaled and topical steroids are allowed.</li>\n <li>\n Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting seven days before each dose and ending seven days after each dose of vaccine administration. (For example, the measles and yellow fever vaccines which are administered at nine months of age according to the standard EPI can be administered to study subjects provided that they are given at least seven days before or at least seven days after any dose of study vaccine).</li>\n <li>\n Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product (pharmaceutical product or device).</li>\n <li>\n Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).</li>\n <li>\n Family history of congenital or hereditary immunodeficiency.</li>\n <li>\n History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.</li>\n <li>\n History of anaphylaxis post-vaccination.</li>\n <li>\n History of any, or documented, serious adverse reaction to rabies vaccination.</li>\n <li>\n Contraindication to rabies vaccination (Rabipur is contraindicated in subjects with an history of a severe hypersensitivity to any of the ingredients in the vaccine. Note that the vaccine contains polygeline and residues of chicken proteins, and may contain traces of neomycin, chlortetracycline and amphotericin B) [Refer to the Rabipur SmPC, 2010].</li>\n <li>\n Major congenital defects.</li>\n <li>\n Serious chronic illness.</li>\n <li>\n History of any neurological disorders or seizures.</li>\n <li>\n Acute disease and/or fever at the time of enrolment.\n <ul>\n <li>\n <span style=\"white-space:pre\">​</span>Fever is defined as temperature ≥ 37.5°C/99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C/100.4°F for rectal route.</li>\n <li>\n Subjects with a minor illness (such as mild diarrhea, mild upper respiratory infection) without fever may, be enrolled at the discretion of the investigator.</li>\n </ul>\n </li>\n <li>\n Administration of immunoglobulins and/or any blood products during the period starting three months before the first dose of study vaccine or planned administration during the study period.</li>\n <li>\n Moderate or severe malnutrition at screening defined as weight for age Z-score < -2 (by WHO growth standard) [WHO, 2006].</li>\n <li>\n Hemoglobin concentration < 8 g/dl at screening.</li>\n <li>\n Same sex twins (to avoid misidentification).</li>\n <li>\n Maternal death.</li>\n <li>\n Prior receipt of an investigational malaria vaccine.</li>\n</ul>\n<div>\n  </div>\n
      • primary_end_points<p>\n <strong>Efficacy: Incremental efficacy of a schedule with a fractional third dose at Month 2 over the standard schedule</strong></p>\n<p>\n To demonstrate the superiority of a 3-dose schedule of GSK Biologicals’ malaria vaccine RTS,S/AS01_E with a fractional third dose at Month 2 compared to a standard schedule of RTS,S/AS01_E with three full doses in terms of vaccine efficacy against clinical malaria (primary case definition) over 12 months post-Dose 3.</p>\n<p>\n <em>Criterion:</em></p>\n<p>\n <em>The lower limit of the 95% CI of the incremental vaccine efficacy estimate is above 0.</em></p>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<div>\n The study will be conducted at the Siaya County Referral Hospital and up to 6 other surrounding health facilities (Ng’iya, Kogelo, Ting’wang’i, Mulaha, Nyathengo and Bar Olengo). These health facilities are located in Karemo Division of Siaya County and lie within the catchment area of the Kenya Medical Research Institute (KEMRI) and Centers for Disease Control and Prevention (CDC) Health and Demographic Surveillance System (HDSS)</div>\n<div>\n The key study staff will include the following:</div>\n<ul>\n <li>\n Co-PI - Dr Aaron Samuels, MD, MHS</li>\n <li>\n Co-PI - Dr Simon Kariuki, PhD</li>\n <li>\n Study Medical Officer - Dr Paul Ndaya Oloo, MD, MSc</li>\n <li>\n Study Pediatrician – Dr Martina Oneko, MD, Paed</li>\n <li>\n Pharmacist - Dr Tony Sang, BPharm</li>\n <li>\n Lab Manager – Kephas Otieno, MSc</li>\n <li>\n Data Manager – Kelvin Onoka BSc</li>\n <li>\n Study Coordinator - TBD</li>\n <li>\n Regulatory Affairs Officer – TBD</li>\n</ul>\n<div>\n Additionally, each of the sites will have the following personnel:</div>\n<ul>\n <li>\n Clinical Officers - 2</li>\n <li>\n Nurses - 2</li>\n <li>\n Laboratory Technicians/ Phlebotomist -1</li>\n <li>\n Data Officers -1</li>\n <li>\n QA/QC officers -1</li>\n</ul>\n<div>\n  </div>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n CDC IRB approved the study on </p>\n<p>\n KEMRI SERU approved the study on</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration5 years
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindNo
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorRabies vaccine
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states2
      • number_of_sites6
      • multi_country_listKenya\nGhana
      • data_monitoring_committeeYes
      • total_enrolment_per_site750
      • total_participants_worldwide1500
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenNo
      • population_adolescentNo
      • population_above_18No
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyInformed consent for subject participation will be sought from parent(s)/guardian(s).
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameAaron
      • investigator1_middle_name
      • investigator1_family_nameSamuels
      • investigator1_qualificationMD
      • investigator1_professional_addressP.O. Box 1578, Kisumu, 40100
      • investigator1_telephone+254 724 255 633
      • investigator1_emailamsamuels@cdc.gov
      • organisations_transferred_Yes
      • number_participants750
      • notification
      • approval_date06-03-2018
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted16-03-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<div>\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"100%\">\n <thead>\n <tr>\n <th style=\"width:25.72%;\">\n <p>\n <strong>Name of sponsor: GlaxoSmithKline Biologicals SA</strong></p>\n </th>\n <th style=\"width:39.58%;\">\n <p>\n <strong>Name of finished product:</strong></p>\n <p>\n GlaxoSmithKline Biologicals’ candidate <em>Plasmodium falciparum</em> malaria vaccine RTS,S/AS01_E</p>\n </th>\n <th style=\"width:34.7%;\">\n <p>\n <strong>Name of active substance:</strong></p>\n <p>\n RTS,S antigen, AS01_E adjuvant</p>\n </th>\n </tr>\n </thead>\n </table>\n <p>\n <strong>Study title:</strong> Phase IIb randomized, open-label, controlled, multi-center study of the efficacy, safety and immunogenicity of GSK Biologicals’ candidate malaria vaccine RTS,S/AS01_E evaluating schedules with or without fractional doses, early Dose 4 and yearly doses, in children 5-17 months of age living in sub-Saharan Africa.</p>\n <p>\n <strong>Principal/Coordinating investigator:</strong> Dr. Simon Kariuki, KEMRI/CDC/CGHR, Kisumu, Kenya and Prof. Tsiri Agbenyega, KNUST, School of Medical Science, Kumasi, Ghana.</p>\n <p>\n <strong>Study centers</strong><strong>:</strong> The study was conducted at 2 centers in 2 countries: 1 center in Siaya, Kenya and 1 center in Presbyterian Hospital, Agogo, Ghana.</p>\n <p>\n <strong>Publication(s):</strong> Samuels AM, Ansong D, Kariuki SK, et al. Lancet Infect Dis. 2022;22(9):1329-1342. Erratum in: Lancet Infect Dis. 2022 Sep 9.</p>\n <p>\n <strong>Study period</strong><strong>:</strong></p>\n <p>\n Study initiation date: 28 September 2017</p>\n <p>\n Study completion date: 14 November 2022</p>\n <p>\n End of study date: 26 April 2023</p>\n <p>\n <strong>Phase of development:</strong> Phase IIb</p>\n <p>\n <strong>Sequence of analyses: </strong></p>\n <ul>\n <li>\n A first interim analysis was performed on data collected up to Month 21 (Visit 25) to evaluate the primary objective and relevant secondary objectives, comprising efficacy data to Month 20 and immunogenicity and safety data to Month 21.</li>\n <li>\n A second interim analysis was performed on data collected up to Month 33 (Visit 31) to evaluate relevant secondary objectives, comprising efficacy data to Month 32 and immunogenicity and safety data to Month 33.</li>\n <li>\n The final analysis was performed at study end (Month 50) on efficacy, immunogenicity and safety data collected up to Month 50 (Visit 38) to evaluate relevant secondary objectives.</li>\n </ul>\n <p>\n <strong>Objectives:</strong></p>\n <table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n <thead>\n <tr>\n <th style=\"width:306px;\">\n <p align=\"center\">\n <strong>OBJECTIVES</strong></p>\n </th>\n <th style=\"width:270px;\">\n <p align=\"center\">\n <strong>ENDPOINTS</strong></p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"width:306px;\">\n <p>\n <strong>Primary Objective</strong></p>\n </td>\n <td style=\"width:270px;\">\n <p>\n <strong>Primary Endpoint</strong></p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Efficacy:</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To demonstrate the superiority of a 3-dose schedule of GSK’s malaria vaccine RTS,S/AS01_E with a fractional (Fx) third dose at Month 2 compared to a standard schedule of RTS,S/AS01_E with 3 full doses in terms of vaccine efficacy (VE) against clinical malaria (primary case definition) over 12 months post-Dose 3.</li>\n </ul>\n <p style=\"margin-left:21.6pt;\">\n <em>Criterion: T</em><em>he lower limit of the 95% confidence interval (CI) of the incremental VE estimate is above 0.</em></p>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of clinical malaria meeting the primary case definition from Month 2.5 up to Month 14.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <p>\n <strong>Secondary Objectives</strong></p>\n </td>\n <td style=\"width:270px;\">\n <p>\n <strong>Secondary Endpoints</strong></p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Efficacy:</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the incremental VE against clinical malaria of a schedule with a Fx third dose at Month 2 versus a schedule with 3 full doses (primary and secondary case definitions) over 12 months post-Dose 3.</li>\n <li>\n To assess the incremental VE against clinical malaria, over 7 and 12 months post-Dose 3, of a schedule with a Fx third dose at Month 7 versus a schedule with a Fx third dose at Month 2.</li>\n <li>\n To assess the incremental VE against clinical malaria, over 7 and 12 months post-Dose 3, of a schedule with a Fx third dose at Month 7 versus a schedule with 3 full doses.</li>\n <li>\n To assess the incremental VE against clinical malaria, over 12 months post-Dose 4, post-Dose 5 and post-Dose 6 of a schedule with a Fx third dose at Month 2 and yearly Fx doses versus a schedule with full doses at Month 0, Month 1, Month 2 and yearly full doses.</li>\n <li>\n To assess the incremental VE against clinical malaria, over 12 months post-Dose 4, of a schedule with a Fx third dose at Month 7 versus a standard schedule with 4 full doses at 0,1,2,20 months.</li>\n <li>\n To assess the VE and impact of each RTS,S/AS01_E schedule over the entire study period by measuring the efficacy against clinical malaria at Months 14, 20, 26, 32, 38 and 50.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of clinical malaria meeting the primary and secondary case definitions from Day 0 up to Month 50.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the prevalence of <em>P. falciparum</em> infections of each RTS,S/AS01_E schedule at cross-sectional visits (monthly from Month 0-20 and every 3 months thereafter till study end).</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The prevalence of <em>P. falciparum</em> infections defined by positive blood slide at each cross-sectional survey.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the VE against incident <em>P. falciparum</em> infections defined by positive blood slide over the entire study period.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of incident <em>P. falciparum</em> infections from Day 0 to Month 50.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Immunogenicity:</strong> Immune response to the CS and HBs antigens (immunogenicity sub-cohort)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To describe the antibody response to the anti-circumsporozoite protein of <em>P. falciparum</em> (anti-CS) for each schedule.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n Anti-CS antibody concentrations and seropositivity measured before Dose 1, 1 month post-Dose 2 (group Fx017-20 only), before and 1 month post-Dose 3, before and 1 month after Dose 4, before and 1 month after each yearly dose and at study end (Month 50).</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To describe the antibody response to the hepatitis B surface antigen (anti-HBs) for each schedule.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n Anti-HBs antibody concentrations, seropositivity and seroprotection measured before Dose 1, 1 month post-Dose 2 (group Fx017-20 only), before and 1 month post-Dose 3, before and 1 month after Dose 4, before and 1 month after each yearly dose and at study end (Month 50).</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Safety and reactogenicity:</strong> All participants</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the safety of RTS,S/AS01_E for each schedule in terms of serious adverse events (SAEs), unsolicited adverse events (AEs) and AEs of specific interest (AESI).</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of SAEs (all, fatal and related) during the whole study period according to the Medical Dictionary for Regulatory Activities (MedDRA) classification.</li>\n <li>\n The occurrence of AEs and SAEs leading to withdrawal from further vaccination from Dose 1 (Day 0) up to Month 50, according to the MedDRA classification.</li>\n <li>\n The occurrence of severe malaria cases and cerebral malaria cases during the whole study period.</li>\n <li>\n The occurrence of potential immune-mediated diseases (pIMDs) from Day 0 up to Month 50, according to the MedDRA classification.</li>\n <li>\n The occurrence of meningitis from Day 0 up to Month 50, according to the MedDRA classification.</li>\n <li>\n The occurrence of seizures within 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine, according to the MedDRA classification.</li>\n <li>\n The occurrence of generalized convulsive seizure within 7 days (day of vaccination and 6 subsequent days) after each dose of study vaccine, according to the Brighton Collaboration guidelines.</li>\n <li>\n The occurrence of unsolicited AEs within 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine, according to the MedDRA classification.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n <strong>Safety and reactogenicity:</strong> Reactogenicity (reactogenicity sub-cohort)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the reactogenicity of RTS,S/AS01_E in terms of solicited local and general AEs.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The occurrence of solicited local and general AEs in the first 50 participants enrolled in each group within 4 days (day of vaccination and 3 subsequent days) after Dose 3 of study vaccine (all groups including controls) after Dose 4 (groups R012-20, R012-14, Fx012-14 and Fx017‑20), after Dose 5 (groups R012-14, Fx012-14 and Fx017-20) and after Dose 6 (groups R012-14 and Fx012-14).</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:306px;\">\n <ul>\n <li>\n To assess the safety of RTS,S/AS01_E in terms of biochemistry (alanine aminotransferase [ALT], creatinine) and hematology (hemoglobin, white blood cells [WBCs], platelets) parameters.</li>\n </ul>\n </td>\n <td style=\"width:270px;\">\n <ul>\n <li>\n The concentration of biochemistry (ALT, creatinine) and hematology (hemoglobin, WBCs, platelets) parameters in the first 50 participants (25 participants per site) enrolled in each group (reactogenicity sub-cohort) before Dose 3, 7 days post‑Dose 3 and 30 days post-Dose 3.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:575px;\">\n <p>\n Results of the tertiary objective and endpoint are provided in the body of the report.</p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n <strong>Methodology:</strong> This study was a Phase IIb, randomized, open-label, controlled, multi‑center study with 5 parallel groups, conducted in children aged 5-17 months.</p>\n <table align=\"center\" border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:16.38%;height:30px;\">\n <p align=\"center\">\n <strong>Protocol study group naming</strong></p>\n </td>\n <td style=\"width:16.42%;height:30px;\">\n <p align=\"center\">\n <strong>SAP study group naming</strong></p>\n </td>\n <td style=\"width:67.2%;height:30px;\">\n <p align=\"center\">\n <strong>Vaccination schedule</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n R012-20</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n R012-20</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n RTS,S/AS01_E full dose at Months 0, 1 and 2 + full dose at Month 20</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n R012-14-mD</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n R012-14</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n RTS,S/AS01_E full dose at Months 0, 1 and 2 + yearly full doses at Months 14, 26 and 38</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n Fx012-14-mFxD</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n Fx012-14</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n RTS,S/AS01_E full dose at Months 0 and 1 + RTS,S/AS01_E 1/5^th dose at Months 2, 14, 26 and 38</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n Fx017-mFxD</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n Fx017-20</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n RTS,S/AS01_E full dose at Months 0 and 1 + RTS,S/AS01_E 1/5^th dose at Months 7, 20 and 32</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:16.38%;\">\n <p>\n Control</p>\n </td>\n <td style=\"width:16.42%;\">\n <p>\n Control</p>\n </td>\n <td style=\"width:67.2%;\">\n <p>\n Rabies vaccine at Months 0, 1 and 2</p>\n </td>\n </tr>\n </tbody>\n </table>\n <div style=\"clear:both;\">\n  </div>\n <p>\n SAP = Statistical Analysis Plan</p>\n <p>\n NOTE: group naming in the Clinical Study Report is aligned with the SAP/analyses tables.</p>\n <ul>\n <li>\n Sampling schedule</li>\n </ul>\n <p>\n For the evaluation of anti-CS responses, anti-HBs responses, biochemistry (ALT, creatinine) parameters and hematology (hemoglobin, WBCs, platelets) parameters, a sub-cohort of 50 participants (25 participants per site) enrolled in each group had tests performed on blood drawn at the timepoints described in the table below. In addition, a small amount of blood was taken every month up until Month 20 and thereafter every 3 months in all participants for the evaluation of <em>P. falciparum</em> infections.</p>\n <p>\n  </p>\n</div>\n<p>\n  </p>\n<div>\n <table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"99%\">\n <tbody>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 1</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 2</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 4</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 5</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 6</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 10</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 11</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 12</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 18</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 19</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 24</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 25</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 27</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 28</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 30</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 31</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 33</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 34</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Visit 38</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Study group</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Type of blood sampling</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>Scr</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>D0</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M2</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M2 + 7d</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M3</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M7</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M7 + 7d</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M8</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M14</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M15</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M20</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M21</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M26</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M27</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M32</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M33</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M38</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M39</strong></p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n <strong>M50</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>R012-20</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>R012-14</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Fx012-14</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Fx017-20</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n <strong>Control</strong></p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Safety</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:10.64%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:10.64%;\">\n <p>\n Immunogenicity</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:4.14%;\">\n <p align=\"center\">\n x</p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n NOTE: At screening, hemoglobin was assessed in all participants screened. Hematology and biochemistry were tested in blood samples from a sub-cohort consisting of the first 50 participants enrolled in each group and immunogenicity was tested in the same sub-cohort.</p>\n <p>\n Scr: Screening; M: Month; D: Day</p>\n <p>\n  </p>\n</div>\n<p>\n  </p>\n<ul>\n <li>\n Efficacy surveillance</li>\n</ul>\n<ul>\n <li>\n Capture of malaria cases: malaria cases were captured by passive case detection (PCD). Parents/legally acceptable representatives were advised to present their child to the health center if the child was unwell. Care was administered according to local recommendations. All children with fever and/or history of fever had a blood sample taken for the evaluation of VE. All anti-malaria treatments administered during the study were recorded in the participant’s electronic case report form (eCRF).</li>\n <li>\n Cross-sectional surveys were performed monthly from Month 0-20 and every 3 months thereafter till study end to evaluate VE against incident and prevalent <em>P. falciparum </em>infections.</li>\n <li>\n The research team at each study center provided all screened participants with an insecticide-treated bednet, and malaria diagnosis and treatment was ensured.</li>\n</ul>\n<table align=\"center\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:100.0%;\">\n <ul>\n <li>\n Safety monitoring</li>\n </ul>\n <ul>\n <li>\n This study was overseen by a formally constituted Independent Data Monitoring Committee operating under a charter.</li>\n </ul>\n <ul>\n <li>\n Each participant was observed for at least 30 minutes after vaccination to evaluate and treat any acute AEs.</li>\n <li>\n Cases of severe malaria and cerebral malaria were reported as SAEs, as applicable, as part of the safety surveillance for the duration of the study and clinical details of each case were reported in a specific eCRF screen.</li>\n </ul>\n <p style=\"margin-left:43.2pt;\">\n Case definitions adapted from the World Health Organization case definitions of severe malaria and cerebral malaria were used as reference for diagnosis.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:100.0%;\">\n <ul>\n <li>\n All AEs, SAEs and SAEs leading to withdrawal from further vaccination were reported, as applicable, for the duration of the study.</li>\n <li>\n AESIs comprised meningitis and pIMDs reported for the duration of the study, and seizures occurring within 30 days post-vaccination. Clinical details according to the Brighton Collaboration guidelines pertaining to seizures occurring within 7 days of vaccination were to be documented in a specific eCRF screen.</li>\n </ul>\n <p style=\"margin-left:43.2pt;\">\n All AESIs were to be reported as SAEs.</p>\n <ul>\n <li>\n Solicited local and general AEs were collected in the reactogenicity sub-cohort during 4 days (day of vaccination and 3 subsequent days) after Dose 3 of study vaccine (all groups including controls) after Dose 4 (R012-20, R012-14, Fx012-14 and Fx017-20 groups), after Dose 5 (R012-14, Fx012-14 and Fx017-20 groups) and after Dose 6 (R012-14 and Fx012-14 groups). On the day of vaccination, reactogenicity evaluation was carried out by the study physician at the study center. On Days 1, 2 and 3 after vaccination, trained study personnel visited the children to record solicited AEs on diary cards.</li>\n <li>\n Unsolicited AEs were collected during 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine. Unsolicited AEs were captured through passive surveillance at inpatient and outpatient facilities and during study visits.</li>\n <li>\n Biochemistry (ALT, creatinine) and hematology (hemoglobin, WBCs, platelets) parameters were assessed in the reactogenicity sub-cohort before Dose 3, 7 days post-Dose 3 and 30 days post‑Dose 3.</li>\n </ul>\n <ul>\n <li>\n Case definitions</li>\n </ul>\n <p>\n <u>Clinical malaria and <em>P. falciparum</em> infection</u></p>\n <table align=\"center\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:576px;\" width=\"576\">\n <tbody>\n <tr>\n <td colspan=\"2\" style=\"width:576px;height:11px;\">\n <p>\n <strong>Case definitions of clinical malaria</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:104px;height:11px;\">\n <p>\n <strong>Primary case definition</strong></p>\n </td>\n <td style=\"width:472px;height:11px;\">\n <p>\n <em>P. falciparum</em> asexual parasitemia >5000 parasites/μL</p>\n <p>\n <strong>AND</strong> presence of fever (axillary temperature ³37.5°C) at the time of presentation</p>\n <p>\n <strong>AND</strong> occurring in a child who is unwell and brought for treatment to a healthcare facility</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:104px;height:11px;\">\n <p>\n <strong>Secondary case definition</strong></p>\n </td>\n <td style=\"width:472px;height:11px;\">\n <p>\n <em>P. falciparum</em> asexual parasitemia >0 parasites/μL</p>\n <p>\n <strong>AND</strong> presence of fever (axillary temperature ³37.5°C) at the time of presentation or history of fever within 24 hours of presentation</p>\n <p>\n <strong>AND</strong> occurring in a child who is unwell and brought for treatment to a healthcare facility</p>\n </td>\n </tr>\n </tbody>\n </table>\n <div style=\"clear:both;\">\n  </div>\n <ul>\n <li>\n  </li>\n </ul>\n </td>\n </tr>\n </tbody>\n</table>\n<div style=\"clear:both;\">\n  </div>\n<p>\n  </p>\n<table align=\"center\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:100.0%;\">\n <p>\n <strong>Case definition of incident <em>P. falciparum</em> infection</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:100.0%;\">\n <p>\n A documented <em>P. falciparum</em> asexual parasite density >0 detected by blood slide reading at a cross-sectional survey or as captured by the secondary case definition of clinical malaria (active detection of infection [ADI] and PCD)</p>\n </td>\n </tr>\n </tbody>\n</table>\n<div style=\"clear:both;\">\n  </div>\n<p>\n  </p>\n<table align=\"center\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:100.0%;\">\n <p>\n <strong>Case definition of prevalent <em>P. falciparum</em> infection</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:100.0%;\">\n <p>\n A documented <em>P. falciparum</em> asexual parasite density >0 detected by blood slide reading at a cross-sectional survey (ADI).</p>\n </td>\n </tr>\n </tbody>\n</table>\n<div style=\"clear:both;\">\n  </div>\n<p>\n <strong>Number of participants</strong> <strong>(planned and analyzed):</strong> Approximately 1500 participants (300 per group) were planned to be randomized in this study; 2157 participants were enrolled (signed an informed consent form), 1609 were randomized, 1500 received at least 1 dose of vaccine and 1333 were eligible for analyses in the per protocol set (PPS) for efficacy.</p>\n<p>\n <strong>Diagnosis and main criteria for inclusion:</strong> Healthy male or female participants aged 5-17 months at the time of the first vaccination, and who had previously received 3 documented doses of diphtheria, tetanus, pertussis, hepatitis B vaccine (DTP/HepB), and at least 3 doses of oral polio vaccine, were eligible for enrolment.</p>\n<p>\n <strong>Study intervention, dose, mode of administration and lot number:</strong></p>\n<ul>\n <li>\n RTS,S/AS01_E, administered by intramuscular (IM) injection in the deltoid:</li>\n</ul>\n<ul>\n <li>\n Per 0.5 mL dose:<br />\n 25 mg RTS,S antigen;<br />\n AS01_E adjuvant: 25 mg 3‑O‑desacyl‑4’‑monophosphoryl lipid A (MPL), 25 mg QS-21 with liposomes.</li>\n <li>\n Per Fx 0.1 mL dose:<br />\n 5 mg RTS,S antigen;<br />\n AS01_E adjuvant: 5 mg MPL, 5 mg QS-21 with liposomes.</li>\n <li>\n From the reconstituted vaccine vial, 0.1 mL was withdrawn to administer a Fx dose of RTS,S/AS01_E.</li>\n</ul>\n<ul>\n <li>\n Rabies vaccine (<em>Rabipur</em>) administered by IM injection in the deltoid:</li>\n</ul>\n<ul>\n <li>\n Per 1.0 mL dose: 2.5 IU rabies virus.</li>\n</ul>\n<ul>\n <li>\n Lot numbers:</li>\n</ul>\n<ul>\n <li>\n RTS,S: AMALA002A, AMALA009G, AMALA010B, AMALA011B, AMALA013C</li>\n <li>\n AS01_E: AA1EA005A, AA1EA007A, AA1EA008B, AA1EA008A, AA1EA009A, AA1EA013A</li>\n <li>\n <em>Rabipur</em> antigen: DEXTA542AY, DEXTG218AZ, DEXTG223AZ</li>\n <li>\n <em>Rabipur</em> diluent: DEXTA542AZ, DEXTG218AY, DEXTG223AY</li>\n</ul>\n<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td colspan=\"5\" style=\"width:100.0%;\">\n <p align=\"center\">\n <strong>Vaccine dose details for RTS,S/AS01_E study groups</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;height:47px;\">\n <p>\n <strong>Study Group</strong></p>\n </td>\n <td style=\"width:16.16%;height:47px;\">\n <p align=\"center\">\n <strong>Vaccination months</strong></p>\n </td>\n <td style=\"width:18.04%;height:47px;\">\n <p align=\"center\">\n <strong>RTS,S per vaccination (μg)</strong></p>\n </td>\n <td style=\"width:18.36%;height:47px;\">\n <p align=\"center\">\n <strong>AS01_E per vaccination (μg)</strong></p>\n </td>\n <td style=\"width:29.42%;height:47px;\">\n <p align=\"center\">\n <strong>Volume administered per vaccination (mL)</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;\">\n <p>\n <strong>R012-20</strong></p>\n </td>\n <td style=\"width:16.16%;\">\n <p align=\"center\">\n 0, 1, 2, 20</p>\n </td>\n <td style=\"width:18.04%;\">\n <p align=\"center\">\n 25–25–25-25</p>\n </td>\n <td style=\"width:18.36%;\">\n <p align=\"center\">\n 25–25–25-25</p>\n </td>\n <td style=\"width:29.42%;\">\n <p align=\"center\">\n 0.5–0.5–0.5-0.5</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;\">\n <p>\n <strong>R012-14</strong></p>\n </td>\n <td style=\"width:16.16%;\">\n <p align=\"center\">\n 0, 1, 2, 14, 26, 38</p>\n </td>\n <td style=\"width:18.04%;\">\n <p align=\"center\">\n 25–25–25-25-25-25</p>\n </td>\n <td style=\"width:18.36%;\">\n <p align=\"center\">\n 25–25–25-25-25-25</p>\n </td>\n <td style=\"width:29.42%;\">\n <p align=\"center\">\n 0.5–0.5–0.5-0.5-0.5-0.5</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;\">\n <p>\n <strong>Fx012-14</strong></p>\n </td>\n <td style=\"width:16.16%;\">\n <p align=\"center\">\n 0, 1, 2, 14, 26, 38</p>\n </td>\n <td style=\"width:18.04%;\">\n <p align=\"center\">\n 25–25–5-5-5-5</p>\n </td>\n <td style=\"width:18.36%;\">\n <p align=\"center\">\n 25–25–5-5-5-5</p>\n </td>\n <td style=\"width:29.42%;\">\n <p align=\"center\">\n 0.5–0.5–0.1-0.1-0.1-0.1</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:18.02%;\">\n <p>\n <strong>Fx017-20</strong></p>\n </td>\n <td style=\"width:16.16%;\">\n <p align=\"center\">\n 0, 1, 7, 20, 32</p>\n </td>\n <td style=\"width:18.04%;\">\n <p align=\"center\">\n 25–25–5-5-5</p>\n </td>\n <td style=\"width:18.36%;\">\n <p align=\"center\">\n 25–25–5-5-5</p>\n </td>\n <td style=\"width:29.42%;\">\n <p align=\"center\">\n 0.5–0.5–0.1-0.1-0.1</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n <strong>Duration of study:</strong> The study duration was approximately 50 months per participant.</p>\n<p>\n <strong>Statistical methods:</strong></p>\n<p>\n <em>Analysis Sets</em></p>\n<ul>\n <li>\n The Enrolled Set included all participants who signed informed consent.</li>\n <li>\n The Exposed Set included all participants who received at least 1 dose of study vaccine. The Exposed Set analysis was performed per treatment actually administered.</li>\n <li>\n For the primary analysis of efficacy up to Month 14, the PPS for efficacy included all participants from the Exposed Set who fulfilled eligibility criteria and who received all 3 first vaccinations according to protocol procedures within the protocol specified intervals that contributed to the time at risk in the follow-up period starting 14 days post-Dose 3. <em>NOTE: elimination codes detailed in SAP further classified the participants included in the PPS for efficacy.</em></li>\n <li>\n The PPS for immunogenicity included all participants included in the Exposed Set who received all vaccinations according to protocol procedures within the protocol specified intervals, performed blood samplings for immunogenicity according to protocol intervals, met all eligibility criteria, did not use any medication or blood products forbidden by the protocol and did not have any reported underlying medical condition influencing immune responses. <em>NOTE: elimination codes detailed in SAP further classified the participants included in the PPS for immunogenicity.</em></li>\n</ul>\n<ul>\n <li>\n Immunogenicity sub-cohort: the first 50 participants (25 participants per site) enrolled in each group.</li>\n</ul>\n<ul>\n <li>\n The solicited safety set - including the reactogenicity sub-cohort - included all participants who received at least 1 dose of study vaccine and had solicited safety data.</li>\n</ul>\n<ul>\n <li>\n Reactogenicity sub-cohort: the first 50 participants (25 participants per site) enrolled in each group.</li>\n</ul>\n<p>\n <em>Demography</em></p>\n<ul>\n <li>\n Demographic characteristics (age and gender) and the baseline hemoglobin level were tabulated per study group overall, and by site, for each cohort (Exposed Set, PPS for efficacy and PPS for immunogenicity).</li>\n <li>\n The mean age at first vaccination (in months) (plus range and standard deviation [SD]) of the vaccinated participants as a whole and per group, were calculated.</li>\n</ul>\n<p>\n <em>Efficacy</em></p>\n<p>\n The primary analysis of efficacy was based on the PPS for efficacy.</p>\n<ul>\n <li>\n Measures of incidence (<em>P. falciparum</em> infection and clinical malaria)</li>\n</ul>\n<p>\n <u>First or only episode (Month 21 Interim Analysis only)</u></p>\n<p>\n VE against first or only episode of incident <em>P. falciparum</em> infection or clinical malaria was analyzed by Cox regression stratified by study site, and overall. The 95% CI and p-values of the VE estimates (1- Hazard Ratio) were calculated from this model. Cumulative incidence graphs were produced.</p>\n<p>\n <u>All episodes</u></p>\n<p>\n VE against all episodes of clinical malaria was analyzed by negative binomial regression allowing for interdependence between episodes within the same participant (non-linear mixed model with over dispersion parameter estimated from the random effect). The 95% CI and p-values of the VE estimates (1- Incidence Rate Ratio) were calculated from this model. Fourteen days following an episode meeting the case definition under evaluation was subtracted from the follow-up time. The distribution of the total number of events per participant was tabulated by group. Results per site and overall (adjusted for site as a fixed effect) were summarized in tables and forest plots.</p>\n<ul>\n <li>\n Measure of prevalence (<em>P. falciparum</em> infection)</li>\n</ul>\n<p>\n The prevalence of <em>P. falciparum</em> infection was evaluated on the cross-sectional ADI samples only. At each pre-defined timepoint the prevalence (number of participants with <em>P. falciparum</em> infection/total number of participants) of <em>P. falciparum</em> infection was calculated by group together with 95% CIs. Graphical presentations of the prevalence over time were produced. Results per site and overall were summarized in tables.</p>\n<p>\n The prevalence of gametocytemia was tabulated for each group (Fx017-20, Fx012‑14, R012-20, R012-14 and Control) at each cross-sectional visit. Within gametocyte positive slides, the proportion of male gametocytes was tabulated by group, timepoint and site. Within parasitemia positive participants the geometric mean was tabulated by group, timepoint and by site.</p>\n<ul>\n <li>\n Measure of impact (clinical malaria)</li>\n</ul>\n<p>\n The vaccine impact was estimated by the number of cases of clinical malaria averted over the relevant time frame per 1000 participants vaccinated. The number of cases averted was calculated as the difference of the estimated cases between the Control group and the vaccine group. Estimated cases in each group were calculated as the area under the curve of the incidence of clinical malaria over time and expressed as cumulative cases averted per 1000 participants followed up during the relevant period. Results per site and overall were summarized in tables.</p>\n<p>\n <em>Immunogenicity</em></p>\n<p>\n The primary analysis of immunogenicity was based on the PPS for immunogenicity; analyses on the Exposed Set were also performed.</p>\n<ul>\n <li>\n In the immunogenicity sub-cohort, the percentage of participants with seropositive (≥1.9 EU/mL) levels of anti-CS with 95% CI were determined at specified blood sampling timepoints in each group.</li>\n <li>\n In the immunogenicity sub-cohort, the percentage of participants with seropositive (³6.2 mIU/mL) and seroprotective levels (³10 mIU/mL) of anti-HBs with 95% CI were determined at specified blood sampling timepoints in each group.</li>\n <li>\n Anti-CS and -HBs antibody concentrations were summarized by geometric mean concentrations (GMCs) with 95% CI. Antibody concentrations 1 month after the third dose and each subsequent dose of study vaccine were also investigated using reverse cumulative distribution curves.</li>\n</ul>\n<p>\n <em>Safety and reactogenicity</em></p>\n<p>\n The primary analysis of safety was based on the Exposed Set. Analyses containing only solicited data were based on the solicited safety set.</p>\n<ul>\n <li>\n The percentage of participants reporting a SAE (all, fatal, related), pIMD or meningitis from Dose 1 (Day 0) until Month 50 (i.e. over 50 months’ surveillance per participant), classified by the MedDRA preferred term level, were tabulated with exact 95% CI.</li>\n <li>\n The percentage of participants reporting severe malaria cases (excluding cerebral malaria) and cerebral malaria cases from Day 0 up to Month 50 (i.e. over 50 months’ surveillance per participant) were tabulated with exact 95% CI.</li>\n <li>\n The percentage of participants with at least 1 report of an unsolicited AE, SAE (all, fatal, related) or seizure classified by the MedDRA preferred term level, occurring within 30 days (day of vaccination and 29 subsequent days) after each dose of study vaccine were tabulated with exact 95% CI.</li>\n <li>\n Among the reactogenicity sub-cohort:</li>\n</ul>\n<p>\n The percentage of participants reporting at least 1 local AE (solicited and unsolicited), general AE (solicited and unsolicited) and any AE (solicited and unsolicited) during the 4-day follow-up period post-Dose 3 of study vaccine (all groups including controls) post-Dose 4 (R012-20, R012-14, Fx012-14 and Fx017-20 groups), post-Dose 5 (R012-14, Fx012-14 and Fx017-20 groups) and post-Dose 6 (R012-14 and Fx012-14 groups) was tabulated with exact 95% CI. Similar tables were generated for Grade 3 AEs, AEs considered as causally related to vaccination and Grade 3 causally related AEs.</p>\n<p>\n The percentage by dose (for which solicited safety data were recorded) for each individual solicited local AE (any, Grade 3 and resulting in medically attended visit) and general AE (any, Grade 3, causally related, Grade 3 related, resulting in medically attended visit and for fever, temperature in 0.5°C increments) during the 4-day solicited follow-up period was tabulated with exact 95% CI.</p>\n<p>\n Biochemistry (ALT, creatinine) and hematology (hemoglobin, WBCs, platelets) values outside of the reference ranges were described for the reactogenicity sub‑cohort before Dose 3, 7 days post-Dose 3 and 30 days post-Dose 3. Frequency distribution of results by toxicity grades were tabulated by group.</p>\n<p>\n <strong>Summary:</strong></p>\n<p>\n <strong>Demographics</strong></p>\n<p>\n In the Exposed Set, demographic characteristics were similar across groups (Table 2.1). The mean age of participants ranged from 10.2 to 10.5 months across groups. A similar proportion of males and females were enrolled in all groups except for the R012-20 group in which more males (60.1%) than females (39.9%) were enrolled.</p>\n<p>\n Table 2.1         Summary of demography and baseline characteristics, Overall - Exposed Set</p>\n<table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <thead>\n <tr>\n <th style=\"width:31.28%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.84%;\">\n <p align=\"center\">\n <strong>R012-20<br />\n  N=298</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.84%;\">\n <p align=\"center\">\n <strong>R012-14<br />\n  N=294</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.84%;\">\n <p align=\"center\">\n <strong>Fx012-14<br />\n  N=304</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.84%;\">\n <p align=\"center\">\n <strong>Fx017-20<br />\n  N=311</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th colspan=\"2\" style=\"width:12.8%;\">\n <p align=\"center\">\n <strong>Control<br />\n  N=293</strong></p>\n </th>\n </tr>\n <tr>\n <th style=\"width:31.28%;\">\n <p>\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n <th style=\"width:1.14%;\">\n <p align=\"center\">\n  </p>\n </th>\n <th style=\"width:6.42%;\">\n <p align=\"center\">\n <strong>Value or n</strong></p>\n </th>\n <th style=\"width:6.38%;\">\n <p align=\"center\">\n <strong>%</strong></p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"width:31.28%;\">\n <p>\n Age (Months) at first vaccination</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:6.38%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:31.28%;\">\n <p>\n    n</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 298</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 294</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 304</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 311</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 293</p>\n </td>\n <td style=\"width:6.38%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:31.28%;\">\n <p>\n    Mean</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.2</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.3</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.5</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.2</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 10.5</p>\n </td>\n <td style=\"width:6.38%;\">\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:31.28%;\">\n <p>\n    Standard Deviation</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 3.9</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 3.8</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 4.0</p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:1.14%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:6.42%;\">\n <p align=\"center\">\n 3.8</p>\n
      • implication_results<p>\n The fractional dose is likely to be adopted due to dose implications of giving the full dose, and the vaccine may become part of the national immunization programme as a routine vaccine.</p>\n
      • quantity_imported5480 doses
      • quantity_dispensed3227
      • quantity_destroyed1741
      • quantity_exportedNone
      • balance_site512
      • final_date0000-00-00
      • modified2025-02-28 14:30:36
      • created2017-09-14 15:53:31
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id401
        • application_id632
        • given_nameAaron
        • middle_name
        • family_nameSamuels
        • qualificationMD
        • professional_addressP.O. Box 1578, Kisumu, 40100
        • telephone+254 724 255 633
        • emailamsamuels@cdc.gov
        • created2017-09-14 16:04:14
        • modified2020-03-16 15:05:40
      • 1(array)
        • id402
        • application_id632
        • given_nameSimon
        • middle_name
        • family_nameKariuki
        • qualificationPhD
        • professional_addressP.O. Box 1578, Kisumu, 40100
        • telephone+254 725 389 246
        • emailskariuki@kemricdc.org
        • created2017-09-14 16:08:27
        • modified2020-03-16 15:05:40
    • SiteDetail(array)
      • 0(array)
        • id509
        • application_id632
        • county_id41
        • site_nameSiaya County Referral hospital
        • physical_addressSiaya Town
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:04:14
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 1(array)
        • id510
        • application_id632
        • county_id41
        • site_nameNgiya Health Center
        • physical_addressSouth East Alego
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 2(array)
        • id511
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        • site_nameKogelo Health Center
        • physical_addressNyangoma Kogelo
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 3(array)
        • id512
        • application_id632
        • county_id41
        • site_nameTingwangi
        • physical_addressSouth Alego
        • contact_detailsTel: 0729 295 803
        • contact_personTel: 0729 295 803
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 4(array)
        • id513
        • application_id632
        • county_id41
        • site_nameMulaha
        • physical_addressAlego
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 5(array)
        • id514
        • application_id632
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        • site_nameNyathengo
        • physical_addressEast Alego
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 6(array)
        • id515
        • application_id632
        • county_id41
        • site_nameBal Olengo
        • physical_addressAlego Usonga
        • contact_detailsTel: 0729 295 803
        • contact_personDr Paul Oloo
        • site_capacity(null)
        • misc(null)
        • created2017-09-14 16:18:33
        • modified2020-03-16 15:05:40
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
    • Sponsor(array)
      • 0(array)
        • id323
        • application_id632
        • sponsorGlaxoSmithKline Biologicals
        • sponsor_typeIndustry
        • contact_person
        • addressRue de l’Institut 89, 1330 Rixensart, Belgium
        • telephone_number+32 2 656 81 11
        • fax_number
        • cell_number+32 2 656 81 11
        • email_addressinfo@gskbio.com
        • created2017-09-14 16:04:14
        • modified2020-03-16 15:05:40
  • 2(array)
    • Application(array)
      • id488
      • user_id480
      • trial_status_id5
      • abstract_of_study<div>\n VRC01: human monoclonal antibody (mAb) VRC-HIVMAB060-00-AB in formulation buffer at pH 5.8 in sufficient normal saline (Sodium Chloride for Injection 0.9%, USP) to be administered at a final volume of 150 mL intravenously (IV)</div>\n<div>\n o Control for VRC01: Sodium Chloride for Injection 0.9%, USP administered at a volume of 150 mL IV</div>\n<div>\n o VRC01 or control will be infused every 8 weeks for a total of 10 infusions</div>\n<div>\n o The study products are being provided by the Dale and Betty Bumpers Vaccine Research Center (VRC), NIAID, NIH, DHHS (Bethesda, Maryland, USA)</div>\n
      • study_title<div>\n HVTN 703/HPTN 081</div>\n<div>\n A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection</div>\n
      • laymans_summary<p>\n The AMP Study (also known as HVTN 703/HPTN 081) tests an experimental antibody against HIV. AMP stands for Antibody Mediated Prevention. This is the idea of giving people antibodies that fight HIV to see if they will protect people from becoming HIV infected. The AMP study tests an antibody called VRC01, a manufactured antibody against HIV. This is a new idea for HIV prevention that is related to what has been done in HIV vaccine research. In traditional HIV vaccine studies, people get a vaccine and researchers wait to see if their bodies will make antibodies against HIV in response to the vaccine. In this study, we will skip that step, and give people the antibodies directly.</p>\n<p>\n The study will enroll and follow about 1,900 adult women in sub-Saharan Africa who are at risk of HIV-1 infection. To join this study, a woman must be a healthy adult and not infected with HIV. She cannot be pregnant or breastfeeding.</p>\n
      • short_titleHVTN 703/HPTN 081 Protocol A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection
      • protocol_noECCT/16/04/01
      • version_noVersion 1.0
      • date_of_protocol11-08-2015
      • study_drugVRCO1
      • disease_conditionHIV
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines1
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameVRCO1
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameThe comparitor is a placebo
      • comparator_registeredN/A
      • comparator_countriesN/A
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresseayuo@kemricdc.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_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_charter0
      • applicant_detailed_budget0
      • applicant_indemnity_pi0
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantElizabeth A. Ayuo - Kisumu CRS, CRC JOOTRH hospital grounds
      • declaration_date108-04-2016
      • declaration_principal_investigatorDr. Victor Akelo MD
      • declaration_date208-04-2016
      • placebo_presentYes
      • study_objectives<p>\n Primary objective 1: To evaluate the safety and tolerability of VRC01 mAb administered through IV infusion in sub-Saharan African women Primary objective 2: To determine if the VRC01 mAb prevents HIV-1 infection and to estimate the level of efficacy in sub-Saharan African women</p>\n<p>\n  </p>\n<p>\n Secondary objective 1: To develop a marker(s) of the VRC01 mAb that correlates with the level and antigenic specificity of protection against HIV-1 infection and to provide insight into the mechanistic correlates of protection</p>\n<p>\n  </p>\n<p>\n Exploratory objective 1: To assess use of FTC/TDF in the study cohort</p>\n<p>\n Exploratory objective 2: To assess if prevention efficacy is modified by FTC/TDF use</p>\n<p>\n Exploratory objective 3: To understand changes in risk behavior and the potential for risk compensation for all study participants</p>\n<p>\n Exploratory objective 4: To measure anti-idiotype antibodies to VRC01</p>\n
      • principal_inclusion_criteria<div>\n 1. Age of 18 to 50 years</div>\n<div>\n 2. Access to a participating CRS and willingness to be followed for the planned duration of the study</div>\n<div>\n 3. Ability and willingness to provide informed consent</div>\n<div>\n 4. Assessment of understanding: volunteer demonstrates understanding of this study and completes a questionnaire prior to first infusion with verbal demonstration of understanding of all questionnaire items answered incorrectly</div>\n<div>\n 5. Agrees not to enroll in another study of an investigational research agent for the duration of the participant’s trial participation</div>\n<div>\n 6. Good general health as shown by medical history, physical exam, and screening laboratory tests</div>\n<div>\n HIV-Related Criteria:</div>\n<div>\n 7. Willingness to receive HIV test results</div>\n<div>\n 8. Willingness to discuss HIV infection risks and amenable to HIV risk reduction counseling</div>\n
      • principal_exclusion_criteria<div>\n Investigational research agents received within 30 days before first infusion</div>\n<div>\n 2. Body mass index (BMI) ≥ 40</div>\n<div>\n 3. Pregnant or breastfeeding</div>\n<div>\n 4. Any reactive, indeterminate, or positive HIV test, even if subsequent testing indicates that the individual is not HIV infected.</div>\n<div>\n Monoclonal antibodies and vaccines</div>\n<div>\n 5. Previous receipt of humanized or human mAbs, whether licensed or investigational</div>\n<div>\n 6. HIV vaccine(s) received in a prior HIV vaccine trial. For volunteers who have received control/placebo in an HIV vaccine trial, the HVTN 703/HPTN 081 PSRT will determine eligibility on a case-by-case basis.</div>\n<div>\n Immune System</div>\n<div>\n 7. Serious adverse reactions to VRC01 formulation components such as sodium citrate, sodium chloride, and L-arginine hydrochloride, including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain.</div>\n<div>\n 8. Autoimmune disease, including Type I diabetes mellitus (Not excluded from participation: Volunteer with mild, stable and uncomplicated autoimmune disease that does not require consistent immunosuppressive medication and that, in the judgment of the site investigator, is likely not subject to exacerbation and likely not to complicate reactogenicity and AE assessments)</div>\n
      • primary_end_points<div>\n Primary objectives and endpoints</div>\n<div>\n Primary objective 1:</div>\n<div>\n To evaluate the safety and tolerability of VRC01 mAb administered through IV infusion in each of 2 cohorts</div>\n<div>\n Primary endpoint 1:</div>\n<div>\n Local and systemic reactogenicity signs and symptoms, laboratory measures of safety, AEs, SAEs, and rates of discontinuation</div>\n<div>\n Primary objective 2:</div>\n<div>\n To determine if the VRC01 mAb prevents HIV-1 infection and to estimate the level of efficacy in each of 2 cohorts</div>\n<div>\n Primary endpoint 2:</div>\n<div>\n Documented HIV-1 infection by the Week 80 study visit</div>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyPhase 2b. Safety and Efficasy
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<div>\n Dr. Victor Akelo</div>\n<div>\n MBChB, MPH, MBA</div>\n<div>\n <div>\n Dr. Victor Mudhune</div>\n <div>\n BPharm, MBA, MPH</div>\n</div>\n<div>\n <div>\n Dr Dismas Oketch</div>\n <div>\n MBChB, MSc</div>\n</div>\n<div>\n <div>\n Dr Elisha Okeyo</div>\n <div>\n MD, MPH (c)</div>\n</div>\n<div>\n Arthur Ogendo, MPH</div>\n<div>\n Kevin Cain, MD</div>\n<div>\n David Schnabel, PhD</div>\n<div>\n  </div>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n there are fully equiped clinic rooms that are within clinic block within the CRC (clinical research centre) , well equiped infusion rooms and emergency room adjacent.</p>\n
      • other_details_explanation<p>\n the host country is involved.</p>\n
      • other_details_regulatory_notapproved<p>\n CDC IRB - 1st April 2016</p>\n<p>\n  </p>\n
      • other_details_regulatory_approved<p>\n KEMRI SERU - 3rd March 2016</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n None</p>\n
      • estimated_duration2 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_comparatorplacebo
      • design_controlled_other_medicinalNo
      • design_controlled_placeboYes
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKISUMU CRS
      • single_site_physical_addressAlong kisumu kakamega RD. within Jaramogi Oginga Odinga teaching and referal Hospital
      • single_site_contact_personDr. Victor Akelo
      • single_site_telephone+254721553064
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states29 sites in total
      • number_of_sites
      • multi_country_listUSA, KENYA, SOUTH AFRICA, zimbabwe
      • data_monitoring_committeeYes
      • total_enrolment_per_site100 participants
      • total_participants_worldwide1500
      • 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_patientsNo
      • subjects_vulnerable_populationsNo
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameDr. Victor Akelo
      • investigator1_middle_name
      • investigator1_family_nameAkelo
      • investigator1_qualificationMD, MPH
      • investigator1_professional_addressKisumu CRS - Box 1578 - Kisumu 40100
      • investigator1_telephone+254721553064
      • investigator1_emailvakelo@kemricdc.org
      • organisations_transferred_No
      • number_participants90 participants
      • notification<p>\n Drs Kevin P. Cain and David schnabel will not have direct contact with study participants, their roles in the study will be on implementation and overseeing the smooth running of the study. They do not have practising licence for Kenya neither are they covered on indemnities.</p>\n
      • approval_date14-07-2016
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted06-08-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report
      • implication_results
      • quantity_imported1524
      • quantity_dispensed1291
      • quantity_destroyed233
      • quantity_exported0
      • balance_site0
      • final_date0000-00-00
      • modified2022-11-02 08:02:52
      • created2016-04-07 12:23:56
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id324
        • application_id488
        • given_nameDr. Victor Akelo
        • middle_name
        • family_nameAkelo
        • qualificationMD, MPH
        • professional_addressKisumu CRS, box 1578 - Kisumu 40100
        • telephone+254721553064
        • emailvakelo@kemricdc.org
        • created2016-04-07 12:41:08
        • modified2020-08-06 15:05:40
    • SiteDetail(array)
      • 0(array)
        • id387
        • application_id488
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2016-04-07 12:41:08
        • modified2020-08-06 15:05:40
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id256
        • application_id488
        • sponsorDivision of AIDS (DAIDS) National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH) Department of Health and Human Services (DHHS) Bethesda, Maryland, USA
        • sponsor_typeOthers
        • contact_personLawrence Corey
        • addressHVTN; FHCRC 206-667-6770 lcorey@fhcrc.org
        • telephone_number206-667-6770
        • fax_number
        • cell_number206-667-6770
        • email_addresslcorey@fhcrc.org
        • created2016-04-07 12:41:08
        • modified2020-08-06 15:05:40
  • 3(array)
    • Application(array)
      • id928
      • user_id32
      • trial_status_id8
      • abstract_of_study<div>\n It is unknown whether malaria or malaria treatment affects COVID-19 severity, immune responses to SARS-CoV-2 virus, or viral loads and/or duration of shedding and therewith the onwards spread of SARS-COV-2. We will conduct an observational cohort study in 708 newly diagnosed COVID-19 patient of all ages in western Kenya and Burkina-Faso. They will be enrolled in hospitals with COVID-19 testing facilities from a source population screened for SARS-CoV-2 (N~4,720). Approximately 142 of the 708 COVID-19 patients are expected to be co-infected with malaria. They will be enrolled in the nested malaria treatment trial and randomized to receive 3-days of artemether-lumefantrine (the current standard of care) or pyronaridine-artesunate, a highly effective antimalarial with known antiviral properties against SARS-CoV-2 in-vitro, that is newly registered and being rolled out in Africa. Disease progression will be assessed and nasal swabs and blood samples taken during home/clinic visits on days 1, 3, 7, 14, 21, 28, and 42 and blood samples at 3, 6, and 12 months. Patients self-isolating will be phoned daily for the first 14 days to assess signs and symptoms. Hospitalisation, self-isolation and home-based care will follow national guidelines. The WHO clinical progression scale and FLU-PRO plus scales will be used to compare disease progression between COVID-19 patients with and without malaria, and by malaria. Other endpoints include seroconversion/reversion rates, chemokine/cytokine responses, T and B cell responses, viral load and duration of viral carriage. Infection prevention and control (IPC), including use of personal protection equipment (PPE), and measures for patient transport will follow national guidelines in each country. Written informed consent/assent will be sought. Participants will potentially benefit from close observations. Society may benefit from improved understanding of the impact of COVID-19 in malaria-endemic areas. The study is anticipated to start in October 2020 and last for approximately 18 months.</div>\n
      • study_title<div>\n Malaria as a risk factor for COVID-19 in western Kenya and Burkina Faso (MALCOV)</div>\n
      • laymans_summary<div>\n We will conduct a clinical study in western Kenya and Burkina-Faso to determine if malaria affects the severity of COVID-19 or its duration. Some patients with COVID-19 also have malaria. We will determine if the treatment of malaria with pyronaridine-artesunate in these patients has an effect on COVID-19 severity or the immune response to COVID-19. Pyronaridine-artesunate is a highly effective malarial treatment that is being rolled out in Africa. In laboratory tests, pyronaridine-artesunate is able to kill viruses, including SARS-CoV-2, the Coronavirus that causes COVID-19. We will follow 708 patients of all ages with COVID-19 for 12 months (the ‘COVID-19 cohort study’). They will be enrolled from a population of approximately 4,720 patients who are being screened for COVID-19 (‘Screening study’). It is anticipated that about 1 in 5 of the 708 COVID-19 patients will also have malaria (about 142). They will be treated with either artemether-lumefantrine (the current standard malaria treatment) or artemether-lumefantrine. The assignment will be decided by chance (random). Hospitalisation, selfisolation and home-based care will follow national guidelines. All 708 COVID-19 patients will be seen again during home/clinic visits on days 1, 3, 7, 14, 21, 28, and 42 when swabs for COVID-19 tests and blood samples will be taken. They will then be seen again at 3, 6, and 12 months. The severity and duration of symptoms, the immune response, and the time that patients remain infectious (can spread the virus to others) will be compared between COVID-19 patients with malaria and without malaria, and between patients treated with artemether-lumefantrine and with pyronaridine-artesunate. Strict adherence to personal protection equipment (PPE) will be used to limit the transmission of the Coronavirus. The transport arrangements for patients and staff will follow national COVID-19 guidelines. Written informed consent/assent will be sought. Participants will potentially benefit from close observations. There is a potential benefit to society as the study will help to obtain a better understanding of the impact of COVID-19 on people’s health in malaria-endemic areas. The study is anticipated to start in October 2020 and finish approximately 18 months later in March 2022.</div>\n
      • short_titleMALCOV
      • protocol_noECCT/20/10/02
      • version_nov1.2
      • date_of_protocol12-10-2020
      • study_drugPyronaridine-artesunate vs Artemether-lumefantrine
      • disease_conditionMalaria, COVID-19
      • 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_nameArtemether-lumefantrine vs Pyronaridine-artesunate
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresstonysangke@gmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • 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_applicantDr Tony Sang
      • declaration_date129-10-2020
      • declaration_principal_investigatorDr Simon Kariuki (Principal Investigator)
      • declaration_date229-10-2020
      • placebo_presentNo
      • study_objectives<div>\n <u>Screening study (cross-sectional survey source population)</u></div>\n<ul>\n <li>\n To determine if malaria infection is predictive of the prevalence of SARS-CoV-2, adjusted for other risk factors of SARS-CoV-2 infection</li>\n</ul>\n<div>\n  </div>\n<div>\n <u>COVID-19 cohort study</u></div>\n<ul>\n <li>\n To determine if malaria infection affects COVID-19 severity</li>\n</ul>\n<div>\n  </div>\n<div>\n <u>Nested malaria treatment trial</u></div>\n<ul>\n <li>\n To determine if pyronaridine-artesunate compared to artemetherlumefantrine reduces early SARS-CoV-2 viral shedding</li>\n</ul>\n
      • principal_inclusion_criteria<div>\n <strong>Screening study (cross-sectional survey source population)</strong></div>\n<ul>\n <li>\n Patients attending COVID-19 test centres or other clinics conducting testing for COVID-19</li>\n <li>\n Patient population admitted to the COVID-19 isolation facilities</li>\n <li>\n Contacts of confirmed or suspected cases as part of contact tracing</li>\n <li>\n Populations as part of targeted testing of high-risk populations (e.g., frontline health care workers)</li>\n</ul>\n<div>\n  </div>\n<div>\n <strong>COVID-19 cohort study</strong></div>\n<ul>\n <li>\n Laboratory confirmed SARS-CoV-2 infection, with positive molecular test results within the past 72 hours*</li>\n <li>\n Aged >=6 months **</li>\n <li>\n Resident in the study area</li>\n <li>\n The participant or caretaker is willing and able to give informed consent or assent with parent/guardian informed consent for participation in the study</li>\n <li>\n Agrees not to self-medicate with chloroquine, hydroxychloroquine or other antimalarials with potential anti-SARS-CoV-2 properties</li>\n <li>\n Not previously diagnosed with COVID-19</li>\n <li>\n Contactable by phone for follow-up</li>\n</ul>\n<div>\n <div style=\"margin-left: 40px;\">\n * We anticipate that most tests results will be available within 24 hours. The maximum of 72 hours is a target and can be increased in sites that experience significant delays related to routine testing for SARS-CoV-2 by the local health authorities.</div>\n <div style=\"margin-left: 40px;\">\n ** Children < 6 months will be excluded because of the inconvenience of repeated blood sampling and because they have a different clinical presentation of malaria than older children, as they are partially protected from developing clinical malaria due to the protective effect of maternal immunity after birth and through factors that inhibit parasite growth, such haemoglobin F (HbF).</div>\n <div>\n  </div>\n <div>\n <strong>Nested malaria treatment trial</strong></div>\n <ul>\n <li>\n Fulfils all inclusion criteria for the COVID-19 cohort study</li>\n <li>\n Uncomplicated malaria, defined as able to take oral medication</li>\n <li>\n Bodyweight ≥5kg</li>\n <li>\n Confirmed malaria infection by RDT or microscopy</li>\n </ul>\n</div>\n<p>\n  </p>\n
      • principal_exclusion_criteria<div>\n <strong>Screening study (cross-sectional survey source population)</strong></div>\n<ul>\n <li>\n Unwilling or unable to provide informed consent/assent</li>\n</ul>\n<div>\n  </div>\n<div>\n <strong>COVID-19 cohort study</strong></div>\n<ul>\n <li>\n Unwilling or unable to provide informed consent/assent</li>\n <li>\n The participant is judged by the Investigator to be at significant risk of failing to comply with the provisions of the protocol as to cause harm to self or seriously interfere with the validity of the study results</li>\n <li>\n Pregnant or lactating women</li>\n <li>\n Inability/unlikely to be in the study area for the duration of the 28-day follow-up period</li>\n</ul>\n<div>\n  </div>\n<div>\n <strong>Nested malaria treatment trial</strong></div>\n<ul>\n <li>\n Fulfils any of the exclusion criteria for the COVID-19 cohort study</li>\n <li>\n Severe disease requiring parenteral treatment</li>\n <li>\n Currently receiving, or recently received (within the last 28 days) pyronaridine-artesunate or artemether-lumefantrine</li>\n <li>\n Received chloroquine in the last three days</li>\n <li>\n Inability/unlikely to be in the study area for the duration of the 42-day follow-up period</li>\n <li>\n Known hypersensitivity or specific contraindication to the use of any of the study drugs in the treatment arms</li>\n <li>\n Chronic kidney disease (Stage IV or receiving dialysis)</li>\n <li>\n Known liver cirrhosis (Child-Pugh Class B or greater) or signs or symptoms of severe hepatotoxicity</li>\n</ul>\n
      • primary_end_points<div>\n <strong>Screening study (cross-sectional survey source population)</strong></div>\n<ul>\n <li>\n Cross-sectional comparison of the proportion of participants with SARS-CoV-2 in the source population among participants with and without malaria infection expressed as the prevalence ratio for COVID-19 (95% CI)</li>\n</ul>\n<div>\n  </div>\n<div>\n <div>\n <strong>COVID-19 cohort study</strong></div>\n <div>\n <ul>\n <li>\n Comparison of the severity of COVID-19 by day-28 in cases with and without malaria using a severity index score</li>\n </ul>\n </div>\n <div>\n  </div>\n <div>\n <strong>Nested malaria treatment trial</strong></div>\n</div>\n<ul>\n <li>\n Incidence of SARS-CoV-2 clearance (defined as the proportion of participants with a negative nasal swab) on Day 7 after the start of treatment</li>\n</ul>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<div>\n The fieldwork will be conducted as part of the ongoing collaboration between KEMRI, CDC, and LSTM in the following hospitals in western Kenya which are located in areas with intense malaria transmission and local transmission of COVID-19: Kisumu County: Primary Hospital(s): Jaramogi Oginga Odinga Teaching and Referral Hospital (JOORTH), Kisumu County Referral Hospital. Secondary Expansion Hospitals: Lumumba Health Centre, Ahero County Hospital, KMET Cockran Clinic, St Elizabeth Mission Hospital, St Monica’s Mission Hospital; Busia County: Primary Hospital(s): Alupe sub-County Hospital, Secondary Expansion Hospitals: Busia County Teaching and Referral Hospital, Busia GK Prison Dispensary; Siaya County: Primary Hospital(s): Bondo sub-County Hospital, Secondary Expansion Hospitals: Siaya County Teaching And Referral Hospital, Ambira sub-County Hospital; Migori County: Macalder (Nyatike) sub-County Hospital, Migori County Teaching and Referral Hospital; Secondary Expansion Hospitals: Kehancha sub-County Hospital, Migori GK Prison Dispensary, Isebania sub-County Hospital. Other hospitals in the previous Nyanza and western Provinces may be considered if local outbreaks of Covid-19 start to occur in their catchment areas.</div>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n N/A</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_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_comparatorArtemether-Lumefantrine
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states2
      • number_of_sites6 primary sites in 4 counties with an additional 12 possible secondary expansion hospitals
      • multi_country_listKenya\nBurkina Faso
      • data_monitoring_committeeYes
      • total_enrolment_per_siteMinimum is 0, maximum is 142
      • total_participants_worldwide142
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenYes
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyParental/ guardian\'s consent will be sought for all children below 18 years old. Additionally children aged 13 to 17 will be required to provide assent.\nFor illiterate participants, an independent witness will be present during the informed consent process and will sign the consent form as a witness, while the participant will be asked to indicate consent by use of thumbprint.\n
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameFeiko
      • investigator1_middle_nameter
      • investigator1_family_nameKuile
      • investigator1_qualificationMd, PhD
      • investigator1_professional_addressLiverpool School of Tropical Medicine (LSTM), United Kingdom
      • investigator1_telephone+44 151 705 3287
      • investigator1_emailFeiko.terKuile@lstmed.ac.uk
      • organisations_transferred_No
      • number_participants142\nEnrollment will be competitive until the desired sample size is achieved.
      • notification
      • approval_date23-11-2020
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted23-11-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonApplication approved by the expert committee
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2024-10-16 10:12:42
      • created2020-08-12 15:30:31
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id574
        • application_id928
        • given_nameSimon
        • middle_name
        • family_nameKariuki
        • qualificationPhD
        • professional_addressKEMRI, Centre for Global Health Research,Kisumu , Kenya
        • telephone+254 725 389 246
        • emailskariuki@kemricdc.org
        • created2020-08-18 12:03:47
        • modified2020-11-23 17:05:34
      • 1(array)
        • id575
        • application_id928
        • given_nameHelen
        • middle_name
        • family_nameBarsosio
        • qualificationMD
        • professional_addressKEMRI, Centre for Global Health Research,Kisumu , Kenya
        • telephone+254 724 464 507
        • emailHellen.Barsosio@lstmed.ac.uk
        • created2020-08-18 13:12:27
        • modified2020-11-23 17:05:34
    • SiteDetail(array)
      • 0(array)
        • id803
        • application_id928
        • county_id42
        • site_nameJaramogi Oginga Odinga Teaching and Referral Hospital (JOORTH),
        • physical_addressKisumu
        • contact_detailsMobile: +254 724 464 507, E-mail: Hellen.Barsosio@lstmed.ac.uk
        • contact_personDr Hellen Barsosio
        • site_capacity(null)
        • misc(null)
        • created2020-08-18 12:03:47
        • modified2020-11-23 17:05:34
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 1(array)
        • id818
        • application_id928
        • county_id42
        • site_nameKisumu County Referral Hospital.
        • physical_addressKisumu Town
        • contact_detailsMobile: +254 724 464 507, E-mail: Hellen.Barsosio@lstmed.ac.uk
        • contact_personDr Hellen Barsosio
        • site_capacity(null)
        • misc(null)
        • created2020-10-06 13:00:41
        • modified2020-11-23 17:05:34
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 2(array)
        • id819
        • application_id928
        • county_id40
        • site_nameAlupe sub-County Hospital,
        • physical_addressBusia
        • contact_detailsMobile: +254 724 464 507, E-mail: Hellen.Barsosio@lstmed.ac.uk
        • contact_personDr Hellen Barsosio
        • site_capacity(null)
        • misc(null)
        • created2020-10-06 13:00:41
        • modified2020-11-23 17:05:34
        • County(array)
          • id40
          • county_nameBusia
          • created2012-06-15 10:26:51
          • modified2012-06-15 10:26:51
      • 3(array)
        • id820
        • application_id928
        • county_id41
        • site_nameBondo sub-County Hospital,
        • physical_addressBondo Town
        • contact_detailsMobile: +254 724 464 507, E-mail: Hellen.Barsosio@lstmed.ac.uk
        • contact_personDr Hellen Barsosio
        • site_capacity(null)
        • misc(null)
        • created2020-10-06 13:00:41
        • modified2020-11-23 17:05:34
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 4(array)
        • id821
        • application_id928
        • county_id44
        • site_nameMacalder (Nyatike) sub-County Hospital
        • physical_addressMigori
        • contact_detailsMobile: +254 724 464 507, E-mail: Hellen.Barsosio@lstmed.ac.uk
        • contact_personDr Hellen Barsosio
        • site_capacity(null)
        • misc(null)
        • created2020-10-06 13:02:35
        • modified2020-11-23 17:05:34
        • County(array)
          • id44
          • county_nameMigori
          • created2012-06-15 10:27:16
          • modified2012-06-15 10:27:16
      • 5(array)
        • id822
        • application_id928
        • county_id44
        • site_nameMigori County Teaching and Referral Hospital;
        • physical_addressMigori Town
        • contact_detailsMobile: +254 724 464 507, E-mail: Hellen.Barsosio@lstmed.ac.uk
        • contact_personDr Hellen Barsosio
        • site_capacity(null)
        • misc(null)
        • created2020-10-06 13:02:35
        • modified2020-11-23 17:05:34
        • County(array)
          • id44
          • county_nameMigori
          • created2012-06-15 10:27:16
          • modified2012-06-15 10:27:16
    • Sponsor(array)
      • 0(array)
        • id448
        • application_id928
        • sponsorLiverpool School of Tropical Medicine (LSTM)
        • sponsor_typeResearch Institution
        • contact_person
        • addressPembroke Place, Liverpool L3 5QA, UK
        • telephone_number+44 0151 7053794
        • fax_number
        • cell_number+44 0151 7053794
        • email_addresslstmgov@lstmed.ac.uk
        • created2020-08-18 12:03:47
        • modified2020-11-23 17:05:34
  • 4(array)
    • Application(array)
      • id343
      • user_id32
      • trial_status_id7
      • abstract_of_study<div>\n Artemether-Iumefantrine (AL) was adopted as first-line antimalarial therapy in Kenya in 2006, and dihydroartemisinin-piperaquine (OP) as the second-line therapy in 2010. In order to monitor the efficacy and potential development of resistance of Plasmodium falciparum parasites to these two drugs, we will conduct in-vivo studies to monitor the efficacy of these antimalarial therapies.</div>\n<div>\n  </div>\n<div>\n A standardized World Health Organization (WHO) in-vivo efficacy study will be conducted in western Kenya among children 6-59 months of age with symptomatic, uncomplicated malaria visiting the out-patient department of hospitals and/or clinics in western Kenya.</div>\n<div>\n  </div>\n<div>\n Every two years, 350 children will be randomly aSSigned to be treated with either AL or DP. Clinical, parasitologic, and hematologic parameters will be monitored over a 42-day follow-up period. Molecular analysis will be conducted to determine the frequency of markers of antimalarial resistance, and to differentiate recrudescence from reinfection. Results from this antimalarial drug efficacy study will be used to assist the Kenya national malaria control program (NMCP) in evaluating the national malaria treatment policy.</div>\n
      • study_title<div>\n Open label randomized study evaluating the in vivo efficacies of Artemether-lumefantrine and Dihydroartemisinin-piperaquine in the treatment of uncomplicated Plasmodium falciparum malaria in children under five years of age in western Kenya.</div>\n
      • laymans_summary<div>\n Artemether-Iumefantrine (AL) was adopted as first-line antimalarial therapy in Kenya in 2006, and dihydroartemisinin-piperaquine (OP) as the second-line therapy in 2010. In order to monitor the efficacy and potential development of resistance of Plasmodium falciparum parasites to these two drugs, we will conduct in-vivo studies to monitor the efficacy of these antimalarial therapies.</div>\n<div>\n  </div>\n<div>\n A standardized World Health Organization (WHO) in-vivo efficacy study will be conducted in western Kenya among children 6-59 months of age with symptomatic, uncomplicated malaria visiting the out-patient department of hospitals and/or clinics in western Kenya.</div>\n<div>\n  </div>\n<div>\n Every two years, 350 children will be randomly aSSigned to be treated with either AL or DP. Clinical, parasitologic, and hematologic parameters will be monitored over a 42-day follow-up period. Molecular analysis will be conducted to determine the frequency of markers of antimalarial resistance, and to differentiate recrudescence from reinfection. Results from this antimalarial drug efficacy study will be used to assist the Kenya national malaria control program (NMCP) in evaluating the national malaria treatment policy.</div>\n<div>\n  </div>\n
      • short_titleIn vivo efficacies of AL and DP
      • protocol_noECCT/15/01/05
      • version_no3.0
      • date_of_protocol24-09-2014
      • study_drugArtemether-Lumefantrine & Dihydroartemisinin-Piperaquine
      • disease_conditionMalaria
      • 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_nameArtemether-Lumefantrine & Dihydroartemisinin-Piperaquine
      • 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_letter0
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd0
      • applicant_prev_data1
      • applicant_stability_data0
      • applicant_analysis_cert0
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter0
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african0
      • applicant_hard_copies(null)
      • applicant_signed_checklist0
      • statistical_analysis_plan0
      • applicant_contractual_agreement0
      • declaration_applicantDr Tony Sang
      • declaration_date130-01-2015
      • declaration_principal_investigatorDr Aaron Samuels, Principle Investigator
      • declaration_date230-01-2015
      • placebo_presentNo
      • study_objectives<div>\n <strong>Objectives</strong></div>\n<div>\n  </div>\n<div>\n i.<span style=\"white-space:pre\"> </span>To measure the clinical and parasitological efficacy of AL and DP among patients aged 6–59 months with symptomatic, uncomplicated P. falciparum malaria,</div>\n<div style=\"margin-left: 40px;\">\n a.<span style=\"white-space:pre\"> </span>Primary efficacy endpoint:  PCR-corrected parasitemia by day 42, the adequate clinical and parsitological response (ACPR)</div>\n<div style=\"margin-left: 40px;\">\n b.<span style=\"white-space:pre\"> </span>Secondary efficacy endpoints:  Determine the proportion of children with early treatment failure (ETF) and  late treatment failure (LTF) by determining the presence of parasitemia on days 3, 7, 14, 28, 35, and 42</div>\n<div style=\"margin-left: 40px;\">\n c.<span style=\"white-space:pre\"> </span>Should funds permit: Assess for delayed parasite clearance and late recrudescence of infection by additionally sampling children with infection densities of ≥10,000 parasites per microliter at 6, 12, 24, and 36 hours post-treatment</div>\n<div>\n ii.<span style=\"white-space:pre\"> </span>To determine the frequency of existing molecular markers for drug resistance and identify new molecular markers</div>\n<div>\n iii.<span style=\"white-space:pre\"> </span>Evaluate drug concentration levels at day 7</div>\n<div>\n iv.<span style=\"white-space:pre\"> </span>Evaluate duration of malaria HRP2/pLDH RDT positivity after appropriate treatment with AL and DP </div>\n<div>\n  </div>\n
      • principal_inclusion_criteria<ol>\n <li>\n Age 6-59 months</li>\n <li>\n Weight ~ 5.0 kg</li>\n <li>\n Axillary temperature ~ 37.52 C or history of fever in the past 24 hours</li>\n <li>\n Hemoglobin ~7 grams/deciliter at enrolment</li>\n <li>\n Slide-confirmed mono-infection with P. jalciparum, with asexual parasitemia (2,000-200,000 asexual parasites/~I)</li>\n <li>\n live within the catchment boundaries of the study site</li>\n <li>\n Ability to swallow oral medication</li>\n <li>\n Ability and willingness to comply with the protocol for the duration of the study</li>\n <li>\n Ability and willingness to comply with the study visit schedule on days 2, 3, 7, 14, 21, 28, 35, and 42</li>\n <li>\n Parent or caregiver has access to a phone so that study staff may contact them during study period for visit reminders</li>\n <li>\n Parent/guardian provides written informed consent</li>\n</ol>\n<div>\n Sub-study inclusion and exclusion criteria - Identical to the main study except:</div>\n<ol>\n <li>\n Parasite density ~10,000 to S200,000</li>\n <li>\n Willingness to be hospitalized for the first 24 hours after ACT treatment</li>\n <li>\n Willingness to follow-up at 36 hrs post-treatment, and on days 2, 3, 7, 14,21,28,35,42</li>\n</ol>\n
      • principal_exclusion_criteria<ol>\n <li>\n Presence of severe malaria or danger signs, including prostration, alteration in level of consciousness, respiratory distress, convulsions, and jaundice</li>\n <li>\n Severe malnutrition according to WHO child growth standards</li>\n <li>\n Known hypersensitivity to any of the drugs being tested</li>\n <li>\n Use of antimalarials or other drugs with antimalarial activity in the last 2 weeks</li>\n <li>\n General clinical condition necessitates hospitalization</li>\n <li>\n Evidence of concomitant infections at the time of presentation</li>\n <li>\n Plan to travel or leave the area within the next 3 months</li>\n <li>\n Have previously been enrolled in this study</li>\n</ol>\n
      • primary_end_points<ul>\n <li>\n treatment failure,</li>\n <li>\n completion of the follow-up period without treatment failure,</li>\n <li>\n loss to follow-up, withdrawal from study (voluntary or involuntary, and protocol violation). loss to follow-up occurs when, despite all reasonable effort, an enrolled patient who does not attend the scheduled visits cannot be found within 3 days oftheir scheduled visit.</li>\n</ul>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety0
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<table border=\"1\" cellpadding=\"1\" cellspacing=\"1\" style=\"width: 500px;\">\n <tbody>\n <tr>\n <td>\n <strong>Cadre</strong></td>\n <td>\n <strong>Name & Qualification</strong></td>\n </tr>\n <tr>\n <td>\n PI</td>\n <td>\n Aaron Samuels, MD, MSH</td>\n </tr>\n <tr>\n <td>\n PI</td>\n <td>\n Simon Kariuki, PhD</td>\n </tr>\n <tr>\n <td>\n Co-Investigator</td>\n <td>\n Nelli Westercamp, PhD, MPH</td>\n </tr>\n <tr>\n <td>\n Co-Investigator</td>\n <td>\n Meghna Desai, PhD, MPH</td>\n </tr>\n <tr>\n <td>\n Co-Investigator/Lab Manager</td>\n <td>\n Kephas Otieno, MSc,</td>\n </tr>\n <tr>\n <td>\n Pharmacist</td>\n <td>\n Tony Sang, BPharm</td>\n </tr>\n <tr>\n <td>\n Lead Study Nurse</td>\n <td>\n Mary Owidhi</td>\n </tr>\n <tr>\n <td>\n 3 Clinical Officers</td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n 3 Nurses</td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n 1 Quality Control Officer</td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n 3 Laboratory Technologists</td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n 2 field workers</td>\n <td>\n  </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n Kenya Medical research Institute ERC approved this protocol on 06-Oct-2014</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration6 months
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindYes
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherYes
      • design_controlled_specifyTreatment allocation will be blinded only to the microscopists reading the blood films.
      • design_controlled_comparatorParticipants will be rand
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherYes
      • design_controlled_medicinal_specifyParticipants will be randomised to either receive Artemether-Lumefantrine or Dihydroartemisinin-Piperaquine
      • single_site_member_stateYes
      • location_of_areaSiaya District Hospital
      • single_site_physical_addressSiaya
      • single_site_contact_personSimon Kariuki
      • single_site_telephone0725 389246
      • multiple_sites_member_stateNo
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites
      • multi_country_list
      • data_monitoring_committeeNo
      • total_enrolment_per_site350 participants in total every two years
      • total_participants_worldwide350 participants every two years
      • 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_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyChildren under 5 will be enrolled upon consent given by parent or guardian
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameAaron
      • investigator1_middle_name
      • investigator1_family_nameSamuels
      • investigator1_qualificationMD, MHS(CDC)
      • investigator1_professional_address1600 Clifton Road NE, MIS A06 Atlanta, Georgia 30329
      • investigator1_telephone+1 (404) 718-4779 or 0727 037873
      • investigator1_emailiyp2@cdc.gov
      • organisations_transferred_No
      • number_participants350 participants every two years
      • notification
      • approval_date03-03-2015
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted02-10-2020
      • is_child0
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      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe study has been approved
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      • final_date(null)
      • modified2020-10-02 13:12:43
      • created2014-10-29 10:01:58
      • total_sites(null)
      • ecitizen_invoice(null)
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      • 0(array)
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        • professional_address1600 Clifton Road NE, MIS A06 Atlanta, Georgia 30329
        • telephone+1 (404) 718-4779 or 0727 037873
        • emailiyp2@cdc.gov
        • created2014-10-29 10:06:39
        • modified2020-10-02 13:12:43
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        • given_nameSimon
        • middle_name
        • family_nameKariuki
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        • telephone0725 389 246
        • emailskariuki@kemricdc.org
        • created2014-10-29 10:13:28
        • modified2020-10-02 13:12:43
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        • county_id(null)
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        • created2014-10-29 10:06:39
        • modified2020-10-02 13:12:43
        • County(empty)
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        • id182
        • application_id343
        • sponsorKenya Medical Research Institute
        • sponsor_typeResearch Institution
        • contact_personDr Simion Kariuki
        • address1578-40100 Kisumu Kenya
        • telephone_number+254 57 2022902/29
        • fax_number
        • cell_number+254 725 389 246
        • email_addressskariuki@kemricdc.org
        • created2014-10-29 10:06:39
        • modified2020-10-02 13:12:43
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App Constants

CakePHP Constants

PHP Environment

Included Files

Include Paths

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• 1/var/www/html/ctr/lib
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