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      • id1233
      • user_id659
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      • abstract_of_study<p>\n <strong>Purpose and rationale:</strong></p>\n<p>\n The purpose of this platform study is to evaluate the parasiticidal effect and potential for cure with different anti-malarial agents administered as monotherapy and/or in combination therapy with other anti-malarial agents in adult and adolescent patients with uncomplicated Plasmodium</p>\n<p>\n falciparum malaria. Additionally, the safety, tolerability, and pharmacokinetics of these anti-malarial agents will be evaluated for dose selection for future studies..</p>\n<p>\n  </p>\n<p>\n <strong>Primary Objective(s):</strong></p>\n<p>\n Part A: To assess the parasite clearance time (PCT) of oral doses of an antimalarial</p>\n<p>\n agent administered as monotherapy in patients with uncomplicated P. falciparum malaria</p>\n<p>\n Part B: To assess the effect on adjusted 28-day cure rate of an anti-malarial agent administered orally as combination therapy versus the standard of care (SoC) in patients with uncomplicated P. falciparum malaria.</p>\n<p>\n  </p>\n<p>\n <strong>Secondary Objective(s)</strong></p>\n<p>\n Part A: To assess the effect on adjusted 28-day cure rate of an anti-malarial agent administered orally as monotherapy in patients with uncomplicated P. falciparum malaria</p>\n<p>\n  </p>\n<p>\n Part B: To assess the parasite clearance time (PCT) of oral combinations of anti-malarial agents versus SoC in patients with uncomplicated P. falciparum malaria</p>\n<p>\n  </p>\n<p>\n All parts:</p>\n<p>\n To characterize PK of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy [Part B] in patients with uncomplicated P. falciparum malaria</p>\n<p>\n To assess the safety and tolerability of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy versus SoC [Part B] in patients with uncomplicated P. falciparum malaria</p>\n<p>\n  </p>\n<p>\n <strong>Study design</strong></p>\n<p>\n This is a multi-part, multi-center, open-label platform study, including a parallel and adaptive sequential dose level design in Part A followed by an open-label, randomized, controlled design </p>\n<p>\n in Part B in patients with uncomplicated P. falciparum malaria. Part A will evaluate anti-malarial agents as monotherapy. Part B will evaluate anti-malarial agents as combination therapy.</p>\n<p>\n  </p>\n<p>\n <strong>Study Population</strong></p>\n<p>\n  </p>\n<p>\n The study population will consist of male and female patients aged ≥18 years</p>\n<p>\n for Part A and aged ≥12 years for Part B</p>\n
      • study_title<p style=\"margin-left:2.0in;\">\n (PLATINUM): A multi-part, multi-center PLATform study to assess the efficacy, safety, tolerability and pharmacokinetics of anti-malarial agents administered as monotherapy and/or combination therapy IN patients with Uncomplicated Plasmodium falciparum Malaria</p>\n
      • laymans_summary<p>\n Platform study to evaluate the efficacy and safety of anti-malarial agents in patients with uncomplicated Plasmodium falciparum malaria (PLATINUM</p>\n
      • short_titlePLATINUM STUDY
      • protocol_noECCT/23/03/07
      • version_no00
      • date_of_protocol15-12-2022
      • study_drugINE963, KAE609, KLU156
      • 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_nameINE963, KAE609, KLU156
      • product_type_medical_device_name
      • comparatorYes
      • comparator_name Coartem/Riamet
      • comparator_registeredyes
      • comparator_countriesCountry Local Brand Name Marketing Authorisation Holder - Company Name\nBenin Coartem Novartis Pharma AG\nBotswana Riamet Novartis Pharma Services AG\nBurkina Faso Coartem Novartis Pharma AG\nCameroon Coartem Novartis Pharma AG\nCongo (Brazzaville) Coartem Novartis Pharma AG\nCongo, Democratic Republic Coartem Novartis Pharma AG\nEthiopia Coartem Novartis Pharma Schweiz AG\nGabon Coartem Novartis Pharma AG\nGhana Riamet Novartis Pharma Services AG\nGuinea Coartem Novartis Pharma AG\nIvory Coast Coartem Novartis Pharma AG\nKenya Coartem NVS Kenya Ltd\nLiberia Coartem Novartis Pharma Services AG\nMadagascar Riamet Novartis Pharma Services AG\nMalawi Riamet Novartis Pharma Services AG\nMali Coartem Novartis Pharma AG\nMozambique Riamet Medis Farmaceutica Lda\nNamibia Coartem Novartis Pharma Services AG\nNiger Coartem Novartis Pharma AG\nNigeria Coartem Novartis Nigeria Limited\nSenegal Coartem Novartis Pharma AG\nSudan Coartem Novartis Pharma Schweiz AG\nTanzania Riamet NVS Kenya Ltd\nTogo Coartem Novartis Pharma AG\nUganda Riamet NVS Kenya Ltd\nZambia Riamet Novartis Pharma Services AG\nZimbabwe Riamet Novartis Pharma Services AG\n
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressraps.clinicaltrials@novartis.com
      • applicant_covering_letter1
      • applicant_protocol1
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      • applicant_investigators_cv1
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      • applicant_statement1
      • applicant_participating_countries(null)
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      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african0
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantDenish Maisiba
      • declaration_date121-03-2023
      • declaration_principal_investigatorGodfrey Allan Otieno
      • declaration_date221-03-2023
      • placebo_presentNo
      • study_objectives<p>\n Primary objective(s)</p>\n<p>\n Part A:</p>\n<p>\n • To assess the parasite clearance time (PCT) of oral doses of an anti-malarial agent</p>\n<p>\n administered as monotherapy in patients with uncomplicated P. falciparum malaria</p>\n<p>\n  </p>\n<p>\n Part B:</p>\n<p>\n • To assess the 28-day cure rate of an anti-malarial agent administered orally as</p>\n<p>\n combination therapy versus the standard of care (SoC) in patients with uncomplicated</p>\n<p>\n P. falciparum malaria</p>\n<p>\n  </p>\n<p>\n Secondary objective(s)</p>\n<ul>\n <li>\n Part A:\n <ul>\n <li>\n To assess the 28-day cure rate of an anti-malarial agent administered orally as monotherapy in patients with uncomplicated P. falciparum malaria</li>\n </ul>\n </li>\n <li>\n Part B:\n <ul>\n <li>\n To assess the parasite clearance time (PCT) of oral combinations of anti-malarial agents versus the standard of care (SoC) in patients with uncomplicated P. falciparum malaria</li>\n <li>\n To assess the 28-day cure rate of an anti-malarial agent administered orally as combination therapy versus the SoC in patients with uncomplicated P. falciparum malaria</li>\n </ul>\n </li>\n</ul>\n<p>\n  </p>\n<ul>\n <li>\n For all parts:\n <ul>\n <li>\n To characterize PK of each anti-malarial agent administered orally as monotherapy</li>\n </ul>\n </li>\n</ul>\n<p style=\"margin-left:1.0in;\">\n [Part A] and/or as combination therapy</p>\n<p style=\"margin-left:1.0in;\">\n [Part B] in patients with uncomplicated P. falciparum malaria</p>\n<ul style=\"list-style-type:circle;\">\n <li>\n To assess the safety and tolerability of each anti-malarial agent administered orally as monotherapy [Part A] and/or as combination therapy versus SoC [Part B] in patients with  uncomplicated P. falciparum malaria</li>\n</ul>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n Exploratory objective(s)</p>\n<ul>\n <li>\n For Part B:\n <ul>\n <li>\n To assess the 42-day cure rate of an anti-malarial agent administered as combination therapy versus the SoC in patients with uncomplicated P. falciparum malaria</li>\n </ul>\n </li>\n <li>\n For all parts:</li>\n <li>\n To assess the effect of each anti-malarial agent administered orally as monotherapy and/or as combination therapy on parasite clearance dynamics</li>\n <li>\n To assess the effect of each anti-malarial agent on drug resistance development</li>\n <li>\n To assess the effect of each anti-malarial agent administered orally as monotherapy and as combination therapy on fever clearance time</li>\n <li>\n To explore the exposure-response and/ or exposure-protein levels (e.g., alpha-1 glycoprotein) relationship of anti-malarial agent administered as monotherapy and/or as combination therapy</li>\n <li>\n To explore the effect of each anti-malarial agent on gametocytes and transmission-blocking potential</li>\n <li>\n To explore potential association of biomarker and differential clinical response to each anti-malarial agent</li>\n <li>\n Optional DNA collection: To perform genetic research to investigate drug related response mechanisms, to better understand the disease and/or safety and efficacy of each anti-malarial agent</li>\n</ul>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n Male and female patients ≥18 years of age for Part A and ≥12 years of age for Part B at screening.</p>\n<p>\n • Patients must have acute uncomplicated P. falciparum malaria mono-infection at screening confirmed by a parasite count between 5,000 to 150,000 asexual parasite count/μl of blood for P. falciparum for Part A and between 1,000 to 150,000 asexual parasite count/μl of blood for Part B Patients in Part A must weigh between 40 kg and 90 kg. Patients in Part B must weigh between 35 kg and 90 kg at screening.</p>\n
      • principal_exclusion_criteria<ul>\n <li>\n Patients with signs and symptoms of severe/complicated malaria at screening or mixed Plasmodium infection (i.e., infection with more than one malaria species) at screening</li>\n <li>\n Moderate to severe anemia, chronic hemoglobinopathy (Hemoglobin level < 8 g/dL), or known chronic underlying disease such as sickle cell disease at screening</li>\n <li>\n Known clinically significant liver disease (e.g., chronic hepatitis, liver cirrhosis (compensated or decompensated), history of hepatitis B or C, hepatitis A or B vaccination in the last 3 months, known gallbladder or bile duct disease, acute or chronic pancreatitis. Clinical or laboratory evidence of any of the following at screening:</li>\n <li>\n AST/ALT > 3 x the upper limit of normal range (ULN), regardless</li>\n <li>\n of the level of total bilirubin</li>\n <li>\n AST/ALT > 1.5 and ≤ 2 x ULN and total bilirubin is > ULN</li>\n <li>\n Total bilirubin > 2 x ULN, regardless of the level of AST/ALT</li>\n <li>\n Any known/suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection at screening.</li>\n <li>\n Pregnant or nursing (lactating) women, women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using methods of contraception as outlined in Section 12, and sexually active patients not willing to practice effective contraception.</li>\n <li>\n History or current diagnosis of ECG abnormalities indicating significant risk of safety for patients participating in the study such as:\n <ul>\n <li>\n Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker</li>\n <li>\n History of familial long QT syndrome or known family history of Torsades de Pointe.</li>\n <li>\n Resting heart rate (physical exam or 12 lead ECG) < 60 bpm</li>\n </ul>\n </li>\n</ul>\n<p>\n  </p>\n
      • primary_end_points<p>\n <strong>Primary endpoint:</strong></p>\n<ul>\n <li>\n Parasite clearance time (hours) up to Day 7</li>\n <li>\n Polymerase Chain Reaction (PCR)- corrected adequate clinical and parasitological response (ACPR) at Day 29 (i.e., 28 days post-dose)</li>\n</ul>\n<p>\n  </p>\n<p>\n <strong>Secondary Endpoint(s): </strong></p>\n<ul>\n <li>\n PCR-corrected and uncorrected adequate clinical and parasitological response (ACPR) at Day 29 (i.e., 28 days post-dose)</li>\n <li>\n Parasite clearance time (hours) up to Day 7</li>\n <li>\n PCR- uncorrected adequate clinical and parasitological response (ACPR) at Day 29 (i.e., 28 days post-dose)</li>\n <li>\n PK parameters such as AUC0-t, AUClast, AUCinf, Cmax, Tmax, T1/2, Cl/F, V/F</li>\n <li>\n Adverse events, vital signs, ECG findings,safety laboratory assessments including chemistry, hematology, and urinalysis results up through EOS</li>\n</ul>\n<p>\n  </p>\n<p>\n <strong>Exploratory endpoints: </strong></p>\n<ul>\n <li>\n PCR-corrected and uncorrected adequate clinical and parasitological response (ACPR) at Day 43</li>\n <li>\n Parasite reduction ratio (PRR) at different time-points (such as 12, 24, 48 hours post-dose), Parasite Clearance Estimator Worldwide Antimalarial Resistance Network (PCE half-life), Time to 50 or 90% parasite reduction (PC50, PC90)</li>\n <li>\n Frequency of resistance specific gene mutations (dhfr, dhps, pfcrt, pfmdr1, Kelch13, Pfatp4 and additional parasite genes of interest) using whole genome sequencing and if necessary, targeted genome sequencing approach</li>\n <li>\n IC50 of clinical isolates from treatment failure samples in vitro growth inhibition assays from parasites before and after treatment (recrudescent infections)</li>\n <li>\n Fever clearance time (FCT)</li>\n <li>\n PK parameters (such as Cmax, AUC and concentration on specific day) with efficacy outcomes (e.g., PRR, ACPR29) related to parasite dynamics, cure and protein levels (e.g., alpha-1 glycoprotein) wherever applicable</li>\n <li>\n Presence of gametocytes in patients at baseline (pre-dose) and post-treatment, respectively<br />\n Baseline, and changes from baseline, in expression levels of circulating biomarkers in serum</li>\n <li>\n Genetic data (e.g., polymorphisms)</li>\n</ul>\n
      • scope_diagnosis0
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      • scope_safety1
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      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n <strong><u>Site 5001_Dr. Allan Otieno_Site Capacity</u></strong></p>\n<p>\n  </p>\n<p>\n  KEMRI Kondele Children Hospital- PLATINUM Study</p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n KEMRI Kondele Children’s Hospital study site is located within Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH) in Kisumu city. JOOTRH is a level 5 hospital with a total bed capacity of 710, which receives referral from surrounding health facilities within Kisumu County, and is able to accommodate both outpatient and in-patient adults and pediatric patients for several days.</p>\n<p>\n Staffing (Human Workforce).</p>\n<p>\n The hospital has a total staff of over 500 health workers including, 45 Specialists Consultants, several Medical Officers, Clinical Officers, Pharmacists, Pharmaceutical technologists Laboratory Technologists and 200 Nurses,</p>\n<p>\n The study site in addition has: 2 Pediatricians; 1 medical officers, 2 clinical officers, 4 nurses, 1 pharmacist, 2 Pharmaceutical technologists, 1 pharmaceutical technician, Community interviewers, 1 Data manager, Data clerks, 3 laboratory technologists and microscopists with certificate for malaria microscopy proficiency testing (PT), regulatory officers, quality assurance officers and administrative officer. The site staff are well trained and experienced in conducting clinical trials.</p>\n<p>\n Institutional facilities</p>\n<p>\n KEMRI Kondele Children’s Hospital which is within the JOOTRH is mainly used for research related activities including clinical trials. It holds clinical rooms, emergency room with a fully equipped crash cart, temperature-controlled pharmacy and laboratory, data room, Bulk filing storage space, meeting room with stable internet connectivity.</p>\n<p>\n There are also several facilities within the hospital, which complement research activities. These include:</p>\n<ul>\n <li>\n • An ISO 15189:2012 accredited laboratory which is well-equipped and that handles both routine and specialized tests including, biochemistry, hematology, and microbiology.</li>\n <li>\n • Adult and Pediatric wards that can accommodate any admission referral from the study</li>\n <li>\n • Blood bank to provide blood transfusion services. However, relatives have to donate to replace the given blood.</li>\n <li>\n • Dialysis service available but can only accommodate a few patients at a time.</li>\n</ul>\n<p>\n  </p>\n<p>\n  </p>\n<ul>\n <li>\n • Vital signs equipment is available in both the out-patient and in-patient departments and there are 2 ECG machines available in the at the emergency department and the KEMRI Kondele Children’ Hospital Study site. The study site has a defibrillator machine as well.</li>\n <li>\n • Continuous supply of oxygen through their own oxygen plant as well as commercial supply from bulk oxygen cylinders. However, there is a shortage in ICU trained nurses and only the anesthesia department can carry out artificial ventilation.</li>\n <li>\n • A newly renovated Radiology department with conventional digitalized X-Ray, ultrasound CT scan and MRI scan capabilities is currently in use for the entire JOOTRH.</li>\n</ul>\n<p>\n  </p>\n<p>\n Waste Management and Handling.</p>\n<p>\n The site has established protocols for waste handling and disposal. This is based on sorting the waste according to the different biohazard level. The waste is then disposed according to protocol. There is an incinerator at the hospital to assist in the proper destruction and disposal of the waste.</p>\n<p>\n Quality assurance policies and protocols.</p>\n<p>\n The site has quality assurance SOPs that it follows for all its procedures. The staff are well trained and refresher courses are offered on a regular basis. Quality control / quality assurance checks and source data verification happens on the three major levels:</p>\n<p>\n Level 1 – Self Quality Check: Done on completion of study procedures while still seated with the participant</p>\n<p>\n Level 2 – Quality Control Check: Which entails QC checks that will be performed by the clinic QA officer/MO/SSC on a real-time basis and any errors picked will be addressed there and then.</p>\n<p>\n Level 3 – Quality Assurance Check: Done level are done at the data entry center by the data entry team during the receiving of the data from the clinics and during entry into the data base system to assure completeness and legibility.</p>\n<p>\n  </p>\n<p>\n <strong><u>Site 5002_Dr Orimbo_Site Capacity</u></strong></p>\n<p>\n  </p>\n<p>\n AHERO CLINICAL TRIALS UNIT</p>\n<p>\n Ahero Clinical Trials Unit site is located within the Ahero county hospital in Nyando Sub- County, Kisumu County. Ahero County Hospital is level 4 hospital, with a bed capacity of 40, which receives referral from surrounding peripheral health facilities within Nyando Sub County, and is able to accommodate both outpatient and in-patient adults and pediatric patients for several days.    </p>\n<p>\n  </p>\n<p>\n Staffing [ Human Workforce]</p>\n<p>\n The hospital has a total staff of over 100 health workers including, 2 Medical Officers,15 Clinical Officers,1 Pharmacist, 6 pharmaceutical technologists, Laboratory technologists and 40 Nurses.</p>\n<p>\n The Study Site in addition has: 2 Pediatricians,1 Medical Officer,3 Clinical officers,6 nurses,2 Pharmacist ,1 Pharmaceutical technologist ,1 Pharmaceutical technician, 1Field Coordinator, 2 Field Supervisors, 22 Community health workers, 1Data Manager,4 Data Clerks, 5 Laboratory technologist ,1 laboratory technician and microscopists with certificate for malaria microscopy proficiency testing (PT), regulatory officers, quality assurance officers and administrative officer. Some of our investigators are also part of Ethical Committee at SERU.</p>\n<p>\n  </p>\n<p>\n Institutional facilities</p>\n<p>\n Ahero Clinical Trials Unit which is within the Ahero County Hospital is mainly used for research related activities including clinical trials. It holds clinical rooms, emergency room with a fully equipped crash cart, temperature controlled pharmacy and laboratory, data room with stable internet connectivity for 24hours, Active Archival storage space and monitoring room.</p>\n<p>\n There are also several facilities within the hospital, which complement research activities. These include:</p>\n<ul>\n <li>\n An ISO 15189:2012 accredited laboratory which is well-equipped and that handles both routine and specialized tests including, biochemistry, hematology and microbiology.</li>\n <li>\n Adult and Pediatric wards that can accommodate any admission referral from the study</li>\n <li>\n Vital signs equipment is available in both the out-patient and in-patient departments and at the Ahero Clinical Trials Unit site. The study site has also 1 ECG machine as well.</li>\n <li>\n Continuous supply of oxygen from commercial supply from bulk oxygen cylinder.</li>\n</ul>\n<p>\n  </p>\n<p>\n Waste Management and Handling.</p>\n<p>\n The site has established protocols for waste handling and disposal. This is based on sorting the waste according to the different biohazard level. The waste is then disposed according to protocol. There is an incinerator at the hospital to assist in the proper destruction and disposal of the waste.</p>\n<p>\n Quality assurance policies and protocols.</p>\n<p>\n The site has quality assurance SOPs that it follows for all its procedures. The staff are well trained and refresher courses are offered on a regular basis. Quality control / quality assurance checks and source data verification happens on the three major levels: </p>\n<p>\n Level 1 – Self Quality Check: Done on completion of study procedures while still seated with the participant</p>\n<p>\n Level 2 – Quality Control Check: Which entails QC checks that will be performed by the clinic QA officer/MO/SSC on a real-time basis and any errors picked will be addressed there and then.</p>\n<p>\n Level 3 – Quality Assurance Check: Done level are done at the data entry center by the data entry team during the receiving of the data from the field, clinics and during entry into the data base system to assure completeness and legibility.</p>\n<p>\n  </p>\n
      • other_details_explanation<p>\n Malaria is not prevalent in Switzerland. Hence, study cannot be conducted in Switzerland</p>\n
      • other_details_regulatory_notapproved<p>\n  </p>\n<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"619\">\n <tbody>\n <tr>\n <td style=\"width:103px;\">\n <p>\n Country</p>\n </td>\n <td style=\"width:210px;\">\n <p>\n Agency</p>\n </td>\n <td style=\"width:96px;\">\n <p>\n Status of Clinical Trial Application</p>\n <p>\n “Planned”</p>\n <p>\n “Submitted”</p>\n <p>\n “Approved”; “Refused”</p>\n </td>\n <td style=\"width:102px;\">\n <p>\n Submission Date</p>\n </td>\n <td style=\"width:108px;\">\n <p>\n Decision Date</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:103px;\">\n <p align=\"center\">\n Burkina Faso</p>\n </td>\n <td style=\"width:210px;\">\n <p>\n Ministère de la Santé, de la Population et de la Réforme Hospitalière (MSPR)</p>\n </td>\n <td style=\"width:96px;\">\n <p>\n Planned</p>\n </td>\n <td style=\"width:102px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:108px;\">\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:103px;\">\n <p align=\"center\">\n Kenya</p>\n </td>\n <td style=\"width:210px;\">\n <p>\n Pharmacy and Poisons Board (PPB)  </p>\n </td>\n <td style=\"width:96px;\">\n <p>\n Planned</p>\n <p>\n  </p>\n </td>\n <td style=\"width:102px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:108px;\">\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:103px;\">\n <p align=\"center\">\n Ghana</p>\n </td>\n <td style=\"width:210px;\">\n <p>\n National Agency for Food and Drug Administration and Control</p>\n </td>\n <td style=\"width:96px;\">\n <p>\n Planned</p>\n </td>\n <td style=\"width:102px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:108px;\">\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:103px;\">\n <p align=\"center\">\n Rwanda</p>\n </td>\n <td style=\"width:210px;\">\n <p>\n Rwanda Food and Drugs Authority</p>\n </td>\n <td style=\"width:96px;\">\n <p>\n Planned</p>\n </td>\n <td style=\"width:102px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:108px;\">\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:103px;\">\n <p align=\"center\">\n Gabon</p>\n </td>\n <td style=\"width:210px;\">\n <p>\n Ministère de la Santé</p>\n </td>\n <td style=\"width:96px;\">\n <p>\n Planned</p>\n </td>\n <td style=\"width:102px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:108px;\">\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:103px;\">\n <p align=\"center\">\n Ivory Coast</p>\n </td>\n <td style=\"width:210px;\">\n <p>\n Ministère de la Santé, de la Population et de la Réforme Hospitalière (MSPRH)</p>\n </td>\n <td style=\"width:96px;\">\n <p>\n Planned</p>\n </td>\n <td style=\"width:102px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:108px;\">\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:103px;\">\n <p align=\"center\">\n Uganda</p>\n </td>\n <td style=\"width:210px;\">\n <p>\n National Drug Authority (NDA)</p>\n </td>\n <td style=\"width:96px;\">\n <p>\n Planned</p>\n </td>\n <td style=\"width:102px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:108px;\">\n <p>\n  </p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_regulatory_approved<p>\n None of the countries participating in the study has been approved as yet.</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_durationPart A duration: 31 days Part B duration: 43 days
      • 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_comparatorCoartem
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states7
      • number_of_sites2
      • multi_country_listCountry Agency Status of Clinical Trial Application\n“Planned”\n“Submitted”\n“Approved”; “Refused” Submission Date\nBurkina Faso Ministère de la Santé, de la Population et de la Réforme Hospitalière (MSPR) Planned \nKenya Pharmacy and Poisons Board (PPB) Planned\n \nGhana National Agency for Food and Drug Administration and Control Planned \nRwanda Rwanda Food and Drugs Authority Planned \nGabon Ministère de la Santé Planned \nIvory Coast Ministère de la Santé, de la Population et de la Réforme Hospitalière (MSPRH) Planned \nUganda National Drug Authority (NDA) Planned \n\nCountry Agency Status of Clinical Trial Application\n“Planned”\n“Submitted”\n“Approved”; “Refused” Submission Date\nBurkina Faso Ministère de la Santé, de la Population et de la Réforme Hospitalière (MSPR) Planned \nKenya Pharmacy and Poisons Board (PPB) Planned\n \nGhana National Agency for Food and Drug Administration and Control Planned \nRwanda Rwanda Food and Drugs Authority Planned \nGabon Ministère de la Santé Planned \nIvory Coast Ministère de la Santé, de la Population et de la Réforme Hospitalière (MSPRH) Planned \nUganda National Drug Authority (NDA) Planned \n\n
      • data_monitoring_committeeNo
      • total_enrolment_per_siteEnrollment is competitive\nApproximately 14 Participants per site\n
      • total_participants_worldwideApproximately 180 participants will be randomized
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • 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_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameGodfrey
      • investigator1_middle_nameAllan
      • investigator1_family_nameOtieno
      • investigator1_qualificationMBChB, MMED Paediatrics and Child health
      • investigator1_professional_addressKEMRI-Centre for Clinical Research (CCR)Kondele Children\'s Hospital, Off Kisumu-Kakamega Road, P.O. Box, 54-40100, Kisumu. Kenya
      • investigator1_telephone+254733893481/+254723934706
      • investigator1_emailgaotieno@gmail.com
      • organisations_transferred_No
      • number_participants35
      • notification
      • approval_date21-07-2023
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted02-10-2023
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonAll the queries raised have been addressed through the AVAREF platform and considered adequate for approval.
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-11-17 23:13:41
      • created2023-03-07 12:23:19
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id909
        • application_id1233
        • given_nameGodfrey (Site 5001)
        • middle_nameAllan
        • family_nameOtieno
        • qualificationMBChB, MMED Paediatrics and Child health
        • professional_addressKEMRI-Centre for Clinical Research (CCR)Kondele Children\'s Hospital, Off Kisumu-Kakamega Road, P.O. Box, 54-40100, Kisumu. Kenya
        • telephone+254733893481/+254723934706
        • emailgaotieno@gmail.com
        • created2023-03-07 13:13:57
        • modified2023-10-02 14:56:41
      • 1(array)
        • id910
        • application_id1233
        • given_nameBernhard
        • middle_nameRagama
        • family_nameOgutu
        • qualificationMBChB, MMED Paediatrics and Child health
        • professional_addressKEMRI-Centre for Clinical Research (CCR)Kondele Children\'s Hospital, Off Kisumu-Kakamega Road, P.O. Box, 54-40100, Kisumu. Kenya
        • telephone+254733812613
        • emailogutu6@gmail.com
        • created2023-03-07 13:13:57
        • modified2023-10-02 14:56:41
      • 2(array)
        • id911
        • application_id1233
        • given_nameJohn (Site 5002)
        • middle_name
        • family_nameOrimbo
        • qualificationMedical Doctor
        • professional_addressKEMRI-Ahero Clinical Research Centre, Ahero County Hospital, Ahero, Kenya
        • telephone+254 714644574
        • emailjguda006@gmail.com
        • created2023-03-07 13:41:24
        • modified2023-10-02 14:56:41
    • SiteDetail(array)
      • 0(array)
        • id1460
        • application_id1233
        • county_id42
        • site_nameKEMRI Kondele Children Hospital
        • physical_addressKEMRI-Centre for Clinical Research (CCR)Kondele Children\'s Hospital, Off Kisumu-Kakamega Road, P.O. Box, 54-40100, Kisumu. Kenya
        • contact_detailsP.O. Box, 54-40100, Kisumu. Kenya
        • contact_personDr.Allan Otieno
        • site_capacity(null)
        • misc(null)
        • created2023-03-07 13:13:57
        • modified2023-10-02 14:56:41
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 1(array)
        • id1461
        • application_id1233
        • county_id42
        • site_nameAHERO CLINICAL TRIALS UNIT
        • physical_addressKEMRI-Ahero Clinical Research Centre, Ahero County Hospital, Ahero, Kenya
        • contact_details Ahero County Hospital, Ahero, Kenya
        • contact_personDr.John Orimbo
        • site_capacity(null)
        • misc(null)
        • created2023-03-07 13:13:57
        • modified2023-10-02 14:56:41
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
    • Sponsor(array)
      • 0(array)
        • id648
        • application_id1233
        • sponsorNovartis Pharma AG
        • sponsor_typeIndustry
        • contact_person
        • addressLichtstr. 35, Basel 4056, Switzerland
        • telephone_number+41616967522
        • fax_number+41616967522
        • cell_number+41616967522
        • email_addressdiogo.mato@novartis.com
        • created2023-03-07 13:13:57
        • modified2023-10-02 14:56:41
  • 1(array)
    • Application(array)
      • id539
      • user_id613
      • trial_status_id5
      • abstract_of_study<p style=\"margin-left:5.05pt;\">\n Tuberculosis (TB) is one of the most important global health problems. Kenya is ranked 15th among the 22 high TB burden countries that account for 80% of the global TB burden. An estimated two billion persons carry latent Mycobacterium tuberculosis (MTB). Treatment of latent tuberculosis infection (LTBI) is critical to global tuberculosis control and elimination. Pregnant women are at increased risk of progressing from latent LTBI to active tuberculosis because pregnancy suppresses the immune response. Symptoms of active TB may not be seen until after delivery, when the immune suppression reverses and symptoms are exacerbated. The World Health Organization (WHO) currently recommends treating LTBI with daily isoniazid (INH) for all HIV- infected pregnant women, but few programs have implemented this policy. Adherence and toxicity concerns remain the main barriers to treatment. Pregnancy and infant outcomes of women taking isoniazid for active TB treatment are comparable to normal pregnant women not receiving TB treatment, but toxicity concerns persist due to the suboptimal quality of existing studies. The US Centers for Disease Control and Prevention (CDC) recommends the use of either nine months of daily isoniazid monotherapy or a newer regimen of three months of weekly isoniazid and rifapentine (RPT) which is recommended in otherwise healthy patients over the age of 12 years who have LTBI. Though the CDC states that the regimen can be considered in other populations when it offers “practical advantages,” the regimen is not recommended in pregnant women, because the safety of the regimen in pregnancy is unknown. This study aims to address this gap in knowledge. This study aims to evaluate the pharmacokinetics, safety and tolerability of RPT and INH dosed once weekly for 12 doses in HIV-1 infected and HIV-1 uninfected pregnant women with latent TB infection at high risk for development of TB. The study will also describe the safety infant outcomes among infants born to women receiving once weekly RPT/INH. HIV-1 infected and HIV-1 uninfected pregnant women with latent TB and their infants will be enrolled into two cohorts based on gestation and started on RPT and INH once weekly for 12 weeks. Women in Cohort 1 will be enrolled in the second trimester of pregnancy (≥14 to <28 weeks); women in Cohort 2 will be enrolled in the third trimester of pregnancy (≥28 to ≤34 weeks). The Kericho site will recruit up to 20 participants and after completing the study drug regimen, participants will be followed until 24 weeks postpartum. This study is to inform practice on appropriate use of this regimen in pregnant and postpartum women that achieves concentrations similar to non-pregnant adults, in whom efficacy has been established. It is anticipated that this study will generate useful PK data to help inform next steps for an amendment to this protocol or a separate future study.</p>\n
      • study_title<p style=\"margin-left:2.85pt;\">\n <span style=\"font-size:12px;\">A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and Postpartum Women with Latent Tuberculosis Infection</span></p>\n
      • laymans_summary<p>\n This study is being done because TB is a major cause of illness and death in women of reproductive age. In countries where TB is common, up to half of all women are infected with TB. There are two types of TB that may occur when exposed to TB. In one type, people may become sick with symptoms such as cough and fever and these people are also contagious, meaning they can pass TB to other people. This type of TB is known as active TB disease. In the other type, people do not become sick or contagious, but they still have TB in an inactive form. This inactive form is known as latent TB. If latent TB is not treated, it can become active TB, and this often happens for women around the time of pregnancy. Maternal TB can be passed on to the babies causing illness or death. There are medicines that help prevent latent TB from becoming active TB. These medicines, Rifapentine and Isoniazid are widely used by people who are not pregnant. The purpose of this study is to test how these medicines are taken up in the body also called pharmacokinetic tests (PK), how they are tolerated and the safety of the medicines for pregnant women and their babies.</p>\n<p>\n  </p>\n<p>\n This is a multi-center study that will enroll HIV-1-infected and HIV-1- uninfected pregnant women with latent TB infection and their infants. Women will be enrolled into two cohorts based on gestation and started on RPT and INH once weekly for 12 weeks (at Entry and 11 weekly follow-up visits). Women in Cohort 1 will be enrolled at a pregnancy gestation between 14 and < 28 weeks; women in Cohort 2 will be enrolled at a pregnancy gestation between 28 to 34 weeks. In total across all study sites, up to 82 pregnant women will be enrolled to yield 50 evaluable women (a minimum of 25 evaluable women in each cohort) and their infants. Women are considered evaluable if they contribute any data to the PK sampling collections or complete the study drug regimen. The Kericho site will recruit up to 20 participants and after completing the study drug regimen, participants will be followed until 24 weeks postpartum then they are transitioned to the primary health care providers. The study will benefit the society by informing practice on appropriate use of these medicines in pregnant and postpartum women for prevention of active TB disease. It is anticipated that this study will generate useful data to help inform next steps for an amendment to this protocol or a separate future study.</p>\n<p>\n Participants will be informed of all potential risks from the treatment that they will receive which involve the side effects of medicine to be given. Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the body, and in rare cases, fainting or infection. Taking TB preventative medicine, as well as vitamin B6, may provide a benefit to the mother and her infant. Furthermore, early detection of TB may be a benefit and would help prevent transmission of TB to the infant. Participants will receive clinical examination, laboratory testing, and TB signs and symptoms counseling. For other medical conditions identified as part of the study screening and/or follow-up procedures, participants will be managed at KEMRI WRP CRC or referred to other sources of care available in the community</p>\n
      • short_titleIMPAACT 2001
      • protocol_noECCT/16/08/03
      • version_noVersion 1.0
      • date_of_protocol10-11-2015
      • study_drugRifapentine and Isoniazid
      • disease_conditionLatent Tuberculosis
      • 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_nameRifapentine and Isoniazid
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressdeborah.langat@usamru-k.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_data0
      • 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_applicantKEMRI WRP Kericho P.O Box 1357-20200, Kericho
      • declaration_date125-08-2016
      • declaration_principal_investigatorDeborah C. Langat
      • declaration_date225-08-2016
      • placebo_presentNo
      • study_objectives<h2>\n <span style=\"font-size: 12px;\">Primary Objective</span></h2>\n<ol>\n <li>\n To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of RPT and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the second trimester and third trimester who are receiving once-weekly RPT (900mg or the new study dose, if a dose adjustment is indicated by the interim analysis) and once-weekly INH (900mg).</li>\n <li>\n To estimate the incidence of serious adverse events (SAEs) related to RPT + INH dosed once weekly for 12 weeks (at entry and 11 weekly follow-up visits) in pregnant women.</li>\n <li>\n To describe the infant safety outcomes among infants born to women receiving once-weekly RPT + INH.</li>\n</ol>\n<p>\n Secondary Objectives</p>\n<ol>\n <li>\n To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of RPT and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the postpartum period who are receiving once-weekly RPT (900mg or the new study dose, if a dose adjustment is indicated by the interim analysis) and once-weekly INH (900mg).</li>\n <li>\n To assess the impact of covariates (gestational age, weight, age, HIV status) on primary PK</li>\n <li>\n To compare RPT and desRPT exposure pharmacokinetic parameters (AUC, Cmax, Cmin) for RPT in pregnant and postpartum women versus non-pregnant historical controls, using non-compartmental analyses</li>\n <li>\n To determine the RPT dose in pregnancy that achieves similar estimated exposure (AUC) of RPT</li>\n <li>\n To quantify RPT and desRPT concentrations at delivery among infants born to women receiving once-weekly RPT + INH</li>\n <li>\n To describe the tolerability of RPT + INH dosed once weekly for 12 weeks (at entry and 11 weekly follow-up visits) in pregnant and postpartum women</li>\n <li>\n To assess incidence of active TB in mother-infant pairs up to 24 weeks postpartum</li>\n <li>\n To explore the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of INH in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women (i.e., women who are and are not taking efavirenz (EFV)) who are receiving once-weekly RPT (900mg or the new study dose, if a dose adjustment is indicated by the interim analysis) and once-weekly INH (900mg).</li>\n</ol>\n<p>\n Exploratory Objectives</p>\n<ol>\n <li>\n To quantify RPT and desRPT concentrations in breast milk of postpartum women receiving once- weekly RPT + INH</li>\n</ol>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n 1.      Age ≥ 18 years at screening and able and willing to provide written informed consent for study. However, for the Kericho site, pregnant women <18 years of age can be enrolled since the Kenyan Ethics Review Committee guidelines considers a pregnant woman who is <18 years of age a mature minor and is permitted to give consent for herself and her child without the permission of her parents.</p>\n<p>\n 2.      At screening, evidence by ultrasound of a viable singleton pregnancy with an estimated gestational age at enrollment of ≥ 14 weeks through ≤ 34 weeks as per screening ultrasound.</p>\n<p>\n 3.      Has at least one of the following risk factors for TB:</p>\n<p style=\"margin-left:.75in;\">\n ·         Per participant report, household contact* with a known active pulmonary TB patient</p>\n<p style=\"margin-left:.75in;\">\n ·         Per medical records, confirmation of HIV-1 infection (see Section 4.1.5 of the core protocol) with single positive TST or IGRA at any time in the past. If not available in medical record, perform at screening</p>\n<p>\n 4.      Documentation of HIV-1 infection status, or confirmation of HIV-1 infection status (if unknown or undocumented.</p>\n<p>\n 5.      If HIV-1-infected, documented current prescription of EFV + 2 NRTI regimen and reports taking regimen for at least two weeks prior to enrollment (regimens containing protease, integrase, or entry inhibitors are not permitted)</p>\n<p>\n 6.      Documented laboratory values obtained within 30 days prior to enrollment:</p>\n<p style=\"margin-left:.75in;\">\n ·         Hemoglobin ≥ 7.5 g/dL</p>\n<p style=\"margin-left:.75in;\">\n ·         ALT <u><</u> 3 times the upper limit of normal (ULN)</p>\n<p style=\"margin-left:.75in;\">\n ·         Total bilirubin <u><</u> 2.5 times the ULN</p>\n<p style=\"margin-left:.75in;\">\n ·         Absolute neutrophil count (ANC) ≥ 750 cells/mm3</p>\n<p style=\"margin-left:.75in;\">\n ·         Platelet count <u>></u> 100,000/mm3</p>\n<p>\n 7.      Per participant report at screening, intent to remain in the current geographical area of residence for the duration of the study.</p>\n<p>\n 8.      Per participant report at screening, able to swallow whole tablets</p>\n<p>\n 9.      Per participant report, intention to keep the pregnancy.</p>\n<p>\n 10.  Per participant report, willingness to permit infant to participate in the study</p>\n
      • principal_exclusion_criteria<p>\n 1.      Women who meet any of the following criteria will be excluded from this study:</p>\n<p>\n 2.      Evidence of confirmed or probable active TB disease per WHO symptom screen and confirmation by Gene Xpert, shielded chest x-ray, or sputum sample.</p>\n<p>\n 3.      Participant report of personal history of INH- or rifampin-resistant, multi-drug resistant (MDR), or extensively drug-resistant (XDR) TB.</p>\n<p>\n 4.      Participant report of personal history of active TB in the past 2 years.</p>\n<p>\n 5.      Participant report of previous treatment for LTBI</p>\n<p>\n 6.      Household contact (as defined above) with known active MDR or XDR TB disease.</p>\n<p>\n 7.      Known major fetal abnormality as detected on ultrasound.</p>\n<p>\n 8.      Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.</p>\n<p>\n 9.      Known history of liver cirrhosis at any time prior to study entry.</p>\n<p>\n 10.  Per participant report and/or medical records, evidence of acute clinical hepatitis, such as a combination of abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to entry.</p>\n<p>\n 11.  Participant report and/or medical records of peripheral neuropathy Grade 2 or higher within 90 days prior to entry</p>\n<p>\n 12.  Current use or history of active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.</p>\n<p>\n 13.  Participant report and/or clinical evidence of porphyria.</p>\n<p>\n 14.  Any other condition that, in the opinion of the IoR/designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives, including taking the study medication.</p>\n<p>\n 15.  Planned or current participation in an interventional drug study.</p>\n<p>\n 16.  Current use of any prohibited or precautionary medications (see Section 5.5 of the core protocol), including didanosine (DDI) or stavudine (D4T)</p>\n
      • primary_end_points<p>\n Primary endpoints</p>\n<p>\n 1. Estimates of CL/F, absorption, and volume of distribution of RPT and its desacetyl-rifapentine metabolite (desRPT).</p>\n<p>\n 2. Maternal safety</p>\n<p>\n 3. Infant safety</p>\n<p>\n Secondary endpoints</p>\n<div>\n 1. Vd, CL/F, Ka for pregnant women in their second or third trimester.</div>\n<div>\n 2. RPT and desRPT concentrations in infants born to women receiving once-weekly RPT + INH.</div>\n<div>\n 3. Tolerability</div>\n<div>\n       o Permanent discontinuation of study drug regimen (i.e., RPT, INH, and pyridoxine)</div>\n<div>\n       o All AEs leading to permanent discontinuation of study drug regimen (i.e., RPT, INH, and pyridoxine)</div>\n<div>\n 4. RPT and des-RPT concentrations in breast milk of postpartum women receiving once-weekly RPT + INH.</div>\n<div>\n 5. Incidence of active TB in mother-infant pairs up to 24 weeks postpartum.</div>\n<div>\n 6. Estimates of CL/F, absorption, and volume of distribution of INH</div>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy1
      • scope_safety1
      • scope_efficacy0
      • scope_pharmacokinetic1
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology1
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n See section on Site Investigators and Contact Information of the Site Specific Addendum and Section 5.1 of the SSA, Kericho site and Population Description</p>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n Walter Reed Army Institute of Research IRB </p>\n
      • other_details_regulatory_approved<p>\n KEMRI SERU approved through letter dated 17 August 2016</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_durationThe site estimated duration of accrual is 1 year and each participant will be followed up for 24 weeks postpartum
      • design_controlled_randomisedNo
      • 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_comparatorRifapentine, Isoniazid
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKenya Medical Research Institute Walter Reed project
      • single_site_physical_addressHospital Road, P.O Box 1357-20200
      • single_site_contact_personDeborah Langat
      • single_site_telephone254 5220 30686
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states7
      • number_of_sites
      • multi_country_listKenya, Haiti, Thailand, Malawi, Zimbabwe, South Africa, United States
      • data_monitoring_committeeYes
      • total_enrolment_per_site20
      • total_participants_worldwide82 pregnant women and their infants
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornYes
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male0
      • subjects_healthyYes
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenYes
      • subjects_nursing_womenYes
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameLorner
      • investigator1_middle_nameChepkoech
      • investigator1_family_nameSoy
      • investigator1_qualificationRN
      • investigator1_professional_addressKEMRI Walter Reed Project P.O Box 1357- 20200, Kericho
      • investigator1_telephone254 5220 30686
      • investigator1_emailLorner.soy@usamru-k.org
      • organisations_transferred_Yes
      • number_participants20
      • notification<p>\n no</p>\n
      • approval_date27-10-2016
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted28-02-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"1053\">\n <tbody>\n <tr>\n <td style=\"width:702px;height:18px;\">\n <p>\n  <strong>A. Study Status at Close-out:</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:85px;\">\n <p>\n [X] Study was completed</p>\n <p>\n [] Study was started but closed prior to completion</p>\n <p>\n [] Study was not started</p>\n <p>\n [] Study is being transferred to another institution</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:42px;\">\n <p>\n <strong>B. Reason study was not started or was closed prior to completion or is being transferred to another institution:</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:28px;\">\n <p>\n N/A</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:24px;\">\n <p>\n <strong>C. Provide a summary of research objectives:</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:79px;\">\n <p>\n This was a multicenter study and the target sample for all the international sites was 50 mother infant pairs. Kericho site was to enroll up to 20 mother infant pairs but due to competitiveness in terms of enrollment, Kericho site enrolled 7 mother infant pairs but all the sites achieved the target sample size of 50 mother infant pairs.</p>\n <h2>\n Primary Objective</h2>\n <ol>\n <li>\n To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of RPT and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the second trimester and third trimester who are receiving once-weekly RPT (900mg or the new study dose, if a dose adjustment is indicated by the interim analysis) and once-weekly INH (900mg).</li>\n <li>\n To estimate the incidence of serious adverse events (SAEs) related to RPT + INH dosed once weekly for 12 weeks in pregnant women.</li>\n <li>\n To describe the infant safety outcomes among infants born to women receiving once-weekly RPT + INH.</li>\n </ol>\n <p>\n <strong><em>Secondary</em></strong><strong><em> Objectives</em></strong></p>\n <ol>\n <li>\n To estimate the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of RPT and its desacetyl-rifapentine metabolite (desRPT) among pregnant women during the postpartum period who are receiving once-weekly RPT (900mg or the new study dose, if a dose adjustment is indicated by the interim analysis) and once-weekly INH (900mg).</li>\n <li>\n To assess the impact of covariates (gestational age, weight, age, HIV status) on primary PK.</li>\n <li>\n To compare RPT and desRPT exposure pharmacokinetic parameters (AUC, Cmax, Cmin) for RPT in pregnant and postpartum women versus non-pregnant historical controls, using non-compartmental analyses.</li>\n <li>\n To determine the RPT dose in pregnancy that achieves similar estimated exposure (AUC) of RPT.</li>\n <li>\n To quantify RPT and desRPT concentrations at delivery among infants born to women receiving once-weekly RPT + INH.</li>\n <li>\n To describe the tolerability of RPT + INH dosed once weekly for 12 weeks in pregnant and postpartum women.</li>\n <li>\n To assess incidence of active TB in mother-infant pairs up to 24 weeks postpartum.</li>\n <li>\n To explore the population pharmacokinetics (PK) (CL/F, absorption, volume of distribution) of INH in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women (i.e., women who are and are not taking efavirenz (EFV)) who are receiving once-weekly RPT (900mg or the new study dose, if a dose adjustment is indicated by the interim analysis) and once-weekly INH (900mg).</li>\n <li>\n To quantify RPT and desRPT concentrations in breast milk of postpartum women receiving once- weekly RPT + INH.</li>\n </ol>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:46px;\">\n <p>\n <strong>D. Summary of Study Results: </strong>Please summarize the results of this research project, even if only for the study cohort enrolled locally.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:35px;\">\n <p>\n The Kericho site was activated to start screening and enrollment on 19 June 2017 after all approvals and study drugs were received on site.  A total of 8 pregnant women were screened and 7 pregnant women (and their infants) enrolled. One pregnant woman who was screened was not eligible for the study. All the 7 mothers and their infants completed and exited the study as per the protocol. Total accrual from all sites was 50 mother infant pairs.</p>\n <p>\n  </p>\n <p>\n This was a Phase I/II trial evaluating the pharmacokinetics and safety of once-Weekly Rifapentine and Isoniazid among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900mg weekly) for 12 weeks. Pharmacokinetic sampling was performed with the first (2nd/3rd trimester) and twelfth (3rd trimester/postpartum) doses. Non-linear mixed effects models were used to estimate drug population pharmacokinetics</p>\n <p>\n  </p>\n <p>\n Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs. 1.53 L/h, p<0.001), with area under the concentration-time curve (AUCSS) of 786 and 673 mg*hr/L, respectively. In pregnant women with HIV, clearance was 30% higher than women without HIV (p<0.001), resulting in a lower AUCss (522 mg*h/L); clearance did not change significantly between pregnancy and postpartum. Pregnancy did not impact isoniazid pharmacokinetics. There were no drug-related serious adverse events, treatment discontinuations, or TB cases in women or infants</p>\n <p>\n The study found that the regimen of weekly isoniazid and rifapentine for three months (3HP) does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:41px;\">\n <p>\n <strong>E. List Outputs arising from study e.g. Manuscripts, Thesis, Research Reports, Technical Briefs, Policy Briefs, Abstracts, Patents, Book Chapter etc. (attach copies of the outputs(s). </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:48px;\">\n <ul style=\"list-style-type:circle;\">\n <li>\n Oral abstracts on Rifapentine Pharmacokinetics and Safety in pregnant women with and without HIV on 3HP was presented on the March 8^th - 11^th March 2020 at the Conference on Retroviruses & Opportunistic Infections (CROI).</li>\n <li>\n Manuscript on Pharmacokinetics and Safety of Three Months of Weekly Rifapentine and Isoniazid for Tuberculosis Prevention in Pregnant Women.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:14px;\">\n <ol style=\"list-style-type:upper-alpha;\">\n <li value=\"6\">\n <strong>Confirm destruction of each study participant’s identifiers and provide an assurance/evidence that the destruction has occurred (send copies of the blacked-out books). </strong></li>\n </ol>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:31px;\">\n <p>\n Study documents have been transferred to a safe, secured, long-term archive room that is only accessible to regulatory personnel. All other research staff do not have access to this archive room. Access to study documents is controlled and restricted and the site is responsible for ensuring that any access is accurately recorded and any documents accessed/removed and returned are recorded. Destruction approval will be obtained from the sponsor and the IRBs will be notified when this is done.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>G. Detail the plan for future use of data from the study (if applicable) </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:33px;\">\n <ul style=\"list-style-type:circle;\">\n <li>\n There are currently no plans for future analysis of individual participant data by study site personnel. Analysis of aggregated data and publication for secondary objectives will continue.</li>\n <li>\n Any plans for future (non-aggregated) analyses will be reviewed and approved by KEMRI SERU prior to the work being completed.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>H. Confirm destruction of surplus investigational agents and provide an assurance/evidence that the destruction has occurred (if applicable) </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:27px;\">\n <table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n <tbody>\n <tr>\n <td style=\"width:646px;height:18px;\">\n <p>\n Please find attached P2001 Study Product Recovery Report.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:646px;height:5px;\">\n <p>\n  </p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>I. Detail the plan for the destruction, storage, or future use of biological specimens obtained as part of this study (include number of samples being destroyed or stored) </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:43px;\">\n <p style=\"margin-left:.25pt;\">\n All work for this study is complete and the samples that were not for safety testing were all shipped out with the approval of KEMRI SERU for analysis. Future use of individually coded data will have to be approved by the IRB. Participants were informed through the informed consent forms that they signed, that the stored samples may be shipped out of the country and used for future IMPAACT -approved TB/HIV related research. The participants were also made aware that any use of the samples and stored data whether locally or out of the country will have to be approved by KEMRI SERU.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>J. Were the study results communicated to the local community? If yes provide details where and when- if not kindly explain why not.</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:27px;\">\n <p>\n The study results have been communicated to the local community through continuous medical education and meeting with the community Advisory Board as well as meetings organized in the community.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>K. Is there a policy implication or best practice that should be forwarded to the MOH or any relevant authority?  </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:81px;\">\n <p>\n Yes, from the Publication:</p>\n <ul style=\"list-style-type:circle;\">\n <li>\n There is no dose adjustment of rifapentine and isoniazid required in pregnancy.</li>\n <li>\n The regimen of weekly isoniazid and rifapentine for three months for tuberculosis prevention was well-tolerated in pregnant women, and target concentrations of both drugs were achieved at standard doses among women with and without HIV.</li>\n </ul>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n<p>\n  </p>\n
      • implication_results<p>\n Yes, from the Publication:</p>\n<ul style=\"list-style-type: circle;\">\n <li>\n There is no dose adjustment of rifapentine and isoniazid required in pregnancy.</li>\n <li>\n The regimen of weekly isoniazid and rifapentine for three months for tuberculosis prevention was well-tolerated in pregnant women, and target concentrations of both drugs were achieved at standard doses among women with and without HIV.</li>\n</ul>\n
      • quantity_importedFind attached product accountability documents
      • quantity_dispensedFind attached product accountability documents
      • quantity_destroyedFind attached product accountability documents
      • quantity_exportedFind attached product accountability documents
      • balance_siteFind attached product accountability documents
      • final_date0000-00-00
      • modified2023-04-28 10:39:27
      • created2016-08-24 09:43:12
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id351
        • application_id539
        • given_nameDeborah
        • middle_nameChepngeno
        • family_nameLangat
        • qualificationMBChB, MSc, DLSHTM
        • professional_addressKEMRI Walter Reed Project P.O Box 1357- 20200, Kericho
        • telephone254 5220 30686
        • emailDeborah.langat@usamru-k.org
        • created2016-08-24 09:59:06
        • modified2020-02-28 12:24:43
    • SiteDetail(array)
      • 0(array)
        • id418
        • application_id539
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2016-08-24 09:59:06
        • modified2020-02-28 12:24:43
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id279
        • application_id539
        • sponsorThe National Institute of Allergy and Infectious Diseases
        • sponsor_typeResearch Institution
        • contact_personEllen Townley
        • addressMaternal Adolescent Pediatric Branch HJF DAIDS, DAIDS/NIAID/NIH 5601 Fishers Lane Room 8B37
        • telephone_number240-292-4784
        • fax_number240-627-3465
        • cell_number240-292-4784
        • email_addressellen.townley@nih.gov
        • created2016-08-24 09:59:06
        • modified2020-02-28 12:24:43
  • 2(array)
    • Application(array)
      • id208
      • user_id43
      • trial_status_id5
      • abstract_of_study<p>\n AIDS-Related Non-Hodgkin’s Lymphoma (AR-NHL)</p>\n<p>\n Approximately 10% of the world population lives in sub-Saharan Africa, but the region is home to approximately 68% of the world population living with HIV1. Most countries in this region have an HIV prevalence of at least 10% with a number of countries having a prevalence that exceeds 20%2. As the AIDS pandemic advances, the burden of related neoplastic disease is increasing in developing nations3,4. While under-developed cancer registries in sub-Saharan Africa bar a definitive statement being made regarding increases in incidence and prevalence in Africa, it is felt that AIDS-Related Non-Hodgkin’s Lymphoma</p>\n<p>\n (AR-NHL) has rising incidence in this setting. Investigators involved in this study have previously published data that outcomes of AR-NHL are worse than NHL in seronegative patients5. Unfortunately, building on this observation is difficult, as there have been few published data on the tolerance and outcomes of treatment for HIV-associated non-Hodgkin lymphoma (NHL) in sub-Saharan Africa or on the most effective treatment regimen(s) in the varied clinical settings that exist within the region. Although all of the AMC African trial</p>\n<p>\n sites cite CHOP as a “standard of care” for initial treatment of HIV-associated NHL, only one, the Uganda Cancer institute (UCI), has published information on treatment outcomes.</p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n The most comprehensive accounting of newly diagnosed NHL, from the UCI and recently published by Bateganya et al6, remains limited; between 2004 and 2008 only 51 HIV-infected patients were identified. Although CHOP chemotherapy was administered to approximately two-thirds of all patients, the estimated median survival, even among HIV-seronegative individuals, was less than 1 year and the authors found no evidence that receipt of chemotherapy improved survival. HIV-positive patients receiving antiretroviral therapy had survival rates approximating those of HIV-negative persons, but the adjusted hazard of death was significantly elevated among HIV-positive patients not receiving antiretroviral therapy [adjusted hazard ratio (HR) 8.99, P < 0.001] compared with HIV-negative patients. An updated and as yet unpublished analysis (P. Imani and C. Casper, Personal Communication, January 2012) showed that of the 37 HIV+ patients in this study who received CHOP</p>\n<p>\n chemotherapy, 34 received at least 70% of the standard dose. However, only 4 of 34 patients received at least 6 cycles of chemotherapy. The estimated median survival for all HIV+ patients who received CHOP was approximately 6 months, and only one patient was known</p>\n<p>\n to be alive at 2 years. Interpreting the reason for the poor outcome for both HIV-infected and HIV-uninfected individuals is complicated by a high loss to follow-up rate and lack of information on therapy-related complications and causes of death7, not to mention issues</p>\n<p>\n related to the purity and potency of locally-sourced chemotherapeutic agents.</p>\n<p>\n  </p>\n<p>\n  </p>\n
      • study_title<p style=\"margin-left:20.0pt;\">\n A Randomized Phase II Trial Of Chop Vs Oral Chemotherapy with Concomitant Antiretroviral Therapy in Patients with HIV-Associated Lymphoma in Sub-Saharan Africa</p>\n
      • laymans_summary<p>\n AMC-068 is a randomized phase II  multi-center clinical trial which compares of intravenous versus oral chemotherapy for HIV-positive individuals with diffuse large B-cell lymphoma. A total of 90 participants are expected to be enrolled with 45 particpants enrolled in each arm.</p>\n<p>\n The purpose of this study is to see if a mixture of anti-cancer medicines given by mouth is as good as a mixture of anti-cancer medicines given by vein for treating Africans with AIDS and NHL. This study will help develop better treatments for people with AIDS and cancer in Africa.</p>\n<p>\n  </p>\n
      • short_titleAMC 068
      • protocol_noECCT/13/02/01
      • version_no3.0
      • date_of_protocol03-08-2012
      • study_drugLomustine, Etoposide, Cyclophosphamide, Procarbazine
      • disease_conditionAIDS ASSOCIATED NON HODGKINS LYMPHOMA
      • 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_nameLomustine, Etoposide, Cyclophosphamide, Procarbazine
      • product_type_medical_device_name
      • comparator(null)
      • comparator_name(null)
      • comparator_registered(null)
      • comparator_countries(null)
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressamckenya@yahoo.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd(null)
      • applicant_prev_data(null)
      • applicant_stability_data(null)
      • applicant_analysis_cert(null)
      • applicant_pictorial_sample(null)
      • applicant_gcp_training(null)
      • applicant_dsmb_charter(null)
      • applicant_detailed_budget(null)
      • applicant_indemnity_pi(null)
      • applicant_practice_license(null)
      • applicant_registration_ctr(null)
      • applicant_pan_african(null)
      • applicant_hard_copies(null)
      • applicant_signed_checklist(null)
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantDR. EVANGELINE NJIRU
      • declaration_date127-08-2013
      • declaration_principal_investigatorDR. NAFTALI BUSAKHALA
      • declaration_date227-08-2013
      • placebo_presentNo
      • study_objectives(null)
      • principal_inclusion_criteria<div>\n <p style=\"margin-left: 5.95pt;\">\n <u>In</u><u>clusion criteria</u></p>\n <ol>\n <li style=\"margin-left: 41.95pt;\">\n  Ability to understand and the willingness to provide informed consent to participate.</li>\n <li style=\"margin-left: 41.95pt;\">\n  Adults, 18 years of age or older. Date of birth and age should be determined based on the best possible information or source documentation available.</li>\n <li style=\"margin-left: 41.95pt;\">\n  HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or confirmed by HIV-1 antigen or plasma HIV-1 RNA viral load > 1,000 copies/mL</li>\n <li style=\"margin-left: 41.95pt;\">\n Biopsy-proven, measurable or assessable systemic NHL that has been confirmed by an AMC- approved site pathologist. If a hard copy of the pathology report is unavailable at the time of enrolment, a verbal report by the pathologist confirming the diagnosis must be documented in the medical chart.</li>\n <li style=\"margin-left: 41.95pt;\">\n Pathology slides from tumor tissue obtained by surgical excision or core biopsy must be reviewed by the designated site pathologist, or backup pathologist, prior to study entry. Confirmation of the diagnosis must be documented by the AMC-approved pathologist prior to study entry. Please reference the AMC-068 MOP for further instructions on documenting the diagnosis</li>\n <li style=\"margin-left: 41.95pt;\">\n Participants must have fifteen blank (unstained) slides or a diagnostic tissue block must be available for central pathology review by the AMC Core Pathology Laboratory</li>\n <li style=\"margin-left: 41.95pt;\">\n ECOG performance status of 0 - 3 within 7 days of enrolment</li>\n <li style=\"margin-left: 41.95pt;\">\n Participants must have an estimated life expectancy of > 6 weeks.</li>\n <li style=\"margin-left: 41.95pt;\">\n The following acceptable end organ function/laboratory parameters within 7 days prior to enrollment.</li>\n <li style=\"margin-left: 41.95pt;\">\n Hematologic (Participants may enroll with lower hematologic values, if bone marrow involvement is documented. In this case, patients should be transfused to hemoglobin > 8 g/dL):</li>\n </ol>\n <ul>\n <li style=\"margin-left: 7.95pt; text-align: justify;\">\n WBC ≥ 3,000 cells/L (3.0 x 109 L) or absolute granulocytes ≥ 1500 cells/μL</li>\n <li style=\"margin-left: 7.95pt; text-align: justify;\">\n (1.5 x 109 L); and</li>\n <li style=\"margin-left: 7.95pt; text-align: justify;\">\n Platelets ≥ 100,000 cells/μL (75 x 10 9 L)</li>\n <li style=\"margin-left: 7.95pt; text-align: justify;\">\n  Hemoglobin > 8 g/dL (5.0 mmol/)</li>\n <li style=\"margin-left: 7.95pt; text-align: justify;\">\n Renal – serum creatinine < 3.0 mg/dL (265.2 µmol/L); and</li>\n <li style=\"margin-left: 7.95pt; text-align: justify;\">\n Hepatic: Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN), unless elevated secondary to lymphomatous involvement of liver or biliary system, or due to other HIV medications (e.g., indinavir, tenofovir, or atazanavir). If secondary to lymphomatous involvement, an initial upper limit of total bilirubin 5 mg/dL (85.5 μM/L) should be utilized - for direct bilirubin > 1.2 mg/dL (20.5 μM/L).</li>\n <li style=\"margin-left: 7.95pt; text-align: justify;\">\n AST/ALT < 2.5 institutional ULN (unless elevated secondary to lymphomatous involvement of the liver)</li>\n </ul>\n <p>\n  </p>\n <p style=\"margin-left: 25.95pt;\">\n 10. Participants must have a lumbar puncture with negative cerebral spinal fluid cytology within 6 weeks prior to enrollment. Participants must be without evidence for CNS lymphoma on neurological exam and have no radiographic evidence (if radiographic studies are done) of CNS lymphoma (inclusive of parenchymal, vitreal, or leptomeningeal involvement).</p>\n <p style=\"margin-left: 25.95pt;\">\n 11. Participants must not have had any prior chemotherapy or radiation therapy and no more than 10 days of corticosteroids in the preceding 30 days prior to enrolment.</p>\n <p style=\"margin-left: 25.95pt;\">\n 12. All participants must be prescribed combination antiretroviral therapy with the goal of virological suppression using an acceptable regimen that adheres to national guidelines for treatment of HIV infection. Non-suppressed, treatment experienced patients, defined as patients with a viral load ></p>\n <p style=\"margin-left: 25.95pt;\">\n 400 copies/mL who have been on antiretroviral therapy for more than 4 months can be enrolled if an alternative ART regimen is available that includes at least two ART drugs that, in the opinion of the site investigator, are expected to have activity based on genotypic testing (if available) and treatment history. Patients are not allowed to receive zidovudine (AZT) as part of concurrent chemotherapy and ART regimen, since it is myelosuppressive. Zidovudine may be discontinued and substituted as clinically indicated prior to or at the time of enrollment.</p>\n <p style=\"margin-left: 25.95pt;\">\n 13. Participants of childbearing potential, defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months), must have a pregnancy test within 7 days prior to enrollment and agree to use an effective form of contraception (e.g.,barrier contraception, highly effective hormonal contraception)</p>\n <p style=\"margin-left: 7.95pt;\">\n        14. Participants are allowed to have an active infection(s) for which they are receiving drug treatment provided the clinical status is judged to be stable and   survival is estimated to be at least 6 weeks.</p>\n <p style=\"margin-left: 7.95pt;\">\n        15. Participants must, in the opinion of the investigator, be capable of complying with the protocol.</p>\n <p style=\"margin-left: 7.95pt;\">\n        16. Participants must be able to take oral medications</p>\n <p>\n          17. Participants must have a CD4 count performed within 30 days of enrollment</p>\n</div>\n<p>\n  </p>\n
      • principal_exclusion_criteria<ol>\n <li style=\"margin-left: 21.05pt;\">\n Inability to provide informed consent.</li>\n <li style=\"margin-left: 21.05pt;\">\n A medical or psychiatric illness that precludes ability to give informed consent or is likely to interfere with the ability to comply with the protocol stipulations</li>\n <li style=\"margin-left: 21.05pt;\">\n Participants with circumstances that will not permit completion of the study or required follow-up. For instance, if travel to and from treatment site is an issue</li>\n <li style=\"margin-left: 21.05pt;\">\n Pregnant or breastfeeding</li>\n <li style=\"margin-left: 21.05pt;\">\n nability to swallow oral medications</li>\n</ol>\n
      • primary_end_points<p style=\"margin-left:3.05pt;\">\n To compare the efficacy of standard CHOP and an oral chemotherapy regimen for AR-NHL in Sub-Saharan</p>\n<p>\n Africa with respect to overall survival (OS).</p>\n
      • scope_diagnosis1
      • scope_prophylaxis1
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p style=\"margin-left:5.2pt;\">\n <u>S</u><u>taff</u></p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Naftali Busakhala MBChB, MMed, Principal Investigator</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Evangeline W. Njiru- MBChB, MMed- Investigator</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Paul Wasike, B Pharm, Pharmacist of Record</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Job Kisuya- Site Coordinator</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Grieven Otieno- Data Manager</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Medical Officer-Mildred Hagembe</p>\n<p style=\"margin-left:5.2pt;\">\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Clinical Officer-Enock Sumukwo</p>\n<p style=\"margin-left:5.2pt;\">\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Study Nurse- Peninah Biwott</p>\n<p style=\"margin-left:5.2pt;\">\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Study Nurse- Phyllis Bartilol</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Gilbert Koech, B Pharm- Back-up Pharmacist</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Fred Kiplagat, Dip Pharm- Back-up Pharmaceutical Technologist</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n <u>S</u><u>ite/Emergency Facilities:</u></p>\n<p>\n  </p>\n<p style=\"margin-left:23.2pt;\">\n ·   AMPATH Program– Has 24 care sites and 34 satellite clinics in North Rift and Western</p>\n<p style=\"margin-left:41.2pt;\">\n Kenya</p>\n<p style=\"margin-left:23.2pt;\">\n ·   AMPATH Oncology Clinic-Has 1 care site and 4 satellite clinics in North Rift and</p>\n<p style=\"margin-left:41.2pt;\">\n Western</p>\n<p style=\"margin-left:23.2pt;\">\n ·   AMPATH Reference Laboratory and MTRH histopathology Laboratory</p>\n<p style=\"margin-left:23.2pt;\">\n ·   Moi Teaching and Referral Hospital (MTRH)- Second largest referral Hospital in Kenya.</p>\n
      • other_details_explanation<p style=\"margin-left:5.2pt;\">\n Eldoret, Kenya is one of the Africa AMC sites. When protocols are developed by the AMC, sites express interests considering the patient population and relevance of the study. Our site expressed interest and was chosen as a participating site.</p>\n<p>\n  </p>\n
      • other_details_regulatory_notapproved<p>\n NONE</p>\n
      • other_details_regulatory_approved<p>\n AUTHORITY: MOI UNIVERSITY INSTITUTIONAL RESEARCH AND ETHICS COMMITTEE</p>\n<p>\n DATE OF APPROVAL : 22ND NOVEMBER 2012</p>\n
      • other_details_regulatory_rejected<p>\n NONE</p>\n
      • other_details_regulatory_halted<p>\n NONE</p>\n
      • estimated_duration72 months
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorCurrent Treatment by CHOP
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaMOI UNIVERSITY CLINICAL RESEARCH CENTER
      • single_site_physical_addressAMPATH CENTER, NANDI ROAD
      • single_site_contact_personDR. NAFTALI BUSAKHALA
      • single_site_telephone0722496933
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states4
      • number_of_sites
      • multi_country_listKENYA: MOI UNIVERSITY CLINICAL RESEARCH CENTER\nUGANDA: UGANDA CANCER INSTITUTE\nZIMBABWE: UNIVERSITY OF ZIMBABWE\nSOUTH AFRICA: WITWATERSRAND UNIVERSITY
      • data_monitoring_committeeYes
      • total_enrolment_per_site90
      • total_participants_worldwide360
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameEVANGELINE
      • investigator1_middle_name
      • investigator1_family_nameNJIRU
      • investigator1_qualificationMBCHB, MMED
      • investigator1_professional_address4606
      • investigator1_telephone0722624353
      • investigator1_emailoyungueva@yahoo.com
      • organisations_transferred_No
      • number_participants90
      • notification
      • approval_date22-11-2012
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted27-08-2013
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<p>\n AMC-068 was a randomized phase II comparison of intravenous versus oral chemotherapy for HIV-positive diffuse large B-cell lymphoma. Opening in 2016, AMC-068 planned to enroll 90 patients (45 per arm) in Kenya, Malawi, Uganda, and Zimbabwe over 24 months and follow patients for 24 months to assess overall survival. In 2018, the study closed after screening 42 patients but enrolling only 7. Challenges occurred during protocol development, pre-activation, and post activation. During protocol development (2011-2012), major obstacles were limited baseline data to inform study design; lack of consensus among investigators and approving bodies regarding appropriateness of the oral regimen and need for randomized comparison with cyclophosphamide, doxorubicin, vincristine, and prednisone; and heterogeneity across sites in local standards for diagnosis, staging, and treatment. During pre-activation (2012-2016), challenges included unexpected length and layers of regulatory approval across multiple countries, need to upgrade pathology capacity at sites, need to augment existing chemotherapy infusion capacity at sites, and procurement issues for drugs and supplies. Finally, during post activation (2016-2018), challenges included long delays between symptom onset and screening entry for many patients, leading to compromised performance status and organ function; other patient characteristics that frequently led to exclusion, including high tumor proliferative index or other pathologic features that were disallowed; and costs of routine diagnostic procedures often being borne by patients, which also contributed to pre-enrollment delays.</p>\n<p>\n  </p>\n
      • implication_results<p>\n Lessons from AMC-068 are being applied to the design and conduct of new AMC lymphoma trials in SSA, and the study has contributed to a strong operational foundation that will support innovative clinical trials in the future. </p>\n
      • quantity_importedProcarbazine 50mg - 300, Prednisone 50mg - 1500, Lomustine - 160, Etoposide - 180, Cyclosphamide 60mg - 600, Clyclosphamide 500mg - 180, Doxorubicin 2mg/ml - 204 and Vincristine 1mg/ml - 166
      • quantity_dispensedProcarbazine 50mg - 80, Prednisone 50mg - 60, Lomustine - 28, Etoposide - 60, Cyclosphamide 60mg - 100, Clyclosphamide 500mg - 13, Doxorubicin 2mg/ml - 7 and Vincristine 1mg/ml - 12
      • quantity_destroyedProcarbazine 50mg - 220, Prednisone 50mg - 1440, Lomustine - 132, Etoposide - 120, Cyclosphamide 60mg - 500, Clyclosphamide 500mg - 167, Doxorubicin 2mg/ml - 197 and Vincristine 1mg/ml - 154
      • quantity_exportedNot applicable
      • balance_site0
      • final_date0000-00-00
      • modified2024-06-04 14:25:48
      • created2013-08-22 15:41:41
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id139
        • application_id208
        • given_nameNAFTALI
        • middle_nameWISINDI
        • family_nameBUSAKHALA
        • qualificationMBCHB, MMED
        • professional_address4606
        • telephoneO722496933
        • emailnbusakhala@yahoo.com
        • created2013-08-27 16:32:38
        • modified2013-08-27 18:25:49
    • SiteDetail(array)
      • 0(array)
        • id171
        • application_id208
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2013-08-27 16:32:38
        • modified2013-08-27 18:25:49
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id112
        • application_id208
        • sponsorNational Cancer Institute Office of HIV and AIDS Malignancy (OHAM)
        • sponsor_type(null)
        • contact_person
        • address31 Center Drive, Room 3A33 Bethesda, MD, USA 20852-2440
        • telephone_number301-496-4995
        • fax_number
        • cell_number301-496-4995
        • email_addressNCIOHAMContact@mail.nih.gov
        • created2013-08-27 16:32:38
        • modified2013-08-27 18:25:49
  • 3(array)
    • Application(array)
      • id244
      • user_id107
      • trial_status_id6
      • abstract_of_study<p>\n In East Africa, ocular surface squamous neoplasia (OSSN) is a relatively common aggressive disease affecting younger adults. Treatment usually involves surgical excision, however, recurrent disease is quite common (up to 30-66% by 30 months afterwards) and there have been no randomised controlled trials to investigate how to reduce this. For a long time topical 5-fluorouracil (5FU) has been widely used as adjuvant therapy following surgical excision, with many case reports and series in the literature. However, it has not been formally tested in a randomised controlled trial and so we currently do not know if it is effective in preventing recurrent tumours, particularly in the context where more expensive adjuvants or surgical equipment are not readily available. A Cochrane review shows there have been no randomised controlled trials of the various alternatives in clinical practice to investigate how to reduce recurrence.</p>\n<p>\n We propose to conduct a randomised controlled trial to determine whether OSSN recurrence can be reduced by adjuvant topical 5FU chemotherapy following excision. One month after surgical excision of histopathologically confirmed OSSN when the operation site has healed, participants will be randomised to either 5FU eyedrops, or placebo drops to be taken four times a day for 1 month. Patients will be followed for one year to assess the effect. The primary outcome measure is histopathologically confirmed recurrent OSSN.</p>\n
      • study_title<p style=\"margin-left:21.3pt;\">\n A double-masked randomised placebo-controlled trial of adjuvant topical 5-fluorouracil (5FU) treatment following surgical excision of ocular surface squamous neoplasia.</p>\n<p>\n  </p>\n
      • laymans_summary(null)
      • short_title(null)
      • protocol_noECCT/12/04/01
      • version_no1
      • date_of_protocol05-04-2012
      • study_drug5-fluorouracil
      • disease_conditionOcular surface squamous neoplasia (OSSN)
      • 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_name5-FU
      • product_type_medical_device_name
      • comparator(null)
      • comparator_name(null)
      • comparator_registered(null)
      • comparator_countries(null)
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresssgichuhi@uonbi.ac.ke
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd(null)
      • applicant_prev_data(null)
      • applicant_stability_data(null)
      • applicant_analysis_cert(null)
      • applicant_pictorial_sample(null)
      • applicant_gcp_training(null)
      • applicant_dsmb_charter(null)
      • applicant_detailed_budget(null)
      • applicant_indemnity_pi(null)
      • applicant_practice_license(null)
      • applicant_registration_ctr(null)
      • applicant_pan_african(null)
      • applicant_hard_copies(null)
      • applicant_signed_checklist(null)
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantDr. Stephen Gichuhi
      • declaration_date116-12-2013
      • declaration_principal_investigatorDr. Stephen Gichuhi (national PI)
      • declaration_date216-12-2013
      • placebo_presentYes
      • study_objectives(null)
      • principal_inclusion_criteria<ol style=\"list-style-type:lower-roman;\">\n <li>\n Histologically proven ocular surface squamous neoplasia (OSSN)</li>\n <li>\n Healed excision site.</li>\n <li>\n At least 18 years of age.</li>\n</ol>\n
      • principal_exclusion_criteria<ol style=\"list-style-type:lower-roman;\">\n <li>\n If the tumour is a recurrence from prior excision.</li>\n <li>\n Prior treatment with topical antimetabolite drugs such as 5FU, Mitomycin C (MMC) to the same eye or systemic cytotoxic drugs.  </li>\n <li>\n Patients who may need more radical surgery than a simple excision eg. intraocular extension or features suggestive of metastasis such as fornix or regional lymph node involvement.</li>\n <li>\n Pregnant or breastfeeding mothers.</li>\n</ol>\n
      • primary_end_points<p>\n The primary end-point in this trial will be the development of histopathologically confirmed recurrent OSSN at any point during the first year after the primary surgery. During follow-up, if the outcome assessor notices a possible recurrence, it will be re-excised and sent for histopathology. We will compare the proportion of recurrences at one year in the two intervention arms. Intention-to-treat analysis will be used. The measure of effect will be the odds ratio with 95% confidence intervals. Kaplan-Meier analysis will be used to plot the survival curves for both arms up to the final visit at one year. Participants with “clinical recurrence” (clinician sees recurrence but participant declines re-excision) will be excluded from the primary analysis of the primary end point and go into secondary analysis.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety0
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use1
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Sites involved in the study</p>\n<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:659px;\" width=\"659\">\n <tbody>\n <tr>\n <td style=\"width:206px;\">\n <p>\n Site</p>\n </td>\n <td style=\"width:454px;\">\n <p>\n Staff, qualifications & experience</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:206px;\">\n <p>\n Kenyatta National Hospital</p>\n </td>\n <td style=\"width:454px;\">\n <p>\n Consultant Ophthalmologists</p>\n <p>\n Dr. Stephen Gichuhi, MBChB  MMed MBA MSc (epid) -  15 years</p>\n <p>\n Dr. Rhoda Munene, MBChB  MMed  Oculoplastics Fellowship – 12 years</p>\n <p>\n Dr. Joseph Wachira, MBChB  MMed  Oculoplastics Fellowship – 10 years</p>\n <p>\n  </p>\n <p>\n Research Assistant (data management)</p>\n <p>\n John Maina, Dip IT</p>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:206px;\">\n <p>\n PCEA Kikuyu Eye Unit</p>\n </td>\n <td style=\"width:454px;\">\n <p>\n Consultant Ophthalmologists</p>\n <p>\n Dr. Joy Kabiru, MBChB  MMed  Oculoplastics Fellowship – 12 years</p>\n <p>\n Dr. M’Bongo Zindamoyen, MBChB  MMed – 12 years</p>\n <p>\n  </p>\n <p>\n Ophthalmic Clinical Officer</p>\n <p>\n Mr. Ephantus Macharia, Dip Clin Ophth, HND eye surgery – 10 years</p>\n <p>\n  </p>\n <p>\n *Dr S. Gichuhi oversees work here 2 days a week</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:206px;\">\n <p>\n Sabatia Eye Hospital</p>\n </td>\n <td style=\"width:454px;\">\n <p>\n Consultant Ophthalmologists</p>\n <p>\n Dr. Ernest Olando, MBChB  MMed  Paed Ophth Fellowship – 5 years</p>\n <p>\n  </p>\n <p>\n Ophthalmic Clinical Officer</p>\n <p>\n Mr. Leonard Wanyama, Dip Clin Ophth, HND eye surgery – 17 years</p>\n <p>\n  </p>\n <p>\n Study Nurse</p>\n <p>\n Sr. Mercy, KRCHN – 10 years</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:206px;\">\n <p>\n Kitale District Hospital Eye Unit</p>\n </td>\n <td style=\"width:454px;\">\n <p>\n Consultant Ophthalmologists</p>\n <p>\n Dr. Hilary Rono, MBChB  MMed  MSc (public eye health) – 8 years</p>\n <p>\n  </p>\n <p>\n Ophthalmic Clinical Officer</p>\n <p>\n William, Dip Clin Ophth, HND eye surgery – 7 years</p>\n <p>\n  </p>\n <p>\n Study Nurse</p>\n <p>\n Sr. Grace Wachira, KRN – 8 years</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:206px;\">\n <p>\n Homa Bay District Hospital Eye Unit</p>\n </td>\n <td style=\"width:454px;\">\n <p>\n Consultant Ophthalmologists</p>\n <p>\n Dr. Ochieng, MBChB, MMed – 5 years</p>\n <p>\n  </p>\n <p>\n *SITE NOT ACTIVATED YET</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n<p>\n All the sites have the following facilities</p>\n<ol>\n <li>\n Fully equipped eye clinic – with slit lamps and all accessories needed for a comprehensive eye examination</li>\n <li>\n Fully equipped eye operating theatre – with resuscitation equipment</li>\n <li>\n HIV comprehensive clinic – to provide support for HIV infected participants</li>\n <li>\n Laboratory – conduct HIV and CD4 testing except Sabatia Eye Hospital where we have made arrangements with the nearby Vihiga District hospital.</li>\n</ol>\n<p>\n  </p>\n
      • other_details_explanation<p>\n The host country of the sponsor is the UK. This study is being conducted in Kenya because  ocular surface squamous neoplasia is a rare disease in the temperate climates. We recently published a systematic review in which we found that the peak incidence is at latitude 16⁰ South. The mean age standardised rate (ASR) worldwide is 0.18 and 0.08 cases/year/100 000 among males and females, respectively but the highest incidence is found in Africa (1.38 and 1.18 cases/year/100,000).</p>\n<p>\n Gichuhi S, Sagoo MS, Weiss HA, Burton MJ. Epidemiology of ocular surface squamous neoplasia in Africa. <strong>Trop Med Int Health</strong><strong>. 2013 Dec;18(12):1424-43</strong></p>\n<p>\n  </p>\n
      • other_details_regulatory_notapproved<p>\n Not applicable</p>\n
      • other_details_regulatory_approved<p>\n 1. Kenyatta National Hospital/University of Nairobi Ethics and Research Committee</p>\n<p>\n 2. London School of Hygiene & Tropical Medicine Ethics committee</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n Not applicable</p>\n
      • estimated_duration24 months
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorPlacebo - artificial tear
      • design_controlled_other_medicinalNo
      • design_controlled_placeboYes
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites4 active, 1 not activated (Homa Bay)
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_siteKikuyu max 350\nOthers max 154
      • total_participants_worldwide504
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultNo
      • population_elderlyNo
      • 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_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameStephen
      • investigator1_middle_name
      • investigator1_family_nameGichuhi
      • investigator1_qualificationMBChB, M.Med (Ophth), MBA, MSc (Epidemiology)
      • investigator1_professional_addressUniversity of Nairobi, Dept of Ophthalmology, Kenyatta National Hospital campus
      • investigator1_telephoneOffice 020-2726300 ext. 43776, mobile 0722873059
      • investigator1_emailsgichuhi@uonbi.ac.ke
      • organisations_transferred_No
      • number_participants504
      • notification<p>\n I will send a copy of the receipt I obtained after paying $1000 once I get it from London.</p>\n<p>\n I attach a copy of the approval letter obtained after the initial application</p>\n
      • approval_date15-03-2012
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted17-12-2013
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2014-11-24 04:28:40
      • created2013-12-16 14:14:17
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id175
        • application_id244
        • given_nameStephen
        • middle_name
        • family_nameGichuhi
        • qualificationMBChB, M.Med (Ophth), MBA, MSc (Epidemiology)
        • professional_addressUniversity of Nairobi, Dept of Ophthalmology, Kenyatta National Hospital campus
        • telephoneOffice 020-2726300 ext. 43776, mobile 0722873059
        • emailsgichuhi@uonbi.ac.ke
        • created2013-12-16 17:08:14
        • modified2013-12-17 17:35:19
    • SiteDetail(array)
      • 0(array)
        • id219
        • application_id244
        • county_id47
        • site_nameKenyatta National Hospital
        • physical_addressHospital Road,Upper Hill,Nairobi 00202, Kenya
        • contact_detailsTel 2726300
        • contact_personDr. Stephen Gichuhi, Consultant Ophthalmologist,
        • site_capacity(null)
        • misc(null)
        • created2013-12-16 17:08:14
        • modified2013-12-17 17:35:19
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 1(array)
        • id220
        • application_id244
        • county_id22
        • site_namePCEA Kikuyu Eye Unit
        • physical_addressPCEA Kikuyu Hospital, Kikuyu Road,Kenya
        • contact_detailsP.O Box 1021, Kikuyu, Kenya
        • contact_personDr. Joy Kabiru, Consultant Ophthalmologist
        • site_capacity(null)
        • misc(null)
        • created2013-12-16 18:09:20
        • modified2013-12-17 17:35:19
        • County(array)
          • id22
          • county_nameKiambu
          • created2012-06-15 10:24:37
          • modified2012-06-15 10:24:37
      • 2(array)
        • id221
        • application_id244
        • county_id37
        • site_nameSabatia Eye Hospital
        • physical_addressVihiga District
        • contact_detailsP.O. Box 214-50311 Wodanga
        • contact_personDr. Ernest Ollando, Director & Consultant Ophthalmologist
        • site_capacity(null)
        • misc(null)
        • created2013-12-16 18:09:20
        • modified2013-12-17 17:35:19
        • County(array)
          • id37
          • county_nameKakamega
          • created2012-06-15 10:26:29
          • modified2012-06-15 10:26:29
      • 3(array)
        • id222
        • application_id244
        • county_id26
        • site_nameKitale District Hospital, Eye Unit
        • physical_addressKitale
        • contact_detailsP.O. Box 98 - 30200, Kitale
        • contact_personDr. Hilary Rono, Consultant Ophthalmologist in charge
        • site_capacity(null)
        • misc(null)
        • created2013-12-16 18:09:20
        • modified2013-12-17 17:35:19
        • County(array)
          • id26
          • county_nameTrans Nzoia
          • created2012-06-15 10:25:05
          • modified2012-06-15 10:25:05
      • 4(array)
        • id223
        • application_id244
        • county_id43
        • site_nameHoma Bay District Hospital, Eye Unit
        • physical_addressHoma Bay
        • contact_detailsP.O Box 52 - 40300, Homa Bay
        • contact_personDr. Ochieng, Consultant Ophthalmologist
        • site_capacity(null)
        • misc(null)
        • created2013-12-16 18:09:20
        • modified2013-12-17 17:35:19
        • County(array)
          • id43
          • county_nameHoma Bay
          • created2012-06-15 10:27:10
          • modified2012-06-15 10:27:10
    • Sponsor(array)
      • 0(array)
        • id141
        • application_id244
        • sponsorLondon School of Hygiene & Tropical Medicine
        • sponsor_type(null)
        • contact_personPatricia Henley
        • addressKeppel Street, London, WC1E 7HT
        • telephone_number+44 (0) 20 7927 2626
        • fax_number+44 (0) 20 7580 5636
        • cell_number+44 (0) 20 7927 2626
        • email_addresspatricia.henley@lshtm.ac.uk
        • created2013-12-16 17:08:14
        • modified2013-12-17 17:35:19
  • 4(array)
    • Application(array)
      • id1563
      • user_id127
      • trial_status_id2
      • abstract_of_study<h1>\n Abstract</h1>\n<p>\n <strong>Background:</strong><br />\n HIV-1 infection remains a persistent global epidemic. In 2023, 39.9 million people were living with HIV, with 1.3 million new infections reported globally. Women and girls accounted for 44% of new HIV infections globally, and in sub-Saharan Africa, they represented 62%. Approximately 4000 adolescent girls and young women aged 15–24 became infected every week, with 3100 of these cases in sub-Saharan Africa. HIV requires lifelong treatment and poses multiple health risks, creating a growing healthcare burden. While WHO-recommended daily oral PrEP, including FTC/TDF and FTC/TAF, is effective, its success depends heavily on strict adherence—often a challenge in high-risk populations. Recently approved injectable PrEP like cabotegravir has improved efficacy but faces access and acceptability barriers. Thus, a long-acting oral PrEP alternative like MK-8527 could address these limitations. The trial tests the efficacy of MK-8527 administered once monthly (qm) compared to FTC/TDF administered once daily (qd) for the prevention of HIV-1 infection, as measured by the annual incidence rate of adjudicated HIV-1 infections. Additionally, the study evaluates the safety and tolerability of MK-8527 qm in comparison to FTC/TDF qd.</p>\n<p>\n <strong>Methodology:</strong><br />\n This Phase 3 randomized, double-blind, active-controlled clinical trial compares once-monthly oral MK-8527 to once-daily FTC/TDF for HIV-1 pre-exposure prophylaxis in cisgender women aged 16–30 at risk of HIV infection. Approximately 4580 participants will be enrolled and followed for up to 24 months, with a 28-day follow-up. Participants will be randomized to receive either MK-8527 or FTC/TDF under blinded design. The primary endpoint is the incidence rate of adjudicated HIV-1 infections.</p>\n<p>\n <strong>Outcomes:</strong><br />\n An interim analysis will occur after ≥24 primary endpoint cases are accrued. MK-8527's long intracellular half-life supports a monthly dosing strategy aimed at improving adherence and acceptability among women. This study may lead to a more practical and preferred HIV prevention option for women at high risk, especially in low-resource and high-burden settings.</p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n
      • study_title<p style=\"margin-left:6.2pt;\">\n A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate the Efficacy and Safety of MK-8527 Oral Once-Monthly as HIV-1 Preexposure</p>\n<p style=\"margin-left:6.2pt;\">\n Prophylaxis in Women</p>\n<p style=\"margin-left:6.2pt;\">\n  </p>\n
      • laymans_summary<h1>\n  Lay Summary</h1>\n<p>\n HIV remains a major global health problem.  Around 40 million people are living with the virus, and more than 1.3 million new cases were reported in 2023. Women and girls make up a large number of these cases, especially in sub-Saharan Africa. In this region, young women aged 15 to 24 are hit the hardest, with over 3,000 new infections happening each week.</p>\n<p>\n To help prevent HIV, medications called PrEP (pre-exposure prophylaxis) are used. These are usually taken as daily pills, but taking a pill every day can be difficult  for some people.  Injections are now available as another option, but they aren’t easy for everyone to get and some people might not like them.</p>\n<p>\n This study is testing a new HIV prevention pill called <strong>MK-8527</strong>, which is taken <strong>once a month</strong><strong>.</strong> It may be easier to use and more attractive for women who find it hard to take a pill every day, or don’t like getting injections. The study involves over 4,500 HIV-negative cisgender women (assigned female sex at birth and identify as a woman) aged 16 to 30, who have a higher chance of getting HIV infection.</p>\n<p>\n <strong>Methods:</strong><br />\n Participants in the study will be randomly placed into one of two groups:  one will take the monthly pill (MK-8527)  , and the other will take  the standard daily PrEP pill (FTC/TDF). They will come in once a month for 24 months for HIV tests, health check-ups, and to track how the medicine is working, with a short follow-up after treatment ends.<br />\n If a participant becomes pregnant and decides to keep taking the study medicine, she will have some extra health checks, including blood sample tests.</p>\n<p>\n  <strong>Outcome:</strong><br />\n If successful, MK-8527 could provide an easier and more preferred way for women to prevent HIV—especially in places where HIV is common and taking a pill every day is hard</p>\n
      • short_titleMK-8527 as HIV-1 PrEP in Women
      • protocol_noECCT/25/08/01
      • version_no0.00
      • date_of_protocol28-04-2025
      • study_drugMK-8527
      • disease_conditionHIV-1
      • 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_nameMK8527 (Investigational)
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameFTC/TDF (Emtricitabine/Tenofovir Disoproxil Fumarate)
      • comparator_registeredYES
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressmaricianah@gmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantDr. Maricianah Onono
      • declaration_date112-08-2025
      • declaration_principal_investigatorProf. Elizabeth Bukusi
      • declaration_date212-08-2025
      • placebo_presentYes
      • study_objectives<p>\n <strong>Primary Objectives:</strong></p>\n<p>\n 1. To evaluate the efficacy of MK-8527 qm compared to FTC/TDF qd for the prevention of HIV-1 infection as assessed by the incidence rate per year of adjudicated HIV-1 infections. Hypothesis: MK-8527</p>\n<p>\n  2. To evaluate the safety and tolerability of MK-8527 qm compared to FTC/TDF qd.</p>\n<p>\n  </p>\n<p>\n <strong>Tertiary Objectives:</strong></p>\n<ol>\n <li>\n  To evaluate aspects of treatment with MK-8527 qm and FTC/TDF qd on participant-reported outcomes.</li>\n <li>\n  To evaluate the pharmacokinetics of MK-8527 qm using sparse PK sampling</li>\n <li>\n To assess association between adherence to MK-8527 qm and efficacy in a nested case control study</li>\n <li>\n To evaluate adherence to MK-8527 qm and FTC/TDF qd</li>\n <li>\n To evaluate the impact of MK-8527 qm on renal function compared to FTC/TDF qd as measured by the change from baseline in renal biomarkers at Weeks 24 and 48</li>\n <li>\n To evaluate viral drug resistance in participants who seroconvert to HIV-1</li>\n <li>\n To measure the plasma concentrations of ENG, MPA, and NET among participants who use an ENG-releasing implant or injectable depot MPA or injectable NET EN</li>\n <li>\n To evaluate the PK of MK-8527 in pregnant participants</li>\n <li>\n To evaluate the impact of MK-8527 qm on body weight and body mass index compared to FTC/TDF qd as measured by the change from baseline through Week48</li>\n <li>\n To explore the relationship between genetic variation and response to the treatment(s) administered, and mechanisms of disease. Variation across the human genome may be analyzed for association with clinical data collected in the study.</li>\n</ol>\n
      • principal_inclusion_criteria<h2>\n Inclusion</h2>\n<p>\n The site will consider a participant eligible for inclusion in the study if the individual meets all of the following criteria:</p>\n<p>\n  </p>\n<p>\n <strong>Type of Participant and Disease Characteristics</strong></p>\n<p>\n 1. Is confirmed HIV-uninfected based on negative HIV-1/HIV-2 test results during screening.</p>\n<p>\n <em>Note: Any positive HIV test during the Screening Period will exclude the participant from the study regardless of a negative confirmatory test. Additional testing to confirm suspected HIV infection during screening will be performed in accordance with local guidelines. If HIV infection is confirmed, participants will be referred for appropriate care, as necessary.</em></p>\n<p>\n 2. Has been sexually active (≥2 vaginal intercourse encounters with cisgender male individual(s) within the last 3 months).</p>\n<p>\n <strong>Demographics</strong></p>\n<p>\n 3. Was assigned female sex at birth, and is cisgender.</p>\n<p>\n 4. Aged from 16 years to 30 years of age inclusive, at the time of providing the informed consent or assent, as applicable.</p>\n<p>\n <em>(Note: Enrolment for 16- to 17-year-old participants may begin only after completion and review of the initial safety review results by the eDMC (as indicated in section 9 of the protocol on statistical considerations).</em></p>\n<p>\n 5. Weighs ≥35 kg at enrolment.</p>\n<p>\n  </p>\n<p>\n <strong>Assigned Female Sex at Birth</strong></p>\n<p>\n 6. A participant assigned female sex at birth is eligible to participate if not breast/chestfeeding.</p>\n<p>\n 7. A POCBP is eligible to participate if not pregnant and if a negative highly sensitive pregnancy test (urine or serum), as required by local regulations, has been obtained within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. </p>\n
      • principal_exclusion_criteria<h3>\n Exclusion Criteria</h3>\n<p>\n The site will exclude and individual from the study if they meet any of the following criteria:</p>\n<p>\n  </p>\n<p>\n <strong>Medical Conditions</strong>:</p>\n<p>\n 1. Has hypersensitivity or other contraindication to any component of the study interventions as determined by the investigator.</p>\n<p>\n  2. Has evidence of acute or chronic hepatitis B infection (HBsAg positive<em>). </em></p>\n<p>\n <em>  Note: Participants with isolated HBcAb positivity (HBsAg and HBsAb negative) will be excluded if HBV DNA is positive.</em></p>\n<p>\n <em>Note: Participants who do not demonstrate immunity to HBV will be offered HBV vaccination.</em></p>\n<p>\n 3. Has a history of malignancy within 5 years of screening except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.</p>\n<p>\n 4. Has a history or current evidence of any condition (eg, active tuberculosis infection or hepatic cirrhosis), therapy, laboratory abnormality or other circumstance (including substance or alcohol use disorder) that might, in the opinion of the investigator, confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to enroll.</p>\n<p>\n  </p>\n<p>\n <strong>Prior/Concomitant Therapy</strong></p>\n<p>\n 5. Has taken cabotegravir, lenacapavir, or any other long-acting HIV prevention product at any time (past or current use). Note: Prior use of ISL (MK-8591) is permitted.</p>\n<p>\n 6. Is currently receiving or is anticipated to require any prohibited therapies as outlined in Section 6.5 of the global protocol (from 30 days prior to Day 1 through the study duration (ie, up to 56 ±5 days following the last dose of blinded monthly study intervention).</p>\n<p>\n <em>Note: Participants taking or starting tenofovir-based PrEP at screening may continue their regimen until 24 hours before the blinded monthly dose on Day 1. Dapivirine ring can be removed on Day 1 prior to administration of study intervention.</em></p>\n<p>\n 7. Has received an HIV vaccine at any time (ie, through past participation in an investigational clinical study) or monoclonal antibodies to HIV within 12 months before Day 1.</p>\n<p>\n  </p>\n<p>\n <strong>Prior/Concurrent Clinical Study Experience</strong></p>\n<p>\n 8. Is currently participating in or has participated in an interventional or prevention clinical study with an investigational compound or device within 30 days prior to Day 1 through the duration of the study.</p>\n<p>\n <em>Note: Concurrent participation in observational or noninterventional studies or longitudinal follow-up from interventional studies may be permitted and should be discussed with the Sponsor before enrollment and through study duration</em>.</p>\n<p>\n  </p>\n<p>\n <strong>Diagnostic Assessments</strong></p>\n<p>\n 9. Has exclusionary laboratory values within 45 days prior to Day 1 as listed in the laboratory exclusion criteria on below.<img alt=\"\" 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\" /></p>\n<p>\n <em>Note: A single repeat of a laboratory screening test will be allowed for test results that are unexpected, but the repeat test results must be available within the 45-day screening window.</em></p>\n<p>\n            </p>\n
      • primary_end_points<p>\n  1. Adjudicated HIV-1 infection</p>\n<p>\n  2. Adverse Events</p>\n<p>\n 3. Adverse events-Adverse events leading to discontinuation of study intervention</p>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">The sites have infrastructure that includes adequate study space, laboratory equipment, experienced staff who have been involved in a number of phase 2 and 3 trials. The staff also have experience in contraceptive counselling, clinical assessment, HIV care and counselling and thus the study takes advantage of this existing infrastructure.</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">The study will be coordinated by:</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">1. Prof. Elizabeth Bukusi MBChB, MMed, MPH, PhD</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">2. Dr. Maricianah Onono MBChB, Msc, PhD, MMed</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">3. Prof. Nelly Mugo MBChB, MMed, MPH, PhD</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">4. Dr. Irene Inwani MBChB, MMed, MPH</span></p>\n
      • other_details_explanation<p>\n <span style=\"font-size:12px;\">Kenya continues to face a significant HIV burden, particularly among women of reproductive age, who account for a large proportion of new infections. Conducting this trial in Kenya allows for the <span style=\"color: rgb(0, 0, 0); font-family: arial, sans-serif; font-variant-ligatures: no-contextual;\">addressing of a critical public health priority through an innovative intervention that aligns with national HIV prevention strategies and </span>for the evaluation of MK-8527, a once-monthly oral PrEP candidate, in a high-risk population where its impact could be most meaningful. The study will generate locally relevant data, support public health efforts, and leverage Kenya’s strong research infrastructure to address a critical unmet need in HIV prevention.</span></p>\n
      • other_details_regulatory_notapproved<p>\n Kenya Medical Research Institute- Scientific Ethics Research Unit (SERU) </p>\n<p>\n Date of application: 26th June 2025</p>\n
      • other_details_regulatory_approved<p>\n None</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n Not Applicable</p>\n
      • estimated_duration24 months
      • 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_comparatorFTC/TDF
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states3
      • number_of_sites4
      • multi_country_listKenya, South Africa and Uganda
      • data_monitoring_committeeYes
      • total_enrolment_per_site150 - 600\n
      • total_participants_worldwide4580
      • 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_elderlyNo
      • gender_female1
      • gender_male0
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenYes
      • subjects_nursing_womenYes
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyAdolescents 16 and 17 years old
      • subjects_othersYes
      • subjects_others_specifyInfants born of consenting pregnant and breast feeding participants who consent to the sub studies
      • investigator1_given_nameElizabeth
      • investigator1_middle_nameAnne
      • investigator1_family_nameBukusi
      • investigator1_qualificationMBChB, M.Med (ObGyn), MPH, PhD , PGD(Research Ethics). MBE (Research Ethics)
      • investigator1_professional_addressCenter for Microbiology Research, KEMRI, Box 19464, post code 00202, Nairobi
      • investigator1_telephoneTel mobile 254 733617503/ 720617503 Fax 254 20 2737658 (Nairobi) 254 57 2021945 (Kisumu) Land line 254 20 6751748(Nairobi) 254 57 2021036 (Kisumu)
      • investigator1_emailebukusi@rctp.or.ke
      • organisations_transferred_Yes
      • number_participants1000
      • notification
      • approval_date21-11-2025
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted11-09-2025
      • is_child0
      • unsubmitted1
      • initial_date_submitted12-08-2025
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments have been addressed.
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-11-21 05:43:56
      • created2025-06-25 20:14:16
      • total_sites1
      • ecitizen_invoice382691
    • InvestigatorContact(array)
      • 0(array)
        • id1311
        • application_id1563
        • given_nameMaricianah
        • middle_name
        • family_nameOnono
        • qualificationMBChB, MSc, PhD, MMed
        • professional_addressBox 19669-40123
        • telephone0732390992
        • emailmaricianah@gmail.com
        • created2025-06-25 20:33:51
        • modified2025-09-11 17:56:24
    • SiteDetail(array)
      • 0(array)
        • id1947
        • application_id1563
        • county_id42
        • site_nameKEMRI-RCTP KISUMU
        • physical_addressCIS Building, Lumumba Subcounty Hospital
        • contact_detailsTel mobile 254 733617503/ 720617503 Fax 254 20 2737658 (Nairobi) 254 57 2021945 (Kisumu) Land line 254 20 6751748(Nairobi) 254 57 2021036 (Kisumu)
        • contact_personProf Elizabeth Anne Bukusi
        • site_capacity(null)
        • misc(null)
        • created2025-06-25 20:33:51
        • modified2025-09-11 17:56:24
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 1(array)
        • id1949
        • application_id1563
        • county_id42
        • site_nameKargeno Research and Policy Hub KEMRI-CMR KISUMU
        • physical_addressStreet Address: Karume Road / Jairo Street Junction, Opposite Administration Police (AP) line Dispensary, Kisumu
        • contact_detailsBox 19669-40123; Tel 0732390992
        • contact_personDr Maricianah Onono
        • site_capacity(null)
        • misc(null)
        • created2025-06-30 12:47:49
        • modified2025-09-11 17:56:24
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 2(array)
        • id1950
        • application_id1563
        • county_id22
        • site_nameKEMRI-PHRD, Thika
        • physical_addressSection 9 OAU, Near Thika Nursing Home, Thika
        • contact_detailsP.O.BOX 54840-00200, Nairobi, Kenya Tel:0723914057
        • contact_personProf. Nelly Rwamba Mugo
        • site_capacity(null)
        • misc(null)
        • created2025-06-30 12:47:49
        • modified2025-09-11 17:56:24
        • County(array)
          • id22
          • county_nameKiambu
          • created2012-06-15 10:24:37
          • modified2012-06-15 10:24:37
      • 3(array)
        • id1951
        • application_id1563
        • county_id43
        • site_nameUW KNH - Rachuonyo County Hospital
        • physical_addressRachuonyo County Referral Hospital
        • contact_detailsP.O.BOX 42-40222, Oyugis,Kenya, Tel: +254722608483
        • contact_personDr. Irene Inwani
        • site_capacity(null)
        • misc(null)
        • created2025-06-30 12:47:49
        • modified2025-09-11 17:56:24
        • County(array)
          • id43
          • county_nameHoma Bay
          • created2012-06-15 10:27:10
          • modified2012-06-15 10:27:10
    • Sponsor(array)
      • 0(array)
        • id849
        • application_id1563
        • sponsorMerck Sharp & Dohme LLC
        • sponsor_typeIndustry
        • contact_personSue Bailey
        • addressMSD (Pty) Ltd, South Africa 117 16th Road, Midrand, 1685, Gauteng, South Africa
        • telephone_number+27116553307
        • fax_number
        • cell_number+27116553307
        • email_addresssue.bailey@msd.com
        • created2025-06-25 20:33:51
        • modified2025-09-11 17:56:24
• page_options(array)
  • 55
  • 1010
• redir
• $request->data(array)
  • Application(empty)
• $this->validationErrors(array)
  • Permission(empty)
  • Aro(empty)
  • Aco(empty)
  • Application(empty)
  • User(empty)
  • TrialStatus(empty)
  • InvestigatorContact(empty)
  • Sponsor(empty)
  • SiteDetail(empty)
  • County(empty)
• Loaded Helpers(array)
  • 0Html
  • 1Form
  • 2Session
  • 3Text
  • 4Number
  • 5SimpleGraph
  • 6Paginator
  • 7DebugTimer
  • 8Toolbar
  • 9HtmlToolbar

App Constants

CakePHP Constants

PHP Environment

Included Files

Include Paths

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

Included Files

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