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    • Application(array)
      • id319
      • user_id73
      • trial_status_id7
      • abstract_of_study<p>\n Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) alone or in combination with emtricitabine (FTC/TDF) reduces the risk of HIV-1 acquisition in high-risk HIV-1-uninfected adults.<a href=\"#_ENREF_1\" title=\"Baeten, 2012 #33\">^1-4</a>  Clinical trials have demonstrated protection efficacies of 44-75% in randomized comparisons to placebo and ~90% in case-control analyses of participants with high PrEP adherence. On the basis of these data, the US Food and Drug Administration (FDA) approved the use of FTC/TDF for PrEP in July 2012<a href=\"#_ENREF_5\" title=\", 2012 #158\">⁵</a>. The World Health Organization also issued guidance on oral PrEP, specifically for heterosexual HIV-1 serodiscordant couples and men and transgender women who have sex with men, regarding use in the context of demonstration projects to garner additional information to facilitate policies about PrEP implementation<a href=\"#_ENREF_6\" title=\"WHO, 2012 #157\">⁶</a>. In addition, the US Centers for Disease Control and Prevention (CDC) issued interim guidance for clinicians considering using PrEP for prevention of HIV-1 infection in high-risk heterosexually active adults<a href=\"#_ENREF_7\" title=\"CDC, #361\">⁷</a>, and identified the need for data on infant safety during pregnancy and postpartum breastfeeding for heterosexual women using FTC/TDF to prevent acquisition of HIV-1. The risk of HIV-1 acquisition is increased two-fold in women during pregnancy and the early post-partum period<a href=\"#_ENREF_8\" title=\"Mugo, 2011 #291\">⁸</a>, and thus PrEP could be an important strategy to reduce risk of HIV-1, if demonstrated to be safe.  Accordingly, it is important to assess whether FTC/TDF when used as PrEP by lactating mothers is excreted into breast milk and absorbed by the nursing infant in biologically significant concentrations. Determining the concentration of FTC/TDF infants are exposed to and subsequently absorbed via breast milk when taken daily as PrEP by lactating women is needed to evaluate the benefits and risks of maternal FTC/TDF PrEP use during lactation. Specially, the concentration of FTC and TDF excreted into and absorbed by nursing infants via breast milk of lactating women using FTC/TDF PrEP for HIV-1 prevention has not been studied. This protocol describes an  interventional, open-label, single-arm, repeat-dose study among heterosexual HIV-1 uninfected lactating women to determine the magnitude and extent of infant exposure to daily FTC/TDF via maternal breast milk when taken over one week as PrEP by lactating women. </p>\n<p>\n <strong>Design:   </strong>Interventional, open-label, single-arm, repeat-dose, pharmacokinetic study Up to 10 days of follow-up per mother-infant pairs</p>\n<p>\n <strong>Population:  </strong>HIV-1 uninfected lactating mother-infant pairs</p>\n<p>\n <strong>Study Site:  </strong>Thika, Kenya and Kampala, Uganda Partners PrEP Study sites</p>\n<p>\n <strong>Approach:  </strong>We will enroll up to 50 mother-infant pairs to characterize infant drug absorption for infant ages 0-24 weeks postpartum. We will conduct quantitative analyses to describe the magnitude and extent of infant exposure to FTC/TDF PrEP through breast milk when used by lactating women.</p>\n<p style=\"margin-left:63.0pt;\">\n <strong>Specific Aim:</strong></p>\n<p>\n To quantify the steady state concentrations of tenofovir (TFV) and emtricitabine (FTC) in infant plasma after FTC/TDF PrEP exposure through maternal breast milk.</p>\n<p>\n Decisions about the safety of breast feeding during maternal ingestion of drugs require knowledge of the amount of drug which might be present in breast milk. Understanding the concentration of FTC/TDF infants are exposed to and subsequently absorbed via breast milk when taken as PrEP by lactating women is needed to permit a thorough evaluation of the benefits and risks of maternal FTC/TDF PrEP use during lactation. We will measure infant plasma, maternal plasma, and breast milk FTC and TFV concentrations in an open-label, repeat dose study of daily FTC/TDF PrEP among HIV-1-uninfected lactating mother-infant pairs.</p>\n<p>\n <em>The primary outcomes of this study will be the steady state infant plasma FTC and TFV levels, infant plasma to maternal breast milk FTC and TFV concentration ratios, and maternal breast-milk to plasma FTC and TFV concentration ratio. A single infant plasma sample will be collected after the maternal 7^th PrEP dose. M</em><em>aternal plasma and breast-milk samples each will be collected for trough and peak levels immediately before administration of the 7^th and 10^th doses and 1-2 hours after the 7^th and 10^th doses, respectively.</em></p>\n
      • study_title<p>\n <strong>An open-label, short-duration, repeat-dose study of breast milk excretion and infant absorption of daily oral Tenofovir Disoproxil Fumarate/Emtricitabine when used by HIV-1 uninfected lactating women </strong></p>\n
      • laymans_summary<p>\n Other research studies have found that pregnant women who take the Truvada® medication do not have increased risks of serious problems with their pregnancy and their babies do not have serious birth defects. More research studies in HIV-uninfected women who are taking Truvada® medication during pregnancy and breast feeding are needed. The purpose of this study is to find out more about using Truvada® during breast feeding. Specifically, this research will study the amount of Truvada® drugs that are transferred into breast milk and then absorbed by the nursing baby when Truvada® is used by breast feeding women as PrEP.</p>\n
      • short_titleBreast Feeding Study
      • protocol_noECCT/14/09/03
      • version_no1.0
      • date_of_protocol08-08-2014
      • study_drugTenofovir Disoproxil Fumarate/Emtricitabine (Truvada)-Breast Feeding Study
      • disease_conditionNone
      • 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_nameTenofovir Disoproxil Fumarate/Emtricitabine (Truvada)
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressRwamba@csrtkenya.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
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      • applicant_complete_form(null)
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      • 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_plan1
      • applicant_contractual_agreement1
      • declaration_applicantDr. Kenneth Ngure
      • declaration_date115-09-2014
      • declaration_principal_investigatorDr. Nelly Rwamba Mugo
      • declaration_date215-09-2014
      • placebo_presentNo
      • study_objectives<p style=\"margin-left:63.0pt;\">\n  </p>\n<p>\n <span style=\"font-size:12px;\">To quantify the steady state concentrations of tenofovir (TFV) and emtricitabine (FTC) in infant plasma after FTC/TDF PrEP exposure through maternal breast milk.</span></p>\n
      • principal_inclusion_criteria<p style=\"margin-left: 0.5in;\">\n For infant’s mother and father          </p>\n<p style=\"margin-left:.5in;\">\n -  Able and willing to provide informed consent for the infant to participate in the study</p>\n<ul>\n <li>\n Of legal age ≥18 years to consent</li>\n</ul>\n<p>\n For HIV-1 uninfected mother, in addition to the criteria noted immediately above:</p>\n<ul>\n <li>\n Willing to provide breast milk samples and breastfeed during the duration of the study 0-24 weeks postpartum</li>\n <li>\n Breastfeeding an infant</li>\n <li>\n HIV-1 uninfected based on negative HIV-1 rapid tests, both at study screening and at the enrollment visit </li>\n <li>\n Adequate renal function, defined by normal creatinine levels and estimated creatinine clearance ≥60 mL/min</li>\n <li>\n Not infected with hepatitis B virus, as determined by a negative hepatitis B surface antigen test</li>\n <li>\n Not currently using PrEP</li>\n <li>\n Enrollment of individuals with active and serious infections or active clinically significant medical problems will be at the discretion of the site investigator</li>\n <li>\n <em>Note: single mothers are eligible to participate in this study. Where possible the father’s permission will be obtained. When the father is unknown, incompetent, deceased, or not reasonably available, or when only the mother has the legal responsibility for the care and custody of the child, the infant participant will be based on the mother’s consent and documentation will be added to file.</em></li>\n</ul>\n<p>\n For infant</p>\n<ul>\n <li>\n Infant born to eligible women</li>\n <li>\n Age 0-24 weeks</li>\n <li>\n Otherwise infant has no serious infections or active clinically significant medical problems</li>\n</ul>\n
      • principal_exclusion_criteria<ul>\n <li>\n Women breastfeeding more than one child</li>\n <li>\n  Preterm babies or infants with low birth weight (i.e. ≤2000mg)</li>\n</ul>\n
      • primary_end_points<p>\n The primary outcomes of this study will be the steady state infant plasma FTC and TFV levels, infant plasma to maternal breast milk FTC and TFV concentration ratios, and maternal breast-milk to plasma FTC and TFV concentration ratio. A single infant plasma sample will be collected after the maternal 7^th PrEP dose. Maternal plasma and breast-milk samples each will be collected for trough and peak levels immediately before administration of the 7^th and 10^th doses and 1-2 hours after the 7^th and 10^th doses, respectively.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety0
      • 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_other1
      • trial_other_specifyDetermining the steady state infant plasma FTC and TFV levels, infant plasma to maternal breast milk FTC and TFV concentration ratios, and maternal breast-milk to plasma FTC and TFV concentration ratio.
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; font-size: 13px; line-height: 20px;\">\n Thika partners in Prevention, Site has 32 full time clinical trial staff (including physicians, nurses, counsellors, pharmacists).</p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; font-size: 13px; line-height: 20px;\">\n Principal Investigator: Dr. Nelly R. Mugo  MBChB,MMED,MPH</p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; font-size: 13px; line-height: 20px;\">\n Study coordinator: Dr. Kenneth Ngure  BSc,MPH,MSc,PhD</p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; font-size: 13px; line-height: 20px;\">\n Lead Physician for the study: Dr. Gabriel Muthuri  MBChB</p>\n
      • other_details_explanation<p>\n More than 2.5 million persons are infected with HIV-1 annually, the majority in sub-Saharan Africa, the region with the highest prevalence. In sub-Saharan Africa, the majority of new HIV-1 infections occur in women of childbearing age.Pregnancy and postpartum breastfeeding represent periods of heightened HIV-1 risk for women and for their infant if acute HIV-1 infection occurs. HIV-1 uninfected women who desire pregnancy with a partner who is HIV-1 infected or at high risk of being infected require protective strategies for themselves and their future children. Novel, effective HIV-1 prevention strategies remain urgently needed, particularly those that are deliverable to and useable by high-risk populations. Daily oral pre-exposure prophylaxis (PrEP) for uninfected persons to prevent HIV-1 acquisition^,peri-coitally dosed tenofovir gel, and antiretroviral treatment (ART) to reduce the infectiousness of HIV-1 infected persons are the most promising new approaches for decreasing HIV-1 spread.  These antiretroviral-based strategies provide an HIV-1 prevention option for women who desire conception or pregnancy and that is under their control; other available HIV-1 prevention strategies of condoms and abstinence, do not allow for conception.</p>\n
      • other_details_regulatory_notapproved<p>\n University of Washington, IRB</p>\n<p>\n    Applications made on 01 September 2014</p>\n
      • other_details_regulatory_approved<p>\n Kenya Medical Research Institute, Ethical Review Committee.</p>\n<p>\n Approved Study on 25 August 2014</p>\n<p>\n Single site each  in both  Kenya and Uganda</p>\n
      • other_details_regulatory_rejected<p>\n None.</p>\n
      • other_details_regulatory_halted<p>\n None.</p>\n
      • estimated_duration1 year
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaPartners in Prevention, Thika Site
      • single_site_physical_addressOAU Road, Near Thika Nursing Home
      • single_site_contact_personDr. Kenneth Ngure
      • single_site_telephone067-22561
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states2
      • number_of_sites
      • multi_country_listKenya\nUganda
      • data_monitoring_committeeNo
      • total_enrolment_per_site25-30 Mother Infant pairs
      • total_participants_worldwide50 Mother Infants pairs
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornYes
      • population_infant_and_toddlerYes
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenYes
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameKenneth
      • investigator1_middle_nameKiggundu
      • investigator1_family_nameMugwanya
      • investigator1_qualificationMBChB, MPH
      • investigator1_professional_address325 Ninth Avenue, UW Box 359927 Seattle, WA 98104
      • investigator1_telephone+1 206 859 3578
      • investigator1_emailmugwanya@uw.edu
      • organisations_transferred_Yes
      • number_participants25-30 Mother Infant pairs
      • notification
      • approval_date19-08-2015
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted17-12-2020
      • is_child0
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      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
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      • balance_site(null)
      • final_date(null)
      • modified2020-12-17 14:59:38
      • created2014-08-25 16:04:55
      • total_sites(null)
      • ecitizen_invoice(null)
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        • id228
        • application_id319
        • given_nameJared
        • middle_nameMurray
        • family_nameBaeten
        • qualificationMD, PhD
        • professional_address325 Ninth Avenue, Seattle, WA 98104
        • telephone+1 206 520 3808
        • emailjbaeten@u.washington.edu
        • created2014-08-25 16:14:12
        • modified2020-12-17 14:59:38
      • 1(array)
        • id229
        • application_id319
        • given_nameNelly
        • middle_nameRwamba
        • family_nameMugo
        • qualificationMBChB, MPH
        • professional_addressUNITID Building, Box 19865-00202, KNH, Nairobi
        • telephone0723 914057
        • emailrwamba@csrtkenya.org
        • created2014-09-03 15:16:38
        • modified2020-12-17 14:59:38
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        • application_id319
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        • created2014-08-25 16:14:12
        • modified2020-12-17 14:59:38
        • County(empty)
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        • id177
        • application_id319
        • sponsorUniversity of Washington
        • sponsor_typeResearch Institution
        • contact_personDr. Nelly R. Mugo
        • addressUNITID Building, Box 19865-00202, KNH, Nairobi
        • telephone_number067-22561
        • fax_numberN/A
        • cell_number0723 914057
        • email_addressrwamba@csrtkenya.org
        • created2014-08-25 16:14:12
        • modified2020-12-17 14:59:38
  • 1(array)
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      • id322
      • user_id94
      • trial_status_id5
      • abstract_of_study<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.78%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:77.06%;\">\n <p>\n Visceral leishmaniasis (VL), the most serious of the various clinical presentations of <em>Leishmania</em> infection, is fatal if not treated. In East Africa, VL is caused by <em>Leishmania donovani</em>.  The disease is characterized by fever, weight loss, hepatosplenomegaly, lymphadenopathy, anaemia, leucopenia and thrombocytopenia. There are 200-400,000 estimated new cases of VL occurring annually and ninety percent of cases occur in six countries: Bangladesh, Brazil, Ethiopia, India, Sudan and South Sudan. Recent epidemics claimed thousands of lives in South Sudan. </p>\n <p>\n The WHO recommended treatment for VL in the Eastern Africa region was revised in 2010 from sodium stibogluconate (SSG) monotherapy for 30 days to a combination of SSG and paromomycin (PM) administered for 17 days, following a phase III trial conducted in the region. The efficacy in the intention to treat population using a complete case analysis was 91% for SSG & PM combination in this trial. The new treatment is an improvement to the SSG monotherapy, but a few limitations still preclude its general use. Although the treatment regimen is shorter, it still requires 17 days of painful injections, necessitating patients being hospitalised during the whole treatment period.  In addition, there are life-threatening toxicities associated with the use of antimony-based treatments such as SSG. These include cardiotoxicity and pancreatitis. Therefore there is a need to explore alternatives that are efficacious, safe, short duration, affordable and suitable to be used in remote areas.</p>\n <p>\n  </p>\n <p>\n To evaluate alternative regimens of VL treatment in Eastern Africa, a phase II clinical trial (LEAP0208) has been conducted in Kenya and Sudan with currently available drugs.  This study assessed the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of the combinations Ambisome+SSG, Ambisome+miltefosine and miltefosine monotherapy. Results of trials showed that none of the treatment regimens used reached the satisfactory efficacy level of <u>></u> 90% to be taken forward in a Phase III trial to compare with the current WHO recommended treatment regimen of SSG+PM.  Ambisome+SSG showed a cure rate of 87% at 6 months follow-up, Ambisome+miltefosine 82%, and miltefosine as monotherapy had 72% efficacy.</p>\n <p>\n Results from the PK and PD studies from LEAP0208 and AMBI0106 indicated that the combination Ambisome+miltefosine regimen could potentially be optimized to reach higher efficacy. However, it would require increased daily dosing as well as longer treatment duration and result in a high cost therapy, which together with other safety and stability limitations would not meet the DND<em>i</em> VL target product profile (TPP).</p>\n <p>\n One of the key characteristics of the VL TPP is to develop new treatments that can be used in remote areas where VL occurs. In this context, an oral efficacious and safe drug would be more adapted to field conditions, to allow short hospitalization (if needed part of the treatment can be done at home) and not requiring safety monitoring such as laboratory evaluations.</p>\n <p>\n In order to respond to this need, upstream research at DNDi has been focused on identification of new chemical entities (NCEs) that meet these requirements. Currently, a phase II PoC study is under development to assess efficacy and safety of fexinidazole, an oral treatment that is under development for human African trypanosomiasis. Other promising NCEs are expected to transition from pre-clinical to clinical research in the coming years, bringing new opportunities for innovation in VL therapy.  </p>\n <p>\n Therefore, it was decided to focus the development on optimizing the use of miltefosine for potential combinations with another oral drug offering a new treatment option with good efficacy and safety profile, which would reduce hospitalization and be suitable for use in remote areas.</p>\n <p>\n Miltefosine, a phosphorylcholine ester of hexadecanol, is a membrane-active alkylphospholipid, it is the first effective oral agent for VL. Miltefosine interferes with the membrane lipid metabolism (<em>e.g</em>. de novo synthesis of phosphatidylcholine) and acts through numerous interactions with cell membrane components and cell signalling pathways. It also induces apoptosis through the PI3K-Akt pathway and possibly through mitochondrial dysfunction. Numerous immune-modulatory actions of miltefosine have been described, potentially contributing indirectly to its mechanism of action <em>in vivo</em>.</p>\n <p>\n Miltefosine is indeed the only oral drug currently available for VL treatment. Although miltefosine is potentially teratogenic, requiring contraceptive coverage in women of child-bearing potential, an oral combination containing miltefosine could particularly benefit children, the main group at risk of VL in Eastern Africa.</p>\n <p>\n  </p>\n <p>\n The miltefosine PK data extracted from LEAP0208 indicated that the dose linearly based on weight (mg/kg), calculated as 2.5 mg/kg/day, does not provide similar drug exposure in children as compared to adults. This is in line with previous published miltefosine PK data from India and Nepal (Dorlo JID 2013 and Dorlo AAC 2012). Children are under-dosed with miltefosine, and therefore significantly under-exposed to the drug, compared to adult drug exposure. Miltefosine keeps accumulating over the treatment duration; therefore the end-of-treatment concentration can be compared (maximal accumulation). In the LEAP0208 study, for the 10 day regimen, the mean end-of-treatment concentration was 14.9 μg/mL (IQR 10.4-18.8 μg/mL)  vs 17.6 μg/mL (IQR 15.9-20.9 μg/mL) (difference 18%, <em>p</em>=0.171, ns), respectively for paediatric (7-12y) vs adult (>12y) patients. For 28 days of treatment, this was 22.1 μg/mL (IQR 16.8-29.1 μg/mL) vs 30.2 μg/mL (IQR 24.7-36.3 μg/mL) (difference 37%, <em>p<</em>0.001), respectively for paediatric vs adult patients.</p>\n <p>\n  </p>\n <p>\n Miltefosine concentration accumulating over time (until end of treatment):</p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n Miltefosine concentration at the end of treatment:</p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n When assessing clinical outcome at D210 (6 months post treatment) by age group, in the Ambisome+miltefosine arm the final cure rate was 74% in patients aged 7-12y vs 90% in patients > 12y (<em>p=</em> 0.25). In the miltefosine monotherapy arm cure was achieved in 59% of patients aged 7-12y vs 86% in patients > 12y (<em>p=</em> 0.061). Although the study was not powered for this sub-group analysis, and the difference is not statistically significant, there is a clear trend of poorer outcome in children as compared to adults. This difference can be at least partially explained by the lower drug exposure in children. This is in line with data from Nepal and India, where the only risk factor found for miltefosine treatment failure was to have an age <12 yrs (Rijal CID 2013, Ostyn PLOS One 2014).</p>\n <p>\n  </p>\n <p>\n In previous studies in India, similar PK results had been observed, and it has been proposed that a linear miltefosine dose based on body weight (mg/kg/day) does not provide appropriate exposure for children and low weight adults, and a revised allometric dosing should be used, accounting for the observed differences in drug clearance over the whole range of body sizes of patients, to allow similar drug exposure between children and adults. In simplified practical terms this allometric dosing entails administering a relatively higher mg/kg/day dose in patients with lower body weight compared to patients with a higher body weight (Dorlo et al AAC 2012).</p>\n <p>\n  </p>\n <p>\n Anthropometric data from 973 VL patients previously enrolled in clinical trials in Eastern Africa was used to compare conventional vs allometric miltefosine dosing. There was no significant difference for patients weighting <u>></u> 30kg, whereas the allometric dose corresponds to an increase in the conventional dose by 20% up to 75% in children with body weights <30kg: lower body weights correspond to a more pronounced difference in terms of mg/kg between conventional and allometric dosing.</p>\n <p>\n  </p>\n <p>\n Conventional vs allometric miltefosine dose in VL patients in Eastern Africa, with the calculated and rounded mg/kg dose on the y-axis and body weight on the x-axis:</p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <br clear=\"ALL\" />\n <p>\n Due to limitations of capsule strength (10mg and 50mg) and limited availability of the 10mg strength, higher doses than the prescribed 2.5mg/kg/day are currently used in routine clinical practice due to practical constraints (<em>e.g.</em>  the Indian national guideline for VL treatment indicates 1 capsule of 50mg for all children 2-11yrs). Therefore safety of allometric dose (especially gastrointestinal AEs) should be closely monitored, but no major safety issues are expected.</p>\n <p>\n The proposed study aims to assess whether drug exposure in children can be increased to equivalent adult drug exposure by using the miltefosine allometric dose given BID for 28 days in paediatric VL patients aged 4-12y and whether this dose is tolerable. The present study is also expected to provide the basis for minimum time to reach sufficient drug exposure for miltefosine activity to guide optimal treatment duration to be used in combination therapy for visceral leishmaniasis. The PK data will be assessed in this trial using a compartmental population PK approach, which means that we can make use of a limited sampling design, significantly reducing the burden of sampling in the pediatric population. Efficacy assessment at end of treatment and 6 months follow-up will be a secondary endpoint for this study.</p>\n <p>\n Since most patients in Eastern Africa are pediatric and the current miltefosine treatment is not optimal in terms of drug exposure in children, this proposed study is pivotal to further optimize miltefosine treatment in children with VL. Results from this are expected to guide how to best adjust miltefosine dose in VL patients (especially children), as well as duration of treatment when used in future combination of oral drugs.</p>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.06%;\">\n <p style=\"margin-left:6.1pt;\">\n <u>Primary Objectives</u>:</p>\n <p style=\"margin-left:42.1pt;\">\n ·       To characterize the drug exposure and PK properties of miltefosine using allometric dosing in children with primary VL in Eastern Africa, and assess whether it is equivalent to adult drug exposure</p>\n <p style=\"margin-left:42.1pt;\">\n ·       To identify PK parameters that are associated with parasite clearance to derive the basis for a definition of what would be sufficient drug exposure for miltefosine activity</p>\n <p style=\"margin-left:42.1pt;\">\n ·       To assess the safety of miltefosine allometric dose in children with primary VL in Eastern Africa</p>\n <p style=\"margin-left:6.1pt;\">\n  </p>\n <p style=\"margin-left:6.1pt;\">\n <u>Secondary Objectives</u>:</p>\n <p style=\"margin-left:42.1pt;\">\n ·       To assess the efficacy of a 28 days miltefosine allometric dose in children with primary VL in Eastern Africa</p>\n <p style=\"margin-left:42.1pt;\">\n ·       To identify secondary PK parameters that are associated with clinical outcome up to D210</p>\n <p style=\"margin-left:42.1pt;\">\n ·       To assess the pharmacodynamics of parasite clearance over time after treatment onset and its correlation with PK parameters and clinical outcome</p>\n <p style=\"margin-left:6.1pt;\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.06%;\">\n <p style=\"margin-left:6.1pt;\">\n <u>Primary Endpoints</u>:</p>\n <p style=\"margin-left:6.1pt;\">\n Pharmacokinetics (PK):</p>\n <p style=\"margin-left:42.1pt;\">\n ·       Total drug exposure (e.g. area under the concentration-time curve [AUC], Css/Cmax) will be assessed. Primary PK parameters (CL, Vd etc.) will be estimated using a population PK approach employing non-linear mixed effects modeling (NONMEM) and will be compared to previously obtained miltefosine PK results from the LEAP0208 study.<br />\n Combined data from LEAP0208 and the present study will be used to identify secondary PK parameters and PK targets to attain that are associated with parasite clearance and/or clinical response, which will provide a basis to define time to reach adequate drug exposure and guide minimum treatment duration needed for miltefosine in children to be used in combination therapies.</p>\n <p style=\"margin-left:24.1pt;\">\n  </p>\n <p style=\"margin-left:6.1pt;\">\n Safety:</p>\n <p style=\"margin-left:42.1pt;\">\n ·       Frequency of SAEs and AEs requiring treatment discontinuation</p>\n <p style=\"margin-left:42.1pt;\">\n ·       Frequency and severity of adverse events</p>\n <p style=\"margin-left:6.1pt;\">\n  </p>\n <p style=\"margin-left:6.1pt;\">\n  </p>\n <p style=\"margin-left:6.1pt;\">\n <u>Secondary Endpoints</u>:</p>\n <p style=\"margin-left:6.1pt;\">\n Efficacy:</p>\n <p style=\"margin-left:42.1pt;\">\n ·       Cure at the D28 assessment, defined as recovery of clinical signs and symptoms and absence of parasites at D28</p>\n <p style=\"margin-left:42.1pt;\">\n ·       Cure at D210 follow-up, defined as absence of signs and symptoms of VL at D210 and no requirement for rescue administration during the trial (<em>e.g</em> no relapse or earlier treatment failure)</p>\n <p>\n  </p>\n <p>\n Pharmacodynamics (PD):</p>\n <p style=\"margin-left:.5in;\">\n ·       Parasite clearance over time (qualitative and quantitative), as measured by qPCR from blood samples, from baseline until D56, and at any suspect of relapse during the trial</p>\n <p style=\"margin-left:.5in;\">\n ·       Correlation of parasite quantification in blood vs tissue samples at baseline, D28 assessment and at any suspect of relapse that requires tissue aspirate for diagnosis confirmation</p>\n <p style=\"margin-left:.5in;\">\n ·       Neopterin levels (marker of macrophage activation) in blood samples measured by ELISA, from baseline until D56, and at any suspect of relapse during the trial.</p>\n <p style=\"margin-left:.5in;\">\n  </p>\n <p>\n ngle primary endpoint</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.06%;\">\n <p style=\"margin-left:1.6pt;\">\n This is a multicenter, non-comparative, open-label clinical trial to assess the PK and safety of miltefosine using an allometric dose algorithm in the treatment of children with primary visceral leishmaniasis in eastern Africa. Efficacy and PD will be assessed as secondary outcomes.</p>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.06%;\">\n <p>\n Patients who fulfill all inclusion criteria and do not present any of the exclusion criteria will be eligible to be enrolled in this study.</p>\n <p>\n  </p>\n <p>\n <strong>Inclusion criteria:</strong></p>\n <p>\n ·       Patients with clinical signs and symptoms of VL and confirmatory parasitological microscopic diagnosis</p>\n <p>\n ·       Patients aged <u>></u> 4 to <u><</u> 12 years who are able to comply with the study protocol.</p>\n <p>\n ·       Patients for whom written informed consent has been signed by parents(s) or legal guardian</p>\n <p>\n ·       Weight < 30 kg</p>\n <p>\n  </p>\n <p>\n <strong>Exclusion criteria:</strong></p>\n <p style=\"margin-left:.25in;\">\n ·       Patients who are relapse cases</p>\n <p style=\"margin-left:.25in;\">\n ·       Patients who have received any anti-leishmanial drugs in the last 6 months</p>\n <p>\n ·       Patients with severe malnutrition (for children aged <5 years, weight-for-height WHO reference curves by gender, z score <-3; for children 5-12 years,  BMI-for-age WHO reference curves for gender, z score < -3)</p>\n <p>\n ·       Patients with positive HIV diagnosis</p>\n <p>\n ·       Patients with previous history of hypersensitivity reaction to miltefosine</p>\n <p>\n ·       Patients suffering from a concomitant severe infection such as TB or any other serious underlying disease (cardiac, renal, hepatic) which would preclude evaluation of the patient’s response to study medication</p>\n <p>\n ·       Patients suffering from other conditions associated with splenomegaly such as schistosomiasis</p>\n <p>\n ·       Pregnant or lactating women or female patient in childbearing age (reached menarche)</p>\n <p>\n ·       Patients with haemoglobin < 5g/dl</p>\n <p>\n ·       Patients with WBC < 1 x 10³/mm³</p>\n <p>\n ·       Patients with platelets < 40,000/mm³</p>\n <p>\n ·       Patients with abnormal liver function (ALT and AST) tests of more than three times the normal range.</p>\n <p>\n ·       Patients with bilirubin more than 1.5 times the upper normal range</p>\n <p>\n ·       Patients with serum creatinine above the ULN for age and gender.</p>\n <p>\n ·       Patients with clinical signs of severe VL disease such as jaundice and bleeding</p>\n <p>\n ·       Patients who cannot comply with the planned scheduled visits and procedures of the study protocol</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.06%;\">\n <p style=\"margin-left:6.1pt;\">\n This study will be implemented taking into account that recruitment period shall last maximum of 4 months + 7 months period for patient participation in the study (28 days treatment + 6 months follow-up post treatment). Therefore, a total of 11 months from first patient in (FPI) to last patient out (LPO). Taking into account the analysis and reporting period, the study shall last 15 months.</p>\n <p style=\"margin-left:6.1pt;\">\n  </p>\n <p style=\"margin-left:6.1pt;\">\n In order to meet recruitment target, multiple sites will be prepared to initiate the trial: Kimalel and Kacheliba in Kenya; Amudat in Uganda; Dooka in Sudan. Once approval is obtained in the country, recruitment shall start, and other sites to be added <em>ad hoc</em> as approvals are obtained. Routine active case search and community awareness activities will be boosted to increase recruitment.</p>\n <p style=\"margin-left:6.1pt;\">\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.06%;\">\n <p>\n All patients in this study will be treated with:</p>\n <p>\n  </p>\n <p style=\"margin-left:42.1pt;\">\n ·       Miltefosine administered in a dosage conform the daily allometric dosing algorithm (based on individual weight and height), as per Dorlo <em>et al</em>. (Antimicrob Agents Chemother. 2012;56(7):3864-72), divided in 2 administrations per day for 28 days.</p>\n <p>\n  </p>\n <p>\n An easy-to-use table with dosing scheme by weight and height will be provided to the investigators to define the exact daily dose to be administered.</p>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.06%;\">\n <p>\n Samples size estimation for this trial was based on the power and precision to estimate the PK parameter AUC, as this the main parameter of drug exposure of interest. This innovative approach to determine the minimum sample size needed for PK trials has been presented (Dorlo et al. Sample size estimates for a clinical trial evaluating allometric dosing of miltefosine in children with visceral leishmaniasis in East Africa. PAGE 23 (2014) Abstr 3236 [www.page-meeting.org/?abstract=3236])</p>\n <p>\n In short, anthropometric data from 454 East-African VL patients aged 4-12 years were obtained from previous DNDi sponsored clinical trials. Miltefosine PK data were simulated for all pediatric patients on allometric dosing (for 28d) with an established 2-compartment population PK model using NONMEM 7.2. Secondary PK parameter AUC was calculated and used as a measure of total drug exposure. The Monte Carlo confidence interval approach was used to evaluate achieved power for various sample sizes. Clinical trials (n=1000) were simulated with a random sample of patients (n=10, 15, 20, etc.) drawn from the pediatric population.</p>\n <p>\n The sample size minimally required to achieve the AUC 95%CI within a 15% precision level (85%-118%) and a power of 95% was 25 patients.</p>\n <p>\n In the LEAP 0208, 12/51 (24%) patients treated with miltefosine 2.5mg/kg/day for 28 days presented at least one episode of vomiting (11 Grade 1 and 1 Grade 2). However, compliance was achieved in 100% of patients (90-110% of intended dose).</p>\n <p>\n In order to account for possible non-compliance due to lower tolerability of the miltefosine allometric dose or unforeseen logistics problems with samples, an adjustment of 15% over the sample size will be incorporated, making a total of 30 patients in the trial.</p>\n <p>\n Data management, analysis and reporting will be done at the DNDi Data Center in Nairobi, Kenya.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.06%;\">\n <p>\n There is no randomization in this trial, as it is a single allocation arm.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.06%;\">\n <p>\n <u>Pharmacokinetics</u></p>\n <p>\n A population PK model of miltefosine will be developed using the miltefosine PK data from this trial using the gold standard software NONMEM for non-linear mixed effects modeling.  Primary PK parameters (e.g. k_a, CL, V2, Q and V3) will be estimated using this approach, allowing for the disentanglement of between- and within-subject variability. A covariate analysis will be performed to assess whether there are significant (clinical, demographic) factors influencing any of the PK parameters. Secondary PK parameters will be derived from this model for each individual and will include: area under the concentration-time curve, elimination half-lives, Cmax/ss, time and AUC above relevant thresholds (e.g. IC90). The population PK model will be evaluated using golden standard procedures and software (Pirana, Xpose, PsN), such as goodness of fit plots and visual predictive checks (Keizer et al. CPT-PSP, 2013). Miltefosine exposure values in children on allometric dosing will be compared to similar adult results obtained in the LEAP0208 study, to assess if the overall pediatric exposure (in this case AUC_0-_∞) in this pediatric population has been increased after administering the allometric dose to a similar level of miltefosine exposure in adults after treatment with miltefosine conventional dose of 2.5 mg/kg/day.</p>\n <p>\n After the PK model has been developed, a population PK-PD model will be developed by integrating PK data with qRT-PCR, which will be used as a marker of parasitological clearance. Clinical outcome and measures (spleen and liver size), appropriate biochemistry values and other selected biomarkers (neopterin) will also be integrated in the PK-PD model, if applicable.</p>\n <p>\n  </p>\n <p>\n <u>Safety</u></p>\n <p>\n Adverse events will be reported during treatment and follow-up periods. AE’s will be tabulated by relation to study drug (ADR) and severity (based on the CTCAE v4).</p>\n <p>\n  </p>\n <p>\n <u>Efficacy</u></p>\n <p>\n The primary population for efficacy analysis will be the intention to treat population.</p>\n <p>\n For efficacy analysis, cure at D28 or D210 will be defined as the proportion of patients with undetectable parasites and or absence of clinical signs and symptoms of VL without the need for rescue administration. The efficacy estimate will be reported with its 95% confidence interval.</p>\n <p>\n  </p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • study_title<p>\n <strong>An open-label clinical trial to assess the pharmacokinetics and safety of miltefosine allometric dose for the treatment of children with primary visceral leishmaniasis in Eastern Africa</strong></p>\n
      • laymans_summary(null)
      • short_title(null)
      • protocol_noECCT/15/02/05
      • version_noProtocol Version/Date Draft 0.3 03 Sept 2014
      • date_of_protocol03-09-2014
      • study_drugMiltefosine
      • disease_conditionLeishmaniasis
      • 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_nameAlkylphosphocholine
      • product_type_medical_device_name
      • comparator(null)
      • comparator_name(null)
      • comparator_registered(null)
      • comparator_countries(null)
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressjmalongo@dndi.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries1
      • 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 Monique Wasunna
      • declaration_date127-02-2015
      • declaration_principal_investigatorDr Rashid Juma
      • declaration_date227-02-2015
      • placebo_presentNo
      • study_objectives(null)
      • principal_inclusion_criteria<p>\n <strong>Inclusion criteria:</strong></p>\n<p>\n ·       Patients with clinical signs and symptoms of VL and confirmatory parasitological microscopic diagnosis</p>\n<p>\n ·       Patients aged <u>></u> 4 to <u><</u> 12 years who are able to comply with the study protocol.</p>\n<p>\n ·       Patients for whom written informed consent has been signed by parents(s) or legal guardian</p>\n<p>\n ·       Weight < 30 kg</p>\n<p>\n  </p>\n<p>\n  </p>\n
      • principal_exclusion_criteria<p>\n <strong>Exclusion criteria:</strong></p>\n<p style=\"margin-left: 0.25in;\">\n ·       Patients who are relapse cases</p>\n<p style=\"margin-left: 0.25in;\">\n ·       Patients who have received any anti-leishmanial drugs in the last 6 months</p>\n<p>\n ·       Patients with severe malnutrition (for children aged <5 years, weight-for-height WHO reference curves by gender, z score <-3; for children 5-12 years,  BMI-for-age WHO reference curves for gender, z score < -3)</p>\n<p>\n ·       Patients with positive HIV diagnosis</p>\n<p>\n ·       Patients with previous history of hypersensitivity reaction to miltefosine</p>\n<p>\n ·       Patients suffering from a concomitant severe infection such as TB or any other serious underlying disease (cardiac, renal, hepatic) which would preclude evaluation of the patient’s response to study medication</p>\n<p>\n ·       Patients suffering from other conditions associated with splenomegaly such as schistosomiasis</p>\n<p>\n ·       Pregnant or lactating women or female patient in childbearing age (reached menarche)</p>\n<p>\n ·       Patients with haemoglobin < 5g/dl</p>\n<p>\n ·       Patients with WBC < 1 x 10³/mm³</p>\n<p>\n ·       Patients with platelets < 40,000/mm³</p>\n<p>\n ·       Patients with abnormal liver function (ALT and AST) tests of more than three times the normal range.</p>\n
      • primary_end_points<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.78%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:77.06%;\">\n <p style=\"margin-left:6.1pt;\">\n <u>Primary Endpoints</u>:</p>\n <p style=\"margin-left:6.1pt;\">\n Pharmacokinetics (PK):</p>\n <p style=\"margin-left:42.1pt;\">\n ·       Total drug exposure (e.g. area under the concentration-time curve [AUC], Css/Cmax) will be assessed. Primary PK parameters (CL, Vd etc.) will be estimated using a population PK approach employing non-linear mixed effects modeling (NONMEM) and will be compared to previously obtained miltefosine PK results from the LEAP0208 study.<br />\n Combined data from LEAP0208 and the present study will be used to identify secondary PK parameters and PK targets to attain that are associated with parasite clearance and/or clinical response, which will provide a basis to define time to reach adequate drug exposure and guide minimum treatment duration needed for miltefosine in children to be used in combination therapies.</p>\n <p style=\"margin-left:24.1pt;\">\n  </p>\n <p style=\"margin-left:6.1pt;\">\n Safety:</p>\n <p style=\"margin-left:42.1pt;\">\n ·       Frequency of SAEs and AEs requiring treatment discontinuation</p>\n <p style=\"margin-left:42.1pt;\">\n ·       Frequency and severity of adverse events</p>\n <p style=\"margin-left:6.1pt;\">\n  </p>\n <p style=\"margin-left:6.1pt;\">\n  </p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<p>\n Kacheliba - 1 Doctor, 4 Clinical Officers, 3 Nurses, 3 Lab techs</p>\n<p>\n Kimalel - 2 Doctors, 3 Clinical Officers, 3 Nurses, 3 Lab techs</p>\n<p>\n Amudat - 2 Doctors, 4 Nurses, 3 Lab techs </p>\n
      • other_details_explanation<p>\n This is a multicenter, non-comparative, phase II, open-label clinical trial to assess the PK and safety of miltefosine using an allometric dose algorithm in the treatment of children with primary visceral leishmaniasis in Eastern Africa. Efficacy and PD will be assessed as secondary outcomes.</p>\n<p>\n In order to have representativeness of VL patients from the different countries and to increase the recruitment capacity, LEAP study sites in Kenya, Uganda and Sudan will participate in this study. </p>\n<p>\n The target population will be children 4-12y, as this is the age group in which exposure to miltefosine is lower when treated with 2.5 mg/kg/day conventional dose, as compared to adults.</p>\n<p>\n The study is being conducted in Kenya and not host country as Leishmaniasis the treatment is intended for populations in East Africa where the previous study LEAP 0208 showed that children are under-dosed with miltefosine, and therefore significantly under-exposed to the drug, compared to adult drug exposure leading to decreased efficacy.</p>\n
      • other_details_regulatory_notapproved<p>\n National Drug Authority - Uganda - Dates to be provided</p>\n<p>\n Federal Medicines and Poisons Board - Sudan - Dates to be provided</p>\n
      • other_details_regulatory_approved<p>\n None: The protocol has been submitted to National Drugs Authority - Uganda</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n None</p>\n
      • estimated_durationone year
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states3 countries
      • number_of_sites2
      • multi_country_listKenya, Uganda and Sudan
      • data_monitoring_committeeNo
      • total_enrolment_per_site30 maximum, no minimum
      • total_participants_worldwide30
      • 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_consentYes
      • subjects_specifyChildren age 4 yrs - 12 yrs
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameMonique
      • investigator1_middle_nameK
      • investigator1_family_nameWasunna
      • investigator1_qualificationMBchB, MMed
      • investigator1_professional_addressP.O. Box 20778 - 00202 Nairobi
      • investigator1_telephone0202077767
      • investigator1_emailafrica@dndi.org
      • organisations_transferred_No
      • number_participants30 maximum
      • notification
      • approval_date09-04-2015
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted27-02-2015
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe study has now been approved.
      • final_report<h1 align=\"left\">\n  </h1>\n<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;width:0px;\" width=\"100%\">\n <thead>\n <tr>\n <th colspan=\"2\" style=\"width:100.0%;\">\n <p align=\"center\">\n <strong>CLINICAL STUDY REPORT SYNOPSIS</strong></p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p style=\"margin-left:142.85pt;\">\n <strong>Name of Sponsor/Company:</strong> DNDi, Chemin Louis Dunant, 15, 1202 Geneva, Switzerland</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Name of Finished Product: </strong>Impavido^®</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Name of Active Ingredient: </strong>Miltefosine</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Protocol Number: </strong>LEAP 0714</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Protocol Title/</strong> <strong>Title of Study: </strong>An Open-Label Clinical Trial to Assess the Pharmacokinetics and Safety of Miltefosine Allometric Dose for the Treatment of Children With Primary Visceral Leishmaniasis in Eastern Africa</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Investigators: </strong>Dr Jane Mbui / Prof Joseph Olobo / Prof Ahmed Musa</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Study Centres: </strong>This was a multicenter study conducted at 1 center each in Kacheliba (Kenya) and Amudat (Uganda).</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;height:31px;\">\n <p>\n <strong>Publications </strong><strong>(Reference): </strong>None</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:51.32%;\">\n <p>\n <strong>Study Period (Date of First Enrolment and Date of Last Completed): </strong>04 June 2015 and 21 March 2016.</p>\n </td>\n <td style=\"width:48.68%;\">\n <p>\n <strong>Phase of Development: </strong>Phase 2</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Study Objective(s):</strong></p>\n <h3>\n <u>Primary Objectives</u><u>:</u></h3>\n <ul>\n <li>\n To characterize the drug exposure and pharmacokinetic (PK) properties of miltefosine (Impavido^®) using allometric dosing in children with primary visceral leishmaniasis (VL) in eastern Africa, and assess whether it was equivalent to adult drug exposure*.</li>\n <li>\n To identify PK parameters that were associated with parasite clearance to derive the basis for a definition of what would be sufficient drug exposure for miltefosine activity.</li>\n <li>\n To assess the safety of miltefosine allometric dose in children with primary VL in eastern Africa*.</li>\n </ul>\n <h3>\n <u>Secondary Objectives</u><u>:</u></h3>\n <ul>\n <li>\n To assess the efficacy of a 28 days miltefosine allometric dose in children with primary VL in eastern Africa*.</li>\n <li>\n To identify secondary PK parameters that are associated with clinical outcome up to Day 210.</li>\n <li>\n To assess the pharmacodynamic (PD) of parasite clearance over time after treatment onset and its correlation with PK parameters and clinical outcome.</li>\n </ul>\n <p>\n *Note: Results for only descriptive PK analysis, and safety and efficacy analysis are reported. The PK analysis associated with PD analysis (parasite clearance and neopterin biomarker) and secondary PK parameters analysis require further modelling and thus will be analyzed subsequently. These results will be reported in a separate report.</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;height:772px;\">\n <p>\n <strong>METHODOLOGY</strong></p>\n <p>\n <strong>Study Design:</strong></p>\n <p>\n This was a multicenter, non-comparative, Phase 2, open-label proof‑of‑concept study whose primary objective was to characterize the drug exposure and PK properties as well as safety of miltefosine using allometric dosing in children with primary VL in eastern Africa. Efficacy assessment was defined as secondary objective in this trial.</p>\n <p>\n Originally, Leishmaniasis East Africa Platform (LEAP) study sites in Kenya, Uganda and Sudan were considered for participation in this study. However, the recruitment target of 30 subjects could be easily reached only with the sites in Kenya and Uganda, therefore Sudan was finally not involved in this trial. Ethiopian sites were not included in this trial as the majority of subjects at the Gondar site are adults, and due to the lengthy approval process it was likely that recruitment would be over at the time of approval. A total of 30 subjects were to be included in this study.</p>\n <p>\n Subjects with primary VL cases with age range between 4 and 12 years and weight <30 kg was defined as the target population, as this was the age group in which exposure to miltefosine was lower when treated with 2.5 mg/kg/day conventional dose, as compared to adults. Recruited subjects were equally distributed by age in order to ensure representativeness in all age categories. Thus 50% of subjects were recruited between ≥4 and <8 years of age and 50% were recruited between ≥8 and ≤12 years of age.</p>\n <p>\n With 2 active sites, the recruitment period lasted for 3 months, while it was anticipated to last for 4 months. Each subject’s participation in the study was for 7 months (28 days treatment and 6 months follow‑up post treatment) see Figure 1. Therefore, the overall study duration was 10 months from first subject in to last subject out.</p>\n <p>\n <strong>Figure </strong><strong>1</strong><strong>.         Overall Study Design</strong></p>\n <p>\n <img height=\"199\" src=\"file:///C:/Users/GMOUAT~1/AppData/Local/Temp/msohtmlclip1/01/clip_image002.gif\" width=\"580\" /></p>\n <p>\n BQ = biochemistry; D = day; EoT = end of treatment; HIV = human immunodeficiency virus; Ht = hematology; ICF = informed consent form; labs = laboratory; PD = pharmacodynamics; PK = pharmacokinetic; VL = visceral leishmaniasis.</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Number of Subjects (Planned and Analysed): </strong></p>\n <p>\n A total of 30 subjects with primary VL and within the age range of 4 to 12 years and weight <30 kg were planned to be included in this study.</p>\n <p>\n A total of 158 subjects were screened and 30 subjects were enrolled in this study. All the 30 enrolled subjects were included in the intention to treat (ITT) and per protocol (PP) analysis population. There were no major protocol deviations so the PP and ITT analysis populations were the same. All the subjects participating in the study were included in the safety population.  There was no lost to follow-up in the trial, all patients completed the study, as per protocol. </p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Diagnosis and Main Criteria for Inclusion:</strong></p>\n <p>\n Subjects with clinical signs and symptoms of VL and confirmatory parasitological microscopic diagnosis; aged ³4 to £12 years with weight of <30 kg for whom written informed consent had been signed by parent(s) or legal guardian.</p>\n <p>\n Excluded were subjects who were relapse cases; who received any anti-leishmanial drugs in the last 6 months; subjects with severe malnutrition (for children aged <5 years, weight‑for-height World Health Organization (WHO) reference curves by gender, Z score <-3; for children 5 to 12 years, body mass index-for-age WHO reference curves by gender, Z score <-3); subjects with positive human immunodeficiency virus diagnosis; subjects with previous history of hypersensitivity reaction to miltefosine; subjects suffering from a concomitant severe infection such as tuberculosis or any other serious underlying disease (cardiac, renal, hepatic) which would preclude evaluation of the subject’s response to study medication; pregnant or lactating women or female subject in childbearing age (reached menarche); subjects with abnormal liver function (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) tests of >3 times the normal range; and subjects who cannot comply with the planned scheduled visits and procedures of the study protocol. </p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;height:103px;\">\n <p>\n <strong>Study Treatments (Test Product and/ or Reference Therapy), Dose and Mode of Administration, Batch Number:</strong></p>\n <p>\n Miltefosine is a phosphocholine analogue from Paladin labs coming as 10 mg and 50 mg capsules in pack of 56 capsules sealed in 8 aluminum blister stripes, each containing 7 capsules.  The study drug was administered orally, as monotherapy treatment given for 28 days. All subjects in this study were treated with miltefosine based on the allometric dosing algorithm (according to sex, weight and height); divided in 2 administrations per day for 28 days.  Administration of the daily dosage were divided in 2 administrations, during or after a meal, to avoid direct gastrointestinal AE of miltefosine, as in Table 1. </p>\n <p>\n  </p>\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <thead>\n <tr>\n <th colspan=\"7\" style=\"width:100.0%;\">\n <p>\n <strong>Table </strong><strong>1</strong><strong>.    Daily Dosage of Subjects Divided in 2 Administrations</strong></p>\n </th>\n </tr>\n <tr>\n <th style=\"width:31.5%;\">\n <p align=\"left\">\n Total Daily Dose, Divided:</p>\n </th>\n <th style=\"width:11.42%;\">\n <p>\n 30 mg</p>\n </th>\n <th style=\"width:11.42%;\">\n <p>\n 40 mg</p>\n </th>\n <th style=\"width:11.42%;\">\n <p>\n 50 mg</p>\n </th>\n <th style=\"width:11.42%;\">\n <p>\n 60 mg</p>\n </th>\n <th style=\"width:11.42%;\">\n <p>\n 70 mg</p>\n </th>\n <th style=\"width:11.42%;\">\n <p>\n 80 mg</p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"width:31.5%;\">\n <p style=\"margin-left:5.05pt;\">\n Morning (breakfast)</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 2 x 10 mg</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 2 x 10 mg</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 1 x 50 mg</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 1 x 50 mg</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 1 x 50 mg</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 1 x 50 mg</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:31.5%;\">\n <p style=\"margin-left:5.05pt;\">\n Afternoon (dinner)</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 1 x 10 mg</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 2 x 10 mg</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n -----</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 1 x 10 mg</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 2 x 10 mg</p>\n </td>\n <td style=\"width:11.42%;\">\n <p align=\"center\">\n 3 x 10 mg</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"7\" style=\"width:100.0%;\">\n <p>\n  </p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n  </p>\n <p>\n Miltefosine commercialized by Paladin labs under the licensed name of Impavido^® was used. Miltefosine was stored in the original package and protected from moisture. The shelf life is 5 years. Both miltefosine 10 mg and 50 mg batches used were produced in Mar/2014 and expire in Mar/2019.</p>\n <p>\n All administrations were directly observed by the study nurse to assure compliance. After each drug intake the subject was observed for vomiting for 30 minutes. All vomiting episodes were recorded. In case of vomiting 30 minutes after intake, the dose was to be re‑administered. If a repeated vomiting occurred (vomiting after re-dose) the treatment was not to be re‑administered. Compliance was assessed by total dose taken by the subject. Full compliance was considered if 90 to 110% of the prescribed dose was administered.</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Duration of Treatment:  </strong></p>\n <p>\n Treatment duration was for a total of 28 days.</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Criteria for Evaluation</strong>:</p>\n <p>\n <u>Efficacy Evaluations</u>:</p>\n <p>\n Evaluation of efficacy was the secondary objective of this study.  Efficacy of the treatment was assessed at the end of treatment (EoT), Day 28 and at the end of 6 months follow-up (Day 210). The efficacy estimate was reported as proportion of subjects cured at each time point with its 95% confidence intervals (CIs).</p>\n <p>\n The primary population for efficacy analysis at Day 28 and Day 210 was the ITT. Furthermore, PP analysis was also performed. The PP population was based on subjects with no pre-specified major protocol deviations relating to treatment compliance and baseline exclusion criteria.</p>\n <p>\n The statistical analysis plan detailing the different analyses approaches was reviewed and approved by the PIs and sponsor prior to data analysis.</p>\n <p>\n The data was analyzed as proportion, according to either ITT or PP. Worst‑case and complete case analysis was performed for both ITT and PP. In worst case analysis, missing data were defined as failures, whereas in the complete case analysis missing data were not included in the analysis.</p>\n <p>\n <u>Pharmacokinetic Evaluations</u>:</p>\n <p>\n Plasma samples were collected on the screening day, during treatment phase at Day 1 (8 hours post first miltefosine dose), Days 7, 14, 21, 28 (all predose) and 2 samples at follow-up period at 1 month post treatment (Day 56) and 6 months post treatment (Day 210). Plasma samples for miltefosine concentration were analyzed using liquid chromatography coupled to tandem mass spectrometry method validated previously at the bioanalytical laboratory of the Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital in Amsterdam, the Netherland.</p>\n <p>\n Calibration and QC samples were prepared by spiking different concentrations of stock and working solutions into blank plasma. The lower limit of quantitation (LLOQ) of the assay was 4 ng/mL and the upper limit of quantitation of the assay was 1,000 ng/mL. The QC samples were 12.2 ng/mL (QC low), 304 ng/mL (QC mid) and 761 mg/mL (QC high). Calibration standards and QC samples were split into aliquots and stored frozen at nominally -20°C until analysis.</p>\n <p>\n If the concentration of a sample deviated extensively (eg ±40%) from the expected concentration (a “PK outlier”), the primary PK sample was re-analyzed in duplicate to exclude the possibility of a bioanalytical error.</p>\n <p>\n <u>Pharmacodynamic Evaluations</u>:</p>\n <p>\n PD assessment were based on real time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for <em>Leishmania donovani</em> in ethylenediaminetetraacetic acid blood or tissue aspirate, based on the amplification of kinetoplastid deoxyribonucleic acid, to assess the parasite clearance over time during the treatment with miltefosine.</p>\n <p>\n The qRT-PCR was performed at the Royal Tropical Institute in Amsterdam, the Netherlands.  Plasma was used for neopterin assays. Neopterin load in blood is increased at time of diagnosis in East African VL subjects and decreases to normal within the treatment period. To evaluate in more detail whether this reflects the therapeutic response in individual subjects, neopterin levels were to be assessed in this trial. Neopterin is measured using commercial enzyme-linked immunosorbent assay kits.</p>\n <p>\n qRT-PCR response and neopterin levels were assessed in this trial and the results will be reported in a separate PD report.</p>\n <p>\n <u>Safety Evaluations</u>:</p>\n <p>\n Safety evaluations included clinical monitoring, vital signs (heart rate, blood pressure), monitoring of adverse events (AEs), and safety evaluation of haematology and blood chemistry parameters.</p>\n <p>\n The severity for an AE was graded using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0). In case of AEs that were not described in the CTCAE Version 4.0, the investigator used the terminology Mild, Moderate, Severe or Life‑threatening.</p>\n <p>\n Hematology parameters hemoglobin, white blood cells with differential and platelets were analyzed at screening, on days 3, 7, 14, 21, 28, 56 and 210. Biochemistry parameters creatinine, AST, ALT and bilirubin were analyzed at screening, on days 3, 7, 14, 21 and 28. Electrocardiogram (ECG) recordings were not performed, as there was no cardiac safety risk associated with miltefosine treatment.</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>Statistical Methods: </strong></p>\n <p>\n Baseline data and continuous data was summarized using mean and standard deviation (SD) and median (inter-quartile range). Binary and categorical data was summarized using counts and proportions.</p>\n <p>\n <u>Pharmacokinetic Analysis:</u></p>\n <p>\n For the primary endpoint on PK, all subjects exposed to at least 1 dose of the medication and who had a PK sample collected were included in the analysis.</p>\n <p>\n As per protocol, it was originally planned to develop a population PK model of miltefosine using the miltefosine PK data from this trial using the gold standard software NONMEM for non-linear mixed effects modeling. Primary PK parameters (eg. ka, CL, V2, Q and V3, depending on the final structural model best fitting the PK data) would have been estimated using this approach, allowing for the disentanglement of between‑and within-subject variability. A covariate analysis would have been performed to assess whether there were any significant (clinical, demographic) factors influencing any of the PK parameters. The population PK model would have been evaluated using golden standard procedures and software (Pirana, Xpose, PsN), such as goodness of fit plots and visual predictive checks.</p>\n <p>\n Miltefosine exposure values in children on allometric dosing would have been compared to similar adult results obtained in the LEAP 0208 study, to see whether the overall pediatric exposure (in this case AUC_0-∞) in this pediatric population would increase after administering the allometric dose to a similar level of miltefosine exposure in adults receiving the conventional dose of 2.5 mg/kg/day. However, due to unforeseen non-linearities in the PK results, the methodology for the PK data analysis was modified as described below. Data cleaning and analysis were performed in R (Version 3.1.2), using the R package “ggplot2” for the graphical presentation. Furthermore, the LEAP 0714 PK observations were compared to simulations based on the population PK model developed with the LEAP 0208 data (Dorlo et al., in preparation). For this comparison, a visual predictive check (VPC) was run with the non-linear mixed-effects modelling software NONMEM 7.3 (ICON plc, Hanover, MD, USA) and Perl‑speaks‑NONMEM (PsN, Uppsala University, Uppsala, Sweden) using fixed parameter estimates from the LEAP 0208 analysis, but using individual dosing and covariate records from the LEAP 0714 subjects. The VPC was visualized with the Xpose4 R‑package (Version 4.4.0, Uppsala University, Uppsala, Sweden). The non‑compartmental PK analysis (NCA) analysis was performed with the R package “ncappc” (Uppsala, University, Uppsala, Sweden).</p>\n <p>\n <u>Safety Analysis:</u></p>\n <p>\n All subjects enrolled in the study and who were administered the first dose of study medication were included in the safety analysis (treatment-emergent AEs). The AE data was coded using Medical Dictionary for Regulatory Activities Version 17.0.</p>\n <p>\n AEs were reported during the entire participation of the subject in the trial, ie treatment and follow-up periods. Furthermore, AEs judged related to study procedures that occurred during the screening period were also reported. AEs were tabulated by System Organ Class (SOC), by relationship to study drug (adverse drug reaction [ADR]) and severity (based on the CTCAE Version 4.0).</p>\n <p>\n Serious adverse events (SAEs) were reported throughout the study duration (from signature of informed consent up to 6 months follow-up at Day 210).</p>\n <p>\n The proportion of subjects experiencing at least 1 AE was presented.</p>\n <ul>\n <li>\n <u>Biological Parameters:</u></li>\n </ul>\n <ul>\n <li>\n <u>Shift Tables:</u> Shift tables were used to present changes between baseline and Day 7, baseline and Day 14 and also baseline and Day 28. Categorizations were made into normal, Grade 1, Grade 2, Grade 3 and Grade 4 according to CTCAE values. The number of subjects in each category is given.</li>\n <li>\n <u>Graphical Representations:</u> Descriptive analyses of the biological parameter data was included in box and whisker plots, scatterplots of parameter value and line graphs.</li>\n </ul>\n <ul>\n <li>\n <u>Time to Fever Clearance:</u> Subject temperature was taken twice daily (morning and evening) during the hospitalization period ie 28 days. In addition, temperature was checked whenever there was reported or suspected fever and recorded on the temperature chart.  Fever clearance was defined as the first date and time point from when the subject becomes fever free and remained fever free for 72 hours consecutively.</li>\n <li>\n <u>Post Kala-azar Dermal Leishmaniasis:</u> The number and percentage of subjects developing Post Kala-azar Dermal Leishmaniasis (PKDL) was tabulated. The number (%) of subjects developing PKDL at Day 28 and after, and the number of each grade type was also tabulated.</li>\n <li>\n <u>Grade 3 and 4 CTCAE:</u> Hematology and blood chemistry laboratory parameters meeting CTC Grade 3 and 4 criteria were reported as AEs.  The number and percentage of subjects with a CTC Grade 3 and 4 AE have been presented for each parameter and time point.</li>\n </ul>\n <p>\n <u>Efficacy Analysis</u>:</p>\n <p>\n The primary population for efficacy analysis at Day 28 and Day 210 was the ITT population. Furthermore, PP analysis was also performed. The PP population was based on subjects with no pre-specified major protocol deviations relating to treatment compliance and baseline exclusion criteria.</p>\n <p>\n The statistical analysis plan detailing the different analyses approaches was reviewed and approved by the PIs and sponsor prior to data analysis.</p>\n <p>\n For efficacy analysis at EoT (Day 28), the following definitions were applied:</p>\n <ul>\n <li>\n <u>Treatment Success:</u> Absence of clinical signs and symptoms of VL and absence of parasites at Day 28 parasitological assessment; hence no rescue medication provided up to this time point.</li>\n <li>\n <u>Treatment Failure:</u> Presence of parasites at Day 28 or requirement for rescue medication due to lack of clinical improvement/response or withdrawn from the study (eg, due to a treatment limiting AE/subject absconded) or death.</li>\n </ul>\n <p>\n For efficacy analysis at the end of follow-up (Day 210), the following definitions were applied:</p>\n <ul>\n <li>\n <u>Treatment Success:</u> Absence of signs and symptoms of VL at Day 210, with no requirement for rescue medication at any time up to this final assessment.</li>\n <li>\n <u>Treatment Failure:</u> Presence of signs and symptoms of VL, confirmed by presence of parasites in a parasitological investigation. It was mandatory that all subjects who had possible presence of the disease had a parasitological assessment (bone marrow/spleen aspirate).</li>\n </ul>\n <p style=\"margin-left:52.85pt;\">\n Subjects who relapsed at any time after Day 28, with confirmatory parasitological examination and needed rescue medication, were defined as failures at Day 210 analysis.</p>\n <p style=\"margin-left:52.85pt;\">\n Subjects who developed severe PKDL and rescue treatment was indicated after Day 28 were also considered treatment failure at Day 210 analysis.</p>\n <p>\n The data was analyzed as proportions, according to either ITT or PP. Worst‑case and complete case analysis was performed for both ITT and PP. In worst case analysis, missing data were defined as failures, whereas in the complete case analysis missing data were not to be included in the analysis.</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:100.0%;\">\n <p>\n <strong>SUMMARY AND CONCLUSIONS</strong></p>\n <p>\n <strong><u>RESULTS</u></strong></p>\n <p>\n <strong>Subject Disposition and Demography:</strong></p>\n <p>\n A total of 158 subjects were screened. A total of 30 subjects (19.0%) were enrolled and were assigned to miltefosine treatment. No subjects discontinued the study. The majority of the subjects were male (73%). The mean age of subjects was 7.7 years, with 16 (53.3%) of subjects in the age range of 4 to 7 year and 14 (46.7%) were in the age range of 8 to 12 years.</p>\n <p>\n <strong>Efficacy Results:</strong></p>\n <h5>\n <u>Cure at Day 28 and Day 210:</u></h5>\n <p>\n Evaluation of efficacy was the secondary objective of the study. The efficacy in both the ITT and PP populations at Day 28 (EoT) was 96.7% with the 95% CI being between 83 to 100% and at Day 210 (end of trial) was 90% with the 95% CI being between 74 to 98%. The results are presented in Table 2.  Three subjects received rescue treatment during the study. One subject was an initial failure and received rescue treatment at Day 25; two other subjects had a relapse episode during the follow-up period, receiving rescue treatment at Day 168 and Day 206. All patients were cured after rescue therapy with Ambisome.</p>\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n <thead>\n <tr>\n <th colspan=\"3\" style=\"width:616px;\">\n <p style=\"margin-left:54.0pt;\">\n <strong>Table </strong><strong>2</strong><strong>.    Efficacy Outcome</strong></p>\n </th>\n </tr>\n <tr>\n <th style=\"width:205px;\">\n <p>\n  </p>\n </th>\n <th style=\"width:205px;\">\n <p align=\"center\">\n <strong>Number Enrolled</strong></p>\n </th>\n <th style=\"width:205px;\">\n <p align=\"center\">\n <strong>Efficacy</strong></p>\n <p align=\"center\">\n <strong>N Cured (%) (95% CI)</strong></p>\n </th>\n </tr>\n <tr>\n <th colspan=\"3\" style=\"width:616px;\">\n <p>\n <strong>Day 28; Efficacy Outcome</strong></p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"width:205px;\">\n <p>\n Intention to treat</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 30</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 29 (96.7) (82.8 to 99.9)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:205px;\">\n <p>\n Per protocol</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 30</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 29 (96.7) (82.8 to 99.9)</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"3\" style=\"width:616px;\">\n <p>\n <strong>Day 210; Efficacy Outcome</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:205px;\">\n <p>\n Intention to treat</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 30</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 27 (90.0) (73.5 to 97.9)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:205px;\">\n <p>\n Per protocol</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 30</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 27 (90.0) (73.5 to 97.9)</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"3\" style=\"width:616px;height:17px;\">\n <p>\n CI = confidence interval; N = number of subjects.</p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n  </p>\n <p>\n <strong>Pharmacokinetic Results:</strong></p>\n <p>\n <u>Total Drug Exposure:</u> All pre-treatment samples were, as expected, below LLOQ. Only 2 out of 28 samples (or 7.1%) from Day 210 were below the LLOQ of 4 ng/mL. One sample was in between the LLOQ and the limit of detection (2.8 ng/mL) and the actual value was reported.</p>\n <p>\n There was no significant difference in EoT concentrations between sexes (excluding PK outliers: median 20,800 ng/mL for females, median 21,000 ng/mL for males). When stratifying the subjects in age categories (4 to 6 year and 7 to 12 year), the mean EoT miltefosine concentration of both groups was 21,600 ng/mL, excluding the outliers. Both outliers were in the 7 to 12 year age group.</p>\n <p>\n <u>LEAP 0714 Versus LEAP 0208: Miltefosine Exposure</u><u>:</u> Age and body weight ranges were different between pediatric subjects enrolled in LEAP 0714 (median age 7 year, median weight 22 kg) and LEAP 0208 (median age 10 year, median weight 24 kg, see Table 3). Pediatric subjects (≤12 years old) included in LEAP 0208 were from Sudan (67%) and Kenya (33%), while subjects included in LEAP 0714 were from Kenya (70%) and Uganda (30%). In the comparison of data from LEAP 0208 and LEAP 0714, the 3 PK outliers were excluded from the LEAP 0714 dataset. Therefore, a total of 21 subjects were included from LEAP 0208 study and 27 subjects from LEAP 0714 study.</p>\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n <thead>\n <tr>\n <th colspan=\"3\" style=\"width:616px;\">\n <p style=\"margin-left:54.0pt;\">\n <strong>Table </strong><strong>3</strong><strong>.    Demographic Differences Between LEAP 0208 (Pediatric Sub-Population ≤12 Years Receiving Miltefosine Monotherapy) and LEAP 0714.</strong></p>\n </th>\n </tr>\n <tr>\n <th style=\"width:205px;\">\n <p>\n  </p>\n </th>\n <th style=\"width:205px;\">\n <p align=\"center\">\n <strong>LEAP 0208</strong></p>\n </th>\n <th style=\"width:205px;\">\n <p align=\"center\">\n <strong>LEAP 0714</strong></p>\n </th>\n </tr>\n <tr>\n <th style=\"width:205px;\">\n <p>\n  </p>\n </th>\n <th style=\"width:205px;\">\n <p align=\"center\">\n N = 21</p>\n </th>\n <th style=\"width:205px;\">\n <p align=\"center\">\n N = 27</p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"width:205px;\">\n <p>\n Age (years)</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 10 (7-12)</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 7 (4-12)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:205px;\">\n <p>\n Weight (kg)</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 24 (16-34)</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 22 (13-30)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:205px;\">\n <p>\n Height (m)</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 1.35 (1.07-1.53)</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 1.25 (0.99-1.45)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:205px;\">\n <p>\n Gender (% female)</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 24%</p>\n </td>\n <td style=\"width:205px;\">\n <p align=\"center\">\n 27%</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"3\" style=\"width:616px;\">\n <p>\n Median (range) unless indicated otherwise.</p>\n <p>\n N = number of subjects.</p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n Drug exposure appears similar with comparable median EoT concentrations reached of 19,500 ng/mL for LEAP 0208 and 20,900 ng/mL for LEAP 0714. Miltefosine seems to accumulate faster in LEAP 0714 with the allometric dosing in the first week of treatment, resulting in a higher drug exposure during the first half of the treatment: eg, Day 7 miltefosine concentrations were generally much higher for LEAP 0714 (median 5,880 ng/mL) than for LEAP 0208 (median 2,670 ng/mL), although this difference was not significant due to large variability in LEAP 0208 Day 7 concentration (p = 0.07, Welch’s 2 sample t-test).</p>\n <p>\n Interestingly, the variability in miltefosine concentrations seems to be substantially higher for the linear dosing regimen (LEAP0208) than for the allometric regimen. This is particularly visible for EoT, where the outliers in miltefosine concentrations on the high (≥30,000 ng/mL) and low end (≤15,000 ng/mL) were subjects from the LEAP 0208 study. The relative standard deviation (%RSD) for the EoT concentration was 16.3% for LEAP 0714 (n = 27) and 35.5% for LEAP 0208 (n = 21), while EoT concentrations were similar.</p>\n <p>\n To further explore results between the 2 studies, 3 age categories were therefore introduced: ≤6 years old (only LEAP 0714), 7 to 9 years old and 10 to 12 years old. However, as mentioned, the variability in analyzed miltefosine concentrations was a lot higher for the linear dosing regimen (LEAP 0208). In the 10 to12 year age category, the mean ± RSD EoT miltefosine concentration of LEAP 0208 was 19,200 ± 37% ng/mL and for the allometric regimen 21,200 ± 16% ng/mL.</p>\n <p>\n <u>LEAP 0714 Versus LEAP 0208: Non-compartmental Analysis</u>: Results for non-compartmental analysis is given in Table 4. For both the Area under the concentration curve for Day 0 to Day 210 (AUC_D0-D210) and maximum observed concentration (C_max) values, the mean value was higher for the LEAP 0208 study, but the median for LEAP 0714 was higher. This can be explained by the effect of positive outliers and overall high variability on the mean in the LEAP 0208 study. The SD was almost twice as high for the LEAP 0208 AUC_D0-D210 (219 µg x day/mL) than for the LEAP 0714 AUC_D0-D210 (112 µg x day/mL).</p>\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n <thead>\n <tr>\n <th colspan=\"5\" style=\"width:616px;\">\n <p style=\"margin-left:54.0pt;\">\n <strong>Table </strong><strong>4</strong><strong>.    Results of Non-compartmental Analysis</strong></p>\n </th>\n </tr>\n <tr>\n <th style=\"width:123px;\">\n <p>\n  </p>\n </th>\n <th style=\"width:123px;\">\n <p>\n  </p>\n </th>\n <th style=\"width:123px;\">\n <p>\n  </p>\n </th>\n <th style=\"width:123px;\">\n <p align=\"center\">\n <strong>AUC_D0-D210</strong> (µg x day/mL)</p>\n </th>\n <th style=\"width:123px;\">\n <p align=\"center\">\n <strong>C_max</strong></p>\n <p align=\"center\">\n (µg/mL)</p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"width:123px;\">\n <p>\n <strong>LEAP 0714</strong></p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n N = 27</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n Mean</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 594</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 21.7</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:123px;\">\n <p>\n 4 to 12 year</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n SD</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 112</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 3.4</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:123px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n Median</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 582</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 21.0</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:123px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n Range</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 392-817</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 15.5-28.6</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:123px;\">\n <p>\n <strong>LEAP 0208</strong></p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n N = 21</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n Mean</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 621</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 22.3</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:123px;\">\n <p>\n 7 to 12 year</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n SD</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 219</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 6.8</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:123px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n Median</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 539</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 19.9</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:123px;\">\n <p>\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n  </p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n Range</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 295-1,110</p>\n </td>\n <td style=\"width:123px;\">\n <p align=\"center\">\n 14.4-37.7</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"5\" style=\"width:616px;\">\n <p>\n AUC = area under the curve; C_max = maximum observed concentration; N = number of subjects.</p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n  </p>\n <p>\n <u>LEAP 0714 Versus LEAP 0208: Reaching the 10 x EC₅₀ Threshold</u><u>: Based in data from Nepal, it is known that t</u>he duration (time) someone is above 10 x EC₅₀ (17.9 µg/mL) as measurement of miltefosine exposure is associated with a lower probability of disease relapse and subsequent rescue treatment. Based on the C_max described in the NCA analysis, 4/27 children (15%) receiving the allometric dose (LEAP 0714) did not reach the 17.9 µg/mL threshold, while 6/21 (29%) children that received the linear dose (LEAP 0208) did not reach this threshold. This is a result of the higher spread in miltefosine concentrations following linear dosing, causing a larger proportion of pediatric subjects to remain under the 17.9 µg/mL threshold.</p>\n <p>\n  </p>\n <p>\n <u>LEAP 0714 Data Versus LEAP 0208 Population PK Model: A Comparison Between Model‑based Predictions and Observed Value</u>s: Higher miltefosine concentrations were expected after allometric dosing in the pediatric population based on simulations with the previously developed PK model. The individual LEAP 0714 allometric dosing and clinical data (eg, body size covariates) were used as input for the population PK model previously developed for LEAP 0208, to simulate individual concentration-time curves in a visual predictive check (N = 200). The results are depicted in Figure 2.</p>\n <p>\n <strong>Figure </strong><strong>2</strong><strong>.         Visual Predictive Check for the LEAP 0714 Data Using Simulations for the LEAP 0714 Subjects Based on LEAP 0208</strong></p>\n <p>\n <em><img height=\"270\" src=\"file:///C:/Users/GMOUAT~1/AppData/Local/Temp/msohtmlclip1/01/clip_image004.gif\" width=\"601\" /></em></p>\n <p>\n Individual observed miltefosine concentrations for LEAP0714 are indicated with the open circles. The fifth and ninety fifth percentiles of the LEAP0714 observed data (broken black line) and the mean of the observations (black line) are indicated by lines, while the grey areas indicate the respective 95% CIs of the fifth, fiftieth and ninety fifth percentiles of the simulations of the LEAP0714 dosing data in the LEAP0208 model (grey areas). The right plot is a cut-out of the total plot on the left and zooms in on the first 35 days of the left plot.</p>\n <p>\n The population PK model of LEAP 0208 included a decreased bioavailability (approximately ‑70%) in the first week of treatment. This seems to be confirmed in the LEAP 0714 study, as the concentrations in the first week of treatment were well predicted with a slight underprediction of the median Day 7 concentration.</p>\n <p>\n In addition, the miltefosine concentrations at the 1- and 6-month follow‑up time point were both overpredicted. However, this was probably an artefact of the overprediction of the EoT concentrations.</p>\n <p>\n <u>LEAP 0714 Versus LEAP 0208, The “Plateau”</u><u>:</u> Interestingly, for LEAP 0714 the miltefosine accumulation seems to stagnate between Day 14 and Day 21 for 40% of the subjects, after which miltefosine concentrations rose again between Day 21 and Day 28. The Day 21 sample was previously not collected for children in LEAP 0208 (sparser sampling), therefore this observation could not be compared nor confirmed with the LEAP 0208 PK data. However, when including the adult data of LEAP 0208, such a plateau could not be observed for adults for whom the Day 21 sample was available.</p>\n <p>\n <strong>Pharmacodynamic Results:</strong></p>\n <p>\n Koninklijk Insituut voor de Tropen (KIT) / Royal Tropical Institute based in Amsterdam, The Netherlands decided to terminate all its biomedical research activities as per 1 July 2016. However, the group fully continued its activities (ie, the same team, same infrastructure) at the Academic Medical Centre (AMC, Amsterdam, The Netherlands), including all the work for LEAP 0714 as per 1 June 2016. An assignment agreement was signed between KIT, AMC and DNDi in order to formalize the transfer.</p>\n <p>\n qRT-PCR response and neopterin levels were assessed in this trial and the results will be reported in a separate PD report.</p>\n <p>\n <strong>Safety Results:</strong></p>\n <p>\n Total number of AEs and number of subjects experiencing AEs are presented in Table 5. All the 30 subjects treated experienced at least 1 treatment-emergent AE (TEAE). The proportion of subjects with ADR was 45%, while the proportion of subjects with unrelated events was 100%.</p>\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <thead>\n <tr>\n <th colspan=\"2\" style=\"width:100.0%;\">\n <br clear=\"all\" />\n <br clear=\"all\" />\n <p style=\"margin-left:54.0pt;\">\n <strong>Table </strong><strong>5</strong><strong>.    Number of Subjects Experiencing Adverse Events</strong></p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n  </p>\n </td>\n <td style=\"width:22.58%;\">\n <p>\n Miltefosine</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n Number enrolled and receiving at least 1 dose</p>\n </td>\n <td style=\"width:22.58%;\">\n <p>\n 30</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n Number of subjects with at least 1 SAE: n (%)</p>\n </td>\n <td style=\"width:22.58%;\">\n <p>\n 2 (7)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n               Adverse drug reaction</p>\n </td>\n <td style=\"width:22.58%;\">\n <p>\n 0 (0)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n               Not related to study drug</p>\n </td>\n <td style=\"width:22.58%;\">\n <p>\n 2 (100)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n Subjects with at least 1 TEAE (whether serious or not): n (%)</p>\n </td>\n <td style=\"width:22.58%;\">\n <p>\n 30 (100)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n               Adverse drug reaction</p>\n </td>\n <td style=\"width:22.58%;\">\n <p align=\"center\">\n 13 (45)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n               Not related to study drug</p>\n </td>\n <td style=\"width:22.58%;\">\n <p align=\"center\">\n 30 (100)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n Total number of TEADR1</p>\n </td>\n <td style=\"width:22.58%;\">\n <p align=\"center\">\n 19 </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n Number of TEADR per subject, median (range)</p>\n </td>\n <td style=\"width:22.58%;\">\n <p align=\"center\">\n 1 (1-6)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n Subjects whose treatment was stopped due to a TEAE, n (%)</p>\n </td>\n <td style=\"width:22.58%;\">\n <p align=\"center\">\n 0 (0)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n               Adverse drug reaction</p>\n </td>\n <td style=\"width:22.58%;\">\n <p align=\"center\">\n 0 (0)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n               Not related to study drug</p>\n </td>\n <td style=\"width:22.58%;\">\n <p align=\"center\">\n 0 (0)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n Subjects experiencing ≥1 episode of repeated vomiting, n (%)</p>\n </td>\n <td style=\"width:22.58%;\">\n <p align=\"center\">\n 0 (0)</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:77.42%;\">\n <p>\n Subjects experiencing ≥1 CTC Grade 3 or 4 TEADR, n (%)</p>\n </td>\n <td style=\"width:22.58%;\">\n <p align=\"center\">\n 5 (17)</p>\n </td>\n </tr>\n </tbody>\n <thead>\n <tr>\n <th colspan=\"2\" style=\"width:100.0%;\">\n <p>\n CTC = Common Toxicity Criteria; n = number of subjects; SAE = serious adverse event; TEADR = treatment‑emergent adverse drug reaction; TEAE = treatment‑emergent adverse event. </p>\n </th>\n </tr>\n <tr>\n <th colspan=\"2\" style=\"width:100.0%;\">\n <p>\n 1.    The number of TEADR out of the total number of adverse events.</p>\n </th>\n </tr>\n </thead>\n </table>\n <p>\n  </p>\n <p>\n There were no deaths or other significant AEs observed during this study. Two SAEs (anemia and transfusion reaction) occurred in this study in 2 subjects (Table 6). None of them were related to miltefosine and both subjects recovered completely. No AEs caused treatment interruption or dose reduction in this trial. There were a total of 14 cases of neutropenia reported in this trial, 4 of them reached Grade 4 severity. These were mainly cases of subjects who had low neutrophils count at baseline, and worsened in severity after treatment initiation. Majority occurred during the first days of treatment, they were temporary, asymptomatic, resolved spontaneously and did not require any intervention. The Investigators assessed these events as non-serious AEs.</p>\n <p>\n  </p>\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n <thead>\n <tr>\n <th colspan=\"8\">\n <p style=\"margin-left:54.0pt;\">\n <strong>Table </strong><strong>6</strong><strong>.    Serious Adverse Events</strong></p>\n </th>\n </tr>\n <tr>\n <th>\n <p align=\"center\">\n <strong>Serial Number</strong></p>\n </th>\n <th>\n <p align=\"center\">\n <strong>Onset Day (Study Day)</strong></p>\n </th>\n <th>\n <p align=\"center\">\n <strong>System Organ Class</strong></p>\n </th>\n <th>\n <p align=\"center\">\n <strong>MedDRA Preferred Term</strong></p>\n </th>\n <th>\n <p align=\"center\">\n <strong>Relation</strong></p>\n </th>\n <th>\n <p align=\"center\">\n <strong>Intensity</strong></p>\n </th>\n <th>\n <p align=\"center\">\n <strong>Seriousness Criteria</strong></p>\n </th>\n <th>\n <p align=\"center\">\n <strong>Outcome</strong></p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 203</p>\n </td>\n <td>\n <p align=\"center\">\n Injury, Poisoning and Procedural Complications</p>\n </td>\n <td>\n <p align=\"center\">\n Transfusion reaction</p>\n </td>\n <td>\n <p align=\"center\">\n Not related</p>\n </td>\n <td>\n <p align=\"center\">\n Moderate</p>\n </td>\n <td>\n <p align=\"center\">\n Yes</p>\n </td>\n <td>\n <p align=\"center\">\n Resolved</p>\n </td>\n </tr>\n <tr>\n <td>\n <p align=\"center\">\n 2</p>\n </td>\n <td>\n <p align=\"center\">\n 19</p>\n </td>\n <td>\n <p align=\"center\">\n Blood and Lymphatic System Disorders</p>\n </td>\n <td>\n <p align=\"center\">\n Anaemia</p>\n </td>\n <td>\n <p align=\"center\">\n Not related</p>\n </td>\n <td>\n <p align=\"center\">\n Life threatening</p>\n </td>\n <td>\n <p align=\"center\">\n Yes</p>\n </td>\n <td>\n <p align=\"center\">\n Resolved</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"8\">\n <p>\n MedDRA = Medical Dictionary for Regulatory Activities.</p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n  </p>\n <p>\n All 30 subjects treated with miltefosine reported at least 1 TEAE (Table 5). Total of 110 TEAEs were reported by 30 subjects. The majority 41/110 (37.3%) of the TEAEs were Grade 1 in severity followed by 33/110 (30.0%) of Grade 2 TEAEs and 31/110 (28.2%) of Grade 3 TEAEs. A total of 5 Grade 4 TEAEs (1 anemia and 4 neutropenia events) were reported in the study. The commonest treatment‑emergent adverse drug reactions were neutropenia (7 events) and vomiting (5 events). There were no permanent discontinuations or dose reductions due to AEs in this study. TEAEs by system organ class and preferred term and its relationship are summarized in Table 7.</p>\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n <thead>\n <tr>\n <th colspan=\"4\">\n <p style=\"margin-left:54.0pt;\">\n <strong>Table </strong><strong>7</strong><strong>.    Treatment‑Emergent Adverse Event Summary by Relationship to Study Medication</strong></p>\n </th>\n </tr>\n <tr>\n <th>\n <p style=\"margin-left:45.0pt;\">\n <strong>System Organ Class<br />\n Preferred MedDRA Term</strong></p>\n </th>\n <th colspan=\"3\">\n <p>\n Miltefosine</p>\n <p>\n N = 30</p>\n </th>\n </tr>\n <tr>\n <th>\n <p>\n  </p>\n </th>\n <th>\n <p align=\"center\" style=\"margin-left:-1.25pt;\">\n <strong>NR</strong>1</p>\n </th>\n <th>\n <p align=\"center\" style=\"margin-left:-1.25pt;\">\n <strong>A</strong><strong>DR</strong>1</p>\n </th>\n <th>\n <p align=\"center\" style=\"margin-left:-1.25pt;\">\n <strong>Total</strong>1</p>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td>\n <p>\n Blood and Lymphatic System Disorders</p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Anaemia</p>\n </td>\n <td>\n <p align=\"center\">\n 13</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 14</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Leukopenia</p>\n </td>\n <td>\n <p align=\"center\">\n 5</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 5</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Neutropenia</p>\n </td>\n <td>\n <p align=\"center\">\n 7</p>\n </td>\n <td>\n <p align=\"center\">\n 7</p>\n </td>\n <td>\n <p align=\"center\">\n 14</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Thrombocytopenia</p>\n </td>\n <td>\n <p align=\"center\">\n 3</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 3</p>\n </td>\n </tr>\n <tr>\n <td>\n <p>\n Gastrointestinal Disorders</p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Constipation</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Diarrhoea</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 2</p>\n </td>\n <td>\n <p align=\"center\">\n 3</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Hyperacidity</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Nausea</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Rectal prolapse</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Vomiting</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 5</p>\n </td>\n <td>\n <p align=\"center\">\n 6</p>\n </td>\n </tr>\n <tr>\n <td>\n <p>\n General Disorders and Administration Site Conditions</p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Hypothermia</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Puncture site pain</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Pyrexia</p>\n </td>\n <td>\n <p align=\"center\">\n 5</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 6</p>\n </td>\n </tr>\n <tr>\n <td>\n <p>\n Infections and Infestations</p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n <td>\n <p align=\"center\">\n  </p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Abscess</p>\n </td>\n <td>\n <p align=\"center\">\n 2</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 2</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Ascariasis</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Bronchopneumonia</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Conjunctivitis</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Fungal infection</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Herpes simplex</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Lower respiratory tract infection</p>\n </td>\n <td>\n <p align=\"center\">\n 2</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 2</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Malaria</p>\n </td>\n <td>\n <p align=\"center\">\n 12</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 12</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Otitis media</p>\n </td>\n <td>\n <p align=\"center\">\n 3</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 3</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Tinea capitis</p>\n </td>\n <td>\n <p align=\"center\">\n 4</p>\n </td>\n <td>\n <p align=\"center\">\n 0</p>\n </td>\n <td>\n <p align=\"center\">\n 4</p>\n </td>\n </tr>\n <tr>\n <td>\n <p style=\"margin-left:45.0pt;\">\n Tonsillitis</p
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2018-10-15 00:37:29
      • created2014-09-08 11:09:20
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id230
        • application_id322
        • given_nameRashid
        • middle_name
        • family_nameJuma
        • qualificationMBChB, MMed
        • professional_addressP.O. Box 20778 - 00202
        • telephone0202722541
        • emailjrashid@kemri.org
        • created2014-09-08 11:11:56
        • modified2015-02-27 18:11:17
    • SiteDetail(array)
      • 0(array)
        • id279
        • application_id322
        • county_id30
        • site_nameKimalel Health Centre
        • physical_addressBaringo
        • contact_detailsP.O. Box 139 30403
        • contact_personDr Rashid Juma
        • site_capacity(null)
        • misc(null)
        • created2014-09-08 11:11:56
        • modified2015-02-27 18:11:17
        • County(array)
          • id30
          • county_nameBaringo
          • created2012-06-15 10:25:39
          • modified2012-06-15 10:25:39
      • 1(array)
        • id280
        • application_id322
        • county_id24
        • site_nameKacheliba District Hospital
        • physical_addressNCPB Depot
        • contact_detailsP.O. Box Kacheliba
        • contact_personDr Rashid Juma
        • site_capacity(null)
        • misc(null)
        • created2014-09-08 11:43:28
        • modified2015-02-27 18:11:17
        • County(array)
          • id24
          • county_nameWest Pokot
          • created2012-06-15 10:24:52
          • modified2012-06-15 10:24:52
    • Sponsor(array)
      • 0(array)
        • id178
        • application_id322
        • sponsorDrugs for Neglected Disease initiative
        • sponsor_type(null)
        • contact_personDr Monique Wasunna
        • addressP.O. Box 20778 - 00202, Nairobi
        • telephone_number0202077767
        • fax_numberN/A
        • cell_number+254728373522
        • email_addressafrica@dndi.org
        • created2014-09-08 11:11:56
        • modified2015-02-27 18:11:17
  • 2(array)
    • Application(array)
      • id1278
      • user_id838
      • trial_status_id6
      • abstract_of_study<p>\n Invasive non-typhoidal <em>Salmonella</em> are an important cause of bacterial infections in sub-Saharan Africa and are associated with a high case fatality. Most cases are known to occur in children less than 5 years of age and are attributable to specific serovars. Detailed serotyping of iNTS isolates in Mali revealed that about 87% of all NTS invasive illnesses were caused by two Group B <em>Salmonella</em> serovars (<em>S</em>. Typhimurium and I:4,5,12:I) and two Group D serovars (<em>S</em>. Enteritidis and <em>S</em>. Dublin). This indicated that if an effective vaccine could be developed based on eliciting protection against Group B and D <em>Salmonella</em> serovars, it would be plausible to control this lethal pediatric infectious scourge by introducing a vaccine into the infant Expanded Program on Immunization (EPI) schedule. It was also noted that important risk factors for the development of serious iNTS infections included malaria infection accompanied by severe anemia, and immunocompromise due to untreated HIV infection. This implies that if one could administer a highly immunogenic vaccine against iNTS early in life, one could protect the infants, at a point when the risk of iNTS disease is greater. Therefore, a vaccine that can provide protection against these serovars and can be incorporated into the Expanded Program on Immunization could potentially control this lethal infection is urgently needed. </p>\n<p>\n This phase II trial will be an age-descending, randomized, placebo-controlled multicenter trial that will evaluate the safety and immunogenicity of a Trivalent <em>Salmonella </em>conjugate vaccine (TSCV). The trial will proceed from adults, to children, to toddlers, and then to infants. Individuals meeting the inclusion criteria will be randomly assigned to either receive TSCV, Typbar-TCV, or placebo. Venous blood will be collected for the measurement of serum-based immune response prior to vaccination (Day 1), 4 weeks (Day 29), 6 months (Day 181) after each study vaccination. Additional sample may be collected 1 year after study vaccination. Study participants who withdraw early or are lost to follow-up will have their immune response measures on available sera. In addition, memory B cells (B_M) specific for Vi, <em>S</em><em>. Typhimurium</em> and <em>S</em><em>. Enteritidis</em> LPS, as well as FliC and TT prior to vaccination (Day 1), 4 weeks (Day 29), and 6 months (Day 181) after each study vaccination will be measured. The duration of individual participation, including screening, ranges from 6 months to 18 months. The end-of-study is considered as the completion of the last visit for the last participant in the study.</p>\n<p>\n The Kenyan site will enroll up to 180 healthy participants per TSCV formulation group within this age range (12 weeks to 35 years) The study will provide information on efficacy, immunogenicity and safety of the selected formulation when administered to pediatric and adult participants.</p>\n
      • study_title<p>\n <strong>Age-descending, randomized, placebo-controlled Phase 2 trial in three sites in sub-Saharan Africa to assess the safety and immunogenicity of a parenteral Trivalent <em>Salmonella</em> (<em>S.</em> Enteritidis/<em>S.</em> Typhimurium/<em>S.</em> Typhi Vi) Conjugate Vaccine (TSCV) versus placebo</strong></p>\n
      • laymans_summary<p>\n <em>Why will be you do this study?</em></p>\n<p>\n Salmonella is a kind of bacteria that causes diarrhea and represents a public health problem in many countries. Children, especially infants, are most likely to get sick from it. This infection can be prevented by good hygiene practices and by vaccination. Information obtained from your participation in this study will inform on a vaccine that can provide protection against this infection and can be incorporated into the Expanded Program on Immunization could potentially control this lethal bacterial infection.</p>\n<p>\n  </p>\n<p>\n <em>What questions are we trying to answer?</em></p>\n<p>\n This study will evaluate stepwise a single dose of Full-strength and Half-strength Trivalent <em>Salmonella </em>Conjugate Vaccine (TSCV) administered to adults and then in progressively younger age groups down to 12 to 18 weeks of age, while comparing the safety and immunogenicity to controls who will receive Typbar-TCV™ or placebo. The trial will proceed from adults, to children, to toddlers, and then to infants.<br />\n  </p>\n<p>\n <em>Where is the study taking place?</em></p>\n<p>\n This study will take place in selected public hospitals in Kenya, Mali and Mozambique</p>\n<p>\n This study will aim to enroll healthy children and adults.<br />\n  </p>\n<p>\n <em>How many participants does it involve?</em></p>\n<p>\n This trial will enroll 180 healthy participants per TSCV formulation group within this age range.<br />\n  </p>\n<p>\n <em>How will they be selected?</em></p>\n<p>\n Participants in this study will be healthy individuals of both gender. Individuals with known hypersensitivity to any component of TSCV and previous vaccination with any licensed or experimental typhoid vaccine will be excluded. </p>\n<p>\n <em>What does the study involve for those taking part?</em></p>\n<p>\n Individuals taking part in this study will be carefully screened then randomly assigned to one of the groups to either receive the receive TSCV, Typbar-TCV, or placebo, then followed up. Blood samples will be collected from the study participants to measure how well the vaccines works, and measures the type of immune responses that the vaccine generates and their magnitude over time. <br />\n  </p>\n<p>\n <em>What are the risks and benefits of taking part?</em></p>\n<p>\n The participants in this study may experience some mild localized pain at the injection site, mild fatigue post-vaccination, vomiting, redness and swelling at the injection site, excessive crying, loss of appetite, irritability, headache, common cold, diarrhea and nausea and vomiting. These symptoms typically resolve in 48 hours. </p>\n<p>\n The study participants may benefit by taking part in this study since randomly allocated study participants will receive a dose of the vaccine and thus will benefit from protection against typhoid fever.<br />\n  </p>\n<p>\n <em>How will the study benefit society?</em></p>\n<p>\n The findings from this study will provide science-based evidence for the need of a vaccine formulation that can provide protection against this lethal infection and can be incorporated into the Expanded Program on Immunization could potentially control this lethal bacterial infection.<br />\n  </p>\n<p>\n <em>When does the study start and finish?</em></p>\n<p>\n This project is planned to start enrollment in March 2023 and to end recruitment in December 2025.</p>\n
      • short_titleTSCV3000
      • protocol_noECCT/23/06/08
      • version_no3.0
      • date_of_protocol30-05-2023
      • study_drugTrivalent Salmonella Conjugate Vaccine (TSCV)
      • disease_conditionInvasive non-typhoidal Salmonella
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines1
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameTyphoid conjugate vaccine (TCV)
      • comparator_registeredYes
      • comparator_countriesLiberia, Zimbabwe, Bangladesh, Burkina Faso, Malawi, and Nepal.
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressomorerichard@gmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_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_applicantRichard Omore
      • declaration_date130-06-2023
      • declaration_principal_investigatorRichard Omore
      • declaration_date230-06-2023
      • placebo_presentYes
      • study_objectives<p>\n 1.     To evaluate the safety and reactogenicity of two, Full-strength and Half-strength, GMP formulations of Trivalent <em>Salmonella </em>(<em>S</em>. Enteritidis/<em>S</em>. Typhimurium/<em>S</em>. Typhi Vi) Conjugate Vaccine (TSCV) administered as a single dose to adults, children, toddlers, and infants in sub-Saharan Africa (sSA), and as two spaced doses (a priming dose at age ~ 12-18 weeks of age and a booster at either 9, 12, or 15-17 months of age), in comparison to Typbar-TCV™ and to placebo.</p>\n<p>\n 2.     To select one of the two formulations of TSCV for further clinical development based on non-inferiority comparisons of the immune response to both COPS antigens following a single dose, a satisfactory safety/reactogenicity profile, and non-inferiority of the Vi antibody responses compared to Typbar-TCV™.</p>\n<p>\n 3.     To evaluate the safety, reactogenicity, and immunogenicity of the selected TSCV formulation given as a priming dose to young infants (age 12-18 weeks) who subsequently receive a booster dose of TSCV at age 9, 12, or 15 months. Immunogenicity will be assessed as the seroconversion rate, geometric mean titer, and geometric mean-fold rise of IgG ELISA antibody to <em>S</em>. Enteritidis and <em>S</em>. Typhimurium COPS, and Typhi Vi, comparing baseline versus the post-vaccination timepoints.</p>\n
      • principal_inclusion_criteria<p>\n a.     Healthy individuals, female or male</p>\n<p>\n b.     Age (all age ranges are inclusive)</p>\n<p>\n                i.         Step 1A: Adults 20-35 years of age</p>\n<p>\n              ii.         Step 1B: Children, 5-9 years of age</p>\n<p>\n             iii.         Step 1 C: Pre-school children, 24-59 mos. of age</p>\n<p>\n             iv.         Step 1D: Older toddlers, 16-23 months of age </p>\n<p>\n               v.         Step 2A: Young toddlers, 12-16 months of age</p>\n<p>\n             vi.         Step 2B: Older infants, 8-11 months of age</p>\n<p>\n           vii.         Step 3: Young infants,12-14 weeks of age OR 16-18 weeks of age</p>\n<p>\n          viii.         Step 4: Young infants, 12-18 weeks of age</p>\n<p>\n c.     For potential pediatric participants, the parents must live within the catchment area of the clinical study facility at the time of the study vaccinations and must intend to continue to reside in the area for the duration of the study </p>\n<p>\n d.     Adult study participants and parents/ guardians of pediatric study participants must have provided informed consent</p>\n<p>\n e.     Infant and toddler study participants in Steps 2, 3, and 4 must have received their scheduled EPI vaccines at least 14 days prior to receiving a study product. </p>\n
      • principal_exclusion_criteria<p>\n a.     A history of documented hypersensitivity to any component of the Trivalent <em>Salmonella</em> Conjugate Vaccine or of Typbar-TCV™</p>\n<p>\n b.     A history of previous vaccination with any licensed or experimental typhoid vaccine</p>\n<p>\n c.     History of a severe allergic reaction such as anaphylaxis, generalized urticaria, or angioedema</p>\n<p>\n d.     A known history of diabetes, tuberculosis, malignancy, chronic kidney disease, cardiac disease, liver disease, progressive neurological disorder, poorly controlled seizure disorder, or a terminal illness based on participant interview and review of screening laboratory results.</p>\n<p>\n e.     Severe malnutrition: i.e., weight-for-length Z-score of less than – 3.</p>\n<p>\n f.      Receipt of any other investigational intervention in the last 6 months</p>\n<p>\n g.     Known HIV infection or other forms of immunocompromise</p>\n<p>\n h.     Receipt of systemic immunosuppressive medication including systemic corticosteroids</p>\n<p>\n i.      For Step 1A, for females of child-bearing potential, a positive pregnancy test at the time of enrollment.</p>\n<p>\n j.      For Step 1B, any female child who has experienced menarche.</p>\n<p>\n k.     Acute illness with or without fever (temperature >37.5^oC) is a temporary exclusion criterion. Enrollment may be postponed until 3 days after the illness has resolved.</p>\n<p>\n l.      Positive malaria test is a temporary exclusion criterion. Participant may be enrolled 3 days after completing treatment.</p>\n<p>\n m.   Any condition determined by the investigators to be likely to interfere with evaluation of the vaccine, to be a significant health risk to the participant, or to make it unlikely that the participant would complete the study</p>\n
      • primary_end_points<ol>\n <li style=\"text-align: justify;\">\n <p>\n The proportion of participants in each product group and within each age group who develop adverse events (AEs) in the first 30 minutes after parenteral immunization and over 7 days post-vaccination.</p>\n </li>\n <li style=\"margin-left: 21.3pt; text-align: justify;\">\n <p>\n The proportion of participants who experience AEs through Day 29 of follow-up post-vaccination.</p>\n </li>\n <li style=\"text-align: justify;\">\n <p>\n The proportion of participants who experience Serious Adverse Events through their participation in the study</p>\n </li>\n <li style=\"text-align: justify;\">\n <p>\n Serum IgG anti-COPS antibodies (to both <em>S</em>. Enteritidis and <em>S</em>. Typhimurium antigens)</p>\n </li>\n <li style=\"text-align: justify;\">\n <p>\n Serum IgG anti-Vi antibodies </p>\n </li>\n <li style=\"text-align: justify;\">\n <p>\n The sera to be compared for non-inferiority will derive from subjects in Steps 1C and 1D, Step 2 and Step 3.</p>\n </li>\n</ol>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyPhase II
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n <img alt=\"page1image59082992\" height=\"82.500000\" src=\"blob:https://ctr.pharmacyboardkenya.org/46c70366-7185-473b-b360-3f766ea05968\" style=\"caret-color: rgb(0, 0, 0); color: rgb(0, 0, 0);\" width=\"138.000000\" /></p>\n<div class=\"page\" style=\"caret-color: rgb(0, 0, 0); color: rgb(0, 0, 0);\" title=\"Page 1\">\n <div class=\"layoutArea\">\n <div class=\"column\">\n <p>\n <span style=\"font-size: 7pt; font-family: Calibri;\">CP1929 – Moçambique –</span></p>\n <p>\n <span style=\"font-size: 12pt; font-family: Arial; font-weight: 700;\">Letter of support to carry out research activities</span></p>\n </div>\n <div class=\"column\">\n <p>\n <span style=\"font-size: 12pt; font-family: ArialMT;\">Manhiça, 05</span><span style=\"font-size: 8pt; font-family: ArialMT; vertical-align: 4pt;\">th </span><span style=\"font-size: 12pt; font-family: ArialMT;\">May, 2023</span></p>\n </div>\n </div>\n <div class=\"layoutArea\">\n <div class=\"column\">\n <p>\n <span style=\"font-size: 12pt; font-family: Arial; font-weight: 700;\">Study: </span><span style=\"font-size: 12pt; font-family: ArialMT;\">“Age-descending, randomized, placebo-controlled Phase 2 trial in three sites in sub-Saharan Africa to assess the safety and immunogenicity of a parenteral Trivalent </span><span style=\"font-size: 12pt; font-family: Arial; font-style: italic;\">Salmonella </span><span style=\"font-size: 12pt; font-family: ArialMT;\">(</span><span style=\"font-size: 12pt; font-family: Arial; font-style: italic;\">S. </span><span style=\"font-size: 12pt; font-family: ArialMT;\">Enteritidis/</span><span style=\"font-size: 12pt; font-family: Arial; font-style: italic;\">S. </span><span style=\"font-size: 12pt; font-family: ArialMT;\">Typhimurium/</span><span style=\"font-size: 12pt; font-family: Arial; font-style: italic;\">S. </span><span style=\"font-size: 12pt; font-family: ArialMT;\">Typhi Vi) Conjugate Vaccine (TSCV) versus placebo</span></p>\n <p>\n <span style=\"font-size: 12pt; font-family: ArialMT;\">This is to confirm that the Centro de Investigação em Saúde de Manhiça (CISM) has been conducting research for more than 25 years, therefore the accumulated experience will facilitate the implementation of the current project. The laboratory is well equipped with facilities needed to successfully carry out clinical trials and basic research studies. The laboratory is organized into the following areas: clinical analyses (hematic parasitology and hematology/biochemistry); microbiology (general bacteriology and mycobacteriology); immunology; molecular biology; and quality assurance & biosafety. All laboratories have periodic audits and receives external quality control assessment. The lab facility is built with level 2 biosafety level including a level 3 for TB. Parasitology: This area performs malaria diagnosis by optical microscopy. It provides diagnostic support to the Manhiça District Hospital and to the other health facilities in the study area, seven days a week, performing semi- quantitative and quantitative readings of the slides. The microbiology lab including TB are specialized for culture, isolation and identification of bacterial pathogens, antimicrobial resistance testing. The immunology lab is specialized for cell isolation (human peripheral blood mononuclear cells – PBMC), identification of immunological markers and cryopreservation in liquid nitrogen (NL2). In the molecular biology lab, there is the entire infrastructure needed to perform DNA-based detection platforms. The Lab is currently ISO 15189 accredited for competence and quality. The Lab is also equipped with a room for storage of samples in 4oC fridges and -20oC / -80oC freezers with more than 10 each.</span></p>\n <p>\n <span style=\"font-size: 12pt; font-family: ArialMT;\">Additionally, our clinical facilities comprised a dedicated building with four rooms for subject examination, vaccine administration and laboratory room for sample collection; a part of a designated front porch as waiting area for subjects to be screened and for observation post vaccine / drug administration. There three Medical doctors full time dedication for the trials supported by other clinicians (e.g. nurse, medical technician)</span></p>\n <p>\n <span style=\"font-size: 12pt; font-family: ArialMT;\">Sincerely,</span></p>\n <p>\n <span style=\"font-size: 12pt; font-family: ArialMT;\">Inácio Mandomando, PhD Site Principal Investigator</span></p>\n </div>\n </div>\n <img alt=\"page1image59093184\" height=\"54.749990\" src=\"blob:https://ctr.pharmacyboardkenya.org/681ff70d-cbcf-4a96-b12e-03adc0bef6d6\" width=\"157.466900\" />\n <div class=\"layoutArea\">\n <div class=\"column\">\n <p>\n <span style=\"font-size: 7pt; font-family: Calibri;\">CP1929 – Moçambique – Tel/Fax (+258) 21810002 – Tel. (+258) 21810181 – Cel. (+258) 823168530 – </span><span style=\"font-size: 7pt; font-family: TimesNewRomanPSMT; color: rgb(0, 0, 255);\">www.cismmanhica.org</span></p>\n </div>\n </div>\n <img alt=\"page1image59081120\" height=\"0.240000\" src=\"blob:https://ctr.pharmacyboardkenya.org/57a93640-2ca3-4b91-9f2a-b3d9c3b1c519\" width=\"64.800000\" /></div>\n<div class=\"page\" style=\"caret-color: rgb(0, 0, 0); color: rgb(0, 0, 0);\" title=\"Page 2\">\n <img alt=\"page2image59251200\" height=\"79.399941\" src=\"blob:https://ctr.pharmacyboardkenya.org/ea9dcc63-eb4e-4252-a3d0-1ca6a36895a2\" width=\"81.967000\" />\n <div class=\"layoutArea\">\n <div class=\"column\">\n <p>\n <span style=\"font-size: 12pt; font-family: LucidaSansUnicode;\">CENTRE POUR LE DEVELOPPEMENT DES VACCINS, MALI</span></p>\n <p>\n <span style=\"font-size: 12pt; font-family: LucidaSansUnicode;\">Projet des Maladies Infectieuses</span></p>\n <p>\n <span style=\"font-size: 10pt; font-family: LucidaSansUnicode;\">Directeur Général : Samba Ousmane SOW, M.D., M.Sc., FASTMH. </span><span style=\"font-size: 8pt; font-family: LucidaSansUnicode;\">Professor of Medicine</span></p>\n <p>\n <span style=\"font-size: 8pt; font-family: LucidaSansUnicode;\">Projet des Maladies Infectieuses : Measles Vaccine Initiative </span><span style=\"font-size: 8pt; font-family: SymbolMT;\">♦ </span><span style=\"font-size: 8pt; font-family: LucidaSansUnicode;\">Enteric Disease Project </span><span style=\"font-size: 8pt; font-family: SymbolMT;\">♦</span><span style=\"font-size: 8pt; font-family: LucidaSansUnicode;\">Pneumococcus, Meningococcus, & Haemophilus influenzae Prevention Program</span></p>\n </div>\n </div>\n <img alt=\"page2image59257648\" height=\"3.000000\" src=\"blob:https://ctr.pharmacyboardkenya.org/46dba676-2e91-486f-9fbb-322bba857cfe\" width=\"471.000000\" />\n <div class=\"layoutArea\">\n <div class=\"column\">\n <p>\n <span style=\"font-size: 8pt; font-family: LucidaSansUnicode;\">Projet de Paludism : Bandiagara Malaria Project </span><span style=\"font-size: 8pt; font-family: SymbolMT;\">♦ </span><span style=\"font-size: 8pt; font-family: LucidaSansUnicode;\">Malaria Training Program </span><span style=\"font-size: 10pt; font-family: Corbel; font-weight: 700;\">To whom it may concern.</span></p>\n <p>\n <span style=\"font-size: 10pt; font-family: Corbel; font-weight: 700;\">Letter of Support to carry Out Research</span></p>\n <p>\n <span style=\"font-size: 10pt; font-family: Corbel; font-weight: 700;\">Study: “Age-descending, randomized, placebo-controlled Phase 2 trial in three sites in sub-Saharan Africa to assess the safety and immunogenicity of a parenteral Trivalent Salmonella (S. Enteritidis/S. Typhimurium/S. Typhi Vi) Conjugate Vaccine (TSCV) versus placebo</span><br />\n <span style=\"font-size: 10pt; font-family: Corbel;\">The Center for Vaccine Development (CVD)- Mali, has extensive experience in conducting of clinical studies and vaccine trials including for Ebola, Rotavirus, Influenza in pregnant women, efficacy of oral azithromycin in preventing stillbirths and mortality in Mali, mass drug administration of azithromycin, assessment of sexual and reproductive health, and child health and mortality prevention surveillance as part of multi-country activities performed in sub- Saharan Africa, South Asia and other parts of the world.</span></p>\n <p>\n <span style=\"font-size: 10pt; font-family: Corbel;\">Established in 2001, CVD-Mali is a research organization that focuses on research and interventions which develop primary health care, to pave the way towards Universal Health Coverage. Our core principles are based around strong technical capacity in epidemiologic surveillance, laboratory capability and clinical trials making us well- positioned to complete the above proposed research.</span></p>\n <p>\n <span style=\"font-size: 10pt; font-family: Corbel;\">CVD-Mali has followed a systematic process in developing its research capacity through epidemiologic field studies, laboratory training and infrastructure, and clinical trials. We have conducted key clinical trials of vaccines that have influenced policy at country and global level - including studies of rotavirus vaccine, meningitis vaccine, influenza vaccine and Ebola vaccines. CVD-Mali has a demographic surveillance system with a population of over 200,000 people, which has served as an important basis for several epidemiologic studies and clinical trials. For example, CVD-Mali has partnered on large studies of diarrheal burden (GEMS) and pneumonia burden (PERCH) using state-of- the art laboratory technologies, including multiplex polymerase chain reaction assays, immunoassay, and bacteriology. We have several new, exciting initiatives in partnership with internationally recognized research and training institutions.</span></p>\n <p>\n <span style=\"font-size: 10pt; font-family: Corbel;\">This study will provide the platform to develop clinical and laboratory site capacity across African countries to conduct future clinical trial studies. The appropriate programmatic and administrative personnel involved in this grant application are aware of the sponsor’s consortium grant policy and are prepared to establish the necessary inter-institutional agreement(s) consistent with that policy. Please forward any documentation of a contractual nature to my attention.</span></p>\n <p>\n <span style=\"font-size: 10pt; font-family: Corbel;\">If you should have any questions, please do not hesitate to contact me via email at ssow@cvd-mali.org. Sincerely,</span></p>\n <p>\n <span style=\"font-size: 10pt; font-family: Corbel; font-weight: 700;\">Prof. Samba O. Sow, </span><span style=\"font-size: 10pt; font-family: TimesNewRomanPS; font-weight: 700;\">MD, MSc, FASTMH </span><span style=\"font-size: 8pt; font-family: TimesNewRomanPS; font-style: italic;\">Commandeur de l’Ordre National du Mali</span></p>\n <p>\n <span style=\"font-size: 6pt; font-family: LucidaSansUnicode;\">CENTRE POUR LE DEVELOPPEMENT DES VACCINS (CVD-MALI) MINISTERE DE LA SANTE ET DE L’HYGIENE PUBLIQUE INSTITUT MARCHOUX, BP 251, BAMAKO, MALI</span></p>\n <p>\n <span style=\"font-size: 6pt; font-family: LucidaSansUnicode;\">Téléphone + (223) 20 23 60 31 Fax (223) 20 22 28 83</span></p>\n <p>\n <span style=\"font-size: 8pt; font-family: LucidaSansUnicode; color: rgb(0, 0, 255);\">ssow@medicine.umaryland.edu /ssow@cvd-mali.org www.cvd-mali.org</span></p>\n </div>\n </div>\n <div class=\"layoutArea\">\n <div class=\"column\">\n <p>\n <span style=\"font-size: 9pt; font-family: Corbel;\">May 16, 2023</span></p>\n </div>\n </div>\n <img alt=\"page2image59260144\" height=\"48.810600\" src=\"blob:https://ctr.pharmacyboardkenya.org/83a97730-bb93-4a2b-8b8d-0ef187ac8164\" width=\"92.197800\" /> <img alt=\"page2image42615344\" height=\"0.360000\" src=\"blob:https://ctr.pharmacyboardkenya.org/31d94db9-9678-4aa7-9683-d65f08433c00\" width=\"204.720000\" /> <img alt=\"page2image59255568\" height=\"0.360000\" src=\"blob:https://ctr.pharmacyboardkenya.org/52365748-7729-407b-a291-5bd90a18e50f\" width=\"71.160000\" /></div>\n<p>\n  </p>\n
      • other_details_explanation<p>\n <span style=\"font-size:14px;\"><span style=\"font-family:times new roman,times,serif;\"><span style=\"color: black;\">The isolation of </span><i font-size:=\"\" new=\"\" style=\"color: black; font-family: \" times=\"\">S. pneumoniae</i><span style=\"color: black;\"> from blood cultures and serotyping of the isolates was critical not only to estimate the magnitude of the burden of Hib and pneumococcal disease (with a view to future introduction of conjugate vaccines) but also to assess whether the 7-valent serotype composition of the pneumococcal conjugate vaccine formulations used in high-income countries would also be relevant for sub-Saharan Africa.</span>Importantly, the infants, toddlers and young children with bacteremia, septicemia, purulent meningitis, and other focal purulent infections caused by NTS were found to be clinically indistinguishable from children with Hib and pneumococcal infections.</span></span></p>\n<p>\n  </p>\n
      • other_details_regulatory_notapproved<p>\n NACOSTI</p>\n
      • other_details_regulatory_approved<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:times new roman,times,serif;\">KEMRI SERU Approved on April 27, 2023</span></span></p>\n<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:times new roman,times,serif;\">COMITÉ NACIONAL DE BIOÉTICA PARA ASAÚDE Approved on May 9, 2023</span></span></p>\n<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:times new roman,times,serif;\">UNIVERSITE DES SCIENCES,DES TECHNIQUES ET DES TECHNOLOGIES DE BAMAKO Approved on March 22, 2023</span></span></p>\n<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:times new roman,times,serif;\"><span style=\"caret-color: rgb(0, 0, 0); color: rgb(0, 0, 0);\">University of Maryland, Baltimore (UMB) IRB Approved on April 3, 2023</span></span></span></p>\n<p>\n  </p>\n
      • other_details_regulatory_rejected<p>\n NONE</p>\n
      • other_details_regulatory_halted<p>\n NA</p>\n
      • estimated_duration3 YEARS
      • 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_comparatorTypbar-TCV
      • design_controlled_other_medicinalYes
      • 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_countriesYes
      • multiple_member_states3
      • number_of_sites2
      • multi_country_listMALI\nMOZAMBIQUE\nKENYA
      • data_monitoring_committeeYes
      • total_enrolment_per_site1216
      • total_participants_worldwide1256
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenYes
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameRICHARD
      • investigator1_middle_nameONYANDO
      • investigator1_family_nameOMORE
      • investigator1_qualificationPHD
      • investigator1_professional_addressKEMRI CGHR P.O BOX 1578 KISUMU
      • investigator1_telephone+254728813788
      • investigator1_emailomorerichard@gmail.com
      • organisations_transferred_Yes
      • number_participants1216
      • notification<p>\n NO ADDITIONAL INFORMATION AT THIS TIME.</p>\n<p>\n IF ANY INFORMATION BECOMES AVAILABLE, WE WILL NOTIFY THE KPPB.</p>\n
      • approval_date25-09-2023
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted30-06-2023
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • 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)
      • modified2025-10-08 11:36:38
      • created2023-06-05 12:35:38
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id935
        • application_id1278
        • given_nameRICHARD
        • middle_nameONYANDO
        • family_nameOMORE
        • qualificationPHD
        • professional_addressKEMRI CGHR P.O BOX 1578 KISUMU
        • telephone+254728813788
        • emailronyando@kemri.go.ke, omorerichard@gmail.com
        • created2023-06-05 13:07:29
        • modified2023-06-30 15:40:57
    • SiteDetail(array)
      • 0(array)
        • id1509
        • application_id1278
        • county_id41
        • site_nameSIAYA COUNTY REFERRAL HOSPITAL
        • physical_addressHospital Road Siaya Township Alego Usonga
        • contact_detailsP.O BOX 144 SIAYA TEL 0758 721993
        • contact_personRICHARD OMORE
        • site_capacity(null)
        • misc(null)
        • created2023-06-05 13:07:29
        • modified2023-06-30 15:40:57
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 1(array)
        • id1540
        • application_id1278
        • county_id41
        • site_nameST. ELIZABETH LWAK HOSPITAL
        • physical_addressLWAK, UYOMA
        • contact_details+254 723 592381
        • contact_personST. JANE MBORI
        • site_capacity(null)
        • misc(null)
        • created2023-06-30 15:17:06
        • modified2023-06-30 15:40:57
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
    • Sponsor(array)
      • 0(array)
        • id669
        • application_id1278
        • sponsorUniversity of Maryland, Baltimore
        • sponsor_typeOthers
        • contact_personMilagritos D. Tapia, MD
        • addressCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
        • telephone_number+1(410) 706-5328
        • fax_number+1(410) 706-6205
        • cell_number+1(410) 706-5328
        • email_addressMTAPIA@som.umaryland.edu
        • created2023-06-05 13:07:29
        • modified2023-06-30 15:40:57
  • 3(array)
    • Application(array)
      • id761
      • user_id21
      • trial_status_id6
      • abstract_of_study<div>\n <p style=\"margin-left:1.5in;\">\n <u>DESIGN</u>                      A Phase III, open-label, multicenter trial with a cluster-randomized superiority design (eligible contacts in the same household [HH] are a cluster), to compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for preventing confirmed or probable active TB during 96 weeks of follow-up among high-risk household contacts (HHCs) of adults with multidrug-resistant tuberculosis (MDR-TB). High-risk HHCs are those with HIV or non-HIV immunosuppression, latent TB infection, and young children below the age of 5 years.</p>\n <p style=\"margin-left:1.5in;\">\n Each site will have a run-in phase, where the site will demonstrate feasibility to identify adults with MDR-TB (index cases), access their HHs, screen HHCs, and enroll and follow eligible HHCs.</p>\n <p style=\"margin-left:1.5in;\">\n <u>DURATION</u>                 96 weeks for each participating HHC and index case.</p>\n <p style=\"margin-left:1.5in;\">\n <u>SAMPLE SIZE</u>            The preliminary estimate of the required sample size is 3452 high-risk HHCs to be enrolled from 1726 HHs with an index case confirmed as having MDR-TB (assuming a mean of two eligible contacts per HH). It is anticipated that about 20% of index cases enrolled won’t be from HHs with eligible high-risk HHCs, therefore, the number of index cases enrolled will be larger than 1726, and will be approximately 2158. Therefore, there will be approximately 5610 participants enrolled (approximately 2158 index cases and 3452 HHCs).</p>\n <p style=\"margin-left:1.5in;\">\n <u>RANDOMIZATION</u>     Randomization will be <strong>balanced</strong> by site with approximately equal numbers of HHs allocated to each of the study arms and no restriction on the number of HHs enrolled per site.</p>\n <p style=\"margin-left:1.5in;\">\n <u>POPULATION</u>            An index case is defined as an adult (18 years and older) with pulmonary MDR-TB who has started MDR-TB treatment within the past 90 days.</p>\n <p style=\"margin-left:1.5in;\">\n An HHC is defined as a person who currently lives or lived in the same dwelling unit or plot of land and shares or has shared the same housekeeping arrangements as the index case and who reports exposure within 90 days prior to the index case starting MDR-TB treatment. Also, shared >4 hours of indoor airspace with the index case during a<strong>ny</strong> one-week period prior to the index case starting MDR-TB treatment.</p>\n <p style=\"margin-left:1.5in;\">\n Following enrollment of an eligible index case with permission to complete an HH visit, HHCs will be screened for eligibility.</p>\n <p style=\"margin-left:1.5in;\">\n Only HHCs of index cases who are at high risk of developing TB will be enrolled into the study:</p>\n <ul style=\"margin-left: 120px;\">\n <li>\n Children 0 to <5 years of age regardless of tuberculin skin test (TST)/interferon gamma release assay (IGRA), or HIV status;</li>\n <li>\n Adults, adolescents, and children ≥5 years of age who are TST-positive (≥5 mm) and/or IGRA-positive and whose HIV status is negative, indeterminate, or unknown and who are not non-HIV immunosuppressed;</li>\n <li>\n Adults, adolescents, and children ≥5 years of age who are HIV-infected or are non-HIV immunosuppressed (defined as receiving anti-tumor necrosis factor (TNF) treatment, or being solid organ or hematologic transplant recipients), regardless of TST/IGRA status.</li>\n </ul>\n <p style=\"margin-left:1.5in;\">\n <u>REGIMEN</u>                   If at least one HHC within an HH is found to be eligible, the HH will be randomized in approximately equal numbers, to one of the following:</p>\n <p style=\"margin-left:1.5in;\">\n Arm A:</p>\n <ul style=\"margin-left: 120px;\">\n <li>\n DLM daily for adults, adolescents, and children, given for 26 weeks</li>\n </ul>\n <p style=\"margin-left:1.5in;\">\n Arm B:</p>\n <ul style=\"margin-left: 120px;\">\n <li>\n INH daily for adults, adolescents, and children, given for 26 weeks  </li>\n <li>\n Pyridoxine (vitamin B6) daily for adults, adolescents, and children, given for 26 weeks</li>\n </ul>\n <p style=\"margin-left:1.5in;\">\n All high-risk HHCs in the same HH will receive the same randomized regimen.</p>\n</div>\n<p>\n  </p>\n
      • study_title<p>\n <strong>A5300B/I2003B/PHOENIx</strong><strong><u> "P</u>rotecting <u>H</u>ouseholds <u>O</u>n <u>E</u>xposure to <u>N</u>ewly Diagnosed <u>I</u>nde<u>x</u> Multidrug-Resistant Tuberculosis Patients"</strong></p>\n
      • laymans_summary<p style=\"margin-left:18.0pt;\">\n This is a phase III, open-label, multicenter trial with a cluster-randomized superiority design (eligible contacts in the same household [HH] are a cluster), to compare the efficacy and safety of 26 weeks of delamanid (DLM) versus 26 weeks of isoniazid (INH) for preventing confirmed or probable active TB during 96 weeks of follow-up among high-risk household contacts (HHCs) of adults with multidrug-resistant tuberculosis (MDR-TB). High-risk HHCs are those with HIV or non-HIV immunosuppression, latent TB infection, and young children below the age of 5 years</p>\n<p>\n The hypothesis is that treating child, adolescent, and adult household contacts (HHCs) of multidrug-resistant tuberculosis (MDR-TB) patients, including those with pre-extensively (pre-XDR) and extensively drug resistant (XDR) TB, who are at high risk of developing TB with delamanid (DLM), will substantially reduce the risk of developing TB compared with treatment with isoniazid (INH) preventive therapy.</p>\n<p>\n The 2 primary objectives are to 1) compare the efficacy of 26 weeks of DLM versus 26 weeks of INH for preventing confirmed or probable active TB during 96 weeks of follow and 2) To compare the safety (permanently stopping study drug due to treatment-related adverse events) of 26 weeks of DLM versus 26 weeks of INH for the treatment of presumed latent TB infection (LTBI) with MDR-TB.</p>\n
      • short_titlePHOENIx MDR-TB
      • protocol_noECCT/19/04/05
      • version_no2.0
      • date_of_protocol25-09-2018
      • study_drugDelamanid
      • disease_conditionMDR-TB Prophylaxis
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals1
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_nameDelamanid
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameIsoniazid
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressaksudoi@hotmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries1
      • applicant_addendum1
      • 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_applicantAllan Sudoi
      • declaration_date112-04-2019
      • declaration_principal_investigatorProf Abraham Siika
      • declaration_date212-04-2019
      • placebo_presentNo
      • study_objectives<p>\n <strong> Primary Objectives: </strong></p>\n<p>\n Among HIV-infected and other child, adolescent, and adult HHCs of MDR-TB patients at high risk of developing TB:</p>\n<ul>\n <li>\n To compare the efficacy of 26 weeks of DLM versus 26 weeks of INH for preventing confirmed or probable active TB during 96 weeks of follow-up.</li>\n <li>\n To compare the safety (permanently stopping study drug due to treatment-related adverse events) of 26 weeks of DLM versus 26 weeks of INH for the treatment of presumed latent TB infection (LTBI) with MDR-TB.</li>\n</ul>\n<p>\n  </p>\n<p>\n <strong>Secondary Objectives:</strong></p>\n<ul>\n <li>\n To compare the efficacy and safety of DLM versus INH for preventing confirmed or probable TB in HHCs of MDR-TB patients by their HIV status (i.e., HIV-infected vs HIV-negative, indeterminate, or have unknown HIV status).</li>\n <li>\n To compare the efficacy and safety of DLM versus INH for preventing confirmed or probable TB in each of the three high risk populations of HHCs enrolled (i.e., children aged <5 years; HIV-infected or non-HIV immunosuppressed adults, adolescents, and children ≥5 years; TST+ and/or IGRA+ adults, adolescents, and children aged ≥5 years who are HIV-negative, indeterminate, or have unknown HIV status and are not non-HIV immunosuppressed).</li>\n <li>\n To compare the efficacy of DLM versus INH for preventing confirmed active MDR-TB.</li>\n <li>\n To compare the efficacy of DLM versus INH in reducing all-cause mortality.</li>\n <li>\n To compare the efficacy of DLM versus INH for reducing the composite outcome of confirmed or probable TB and all-cause mortality.</li>\n <li>\n To compare the proportions of Grades 3 or higher events among HHCs receiving DLM versus INH.</li>\n <li>\n To compare the drug-susceptibility pattern and whole genome sequence of the index case to that of confirmed incident TB cases among HHCs.</li>\n <li>\n To evaluate factors, including index case characteristics, index case TB status at the end of HHC study treatment, household characteristics, and characteristics of HHCs, HHC medication adherence, and pharmacokinetic (PK) measures<strong>,</strong> as predictors of the risk of confirmed or probable TB among HHCs or possible modifiers of the difference in risk between randomized arms.</li>\n <li>\n To describe the PK and safety of DLM administered once daily in children, 0 to <5 years old.</li>\n</ul>\n
      • principal_inclusion_criteria<p>\n The detailed inclusion and exclusion criteria is contained in section 4.1 and 4.2 of the protocol. This is on page 50 to 56 of the protocol version 2.0 dated Sep 25, 2018.</p>\n
      • principal_exclusion_criteria<p>\n The detailed inclusion and exclusion criteria is contained in section 4.1 and 4.2 of the protocol. This is on page 50 to 56 of the protocol version 2.0 dated Sep 25, 2018.</p>\n
      • primary_end_points<p dir=\"rtl\" style=\"margin-right: 1in; text-align: left;\">\n <u>Efficacy</u></p>\n<p dir=\"rtl\" style=\"margin-right: 1in; text-align: left;\">\n The primary outcome measure is the occurrence of confirmed or probable active TB at any time between Day 0 (defined in <a href=\"#S622\">section 6.2.2</a>) and the week 96 study visit (see ACTG Diagnosis Appendix 100 for adults, adolescents, and children ≥15 years of age or A5300B/I2003B/PHOENIx MOPS for modified pediatric definitions for children <15 years of age). This will be evaluated at the individual participant level.</p>\n<p dir=\"rtl\" style=\"margin-right: 1in; text-align: left;\">\n An independent outcomes review committee will review diagnoses of active TB made by the participating sites and deaths. This committee will include clinicians who are experts in the diagnosis of TB in adults, adolescents, and children. The committee will not include members who are directly involved with the care of study participants or who are study team members providing <strong>participant </strong>management guidance to site investigators. The committee will be blinded to treatment assignment. Only confirmed and probable active TB cases that are validated by the independent outcomes review committee will be included in the primary efficacy analysis. The independent outcomes review committee will also determine the date that a HHC first met the criteria for confirmed or probable active TB.</p>\n<p dir=\"rtl\" style=\"margin-right: 1in; text-align: left;\">\n  </p>\n<p dir=\"rtl\" style=\"margin-right: 1in; text-align: left;\">\n <u>Safety</u></p>\n<p dir=\"rtl\" style=\"text-align: left;\">\n The primary safety outcome measure is the permanent discontinuation of randomized study drug (DLM or INH) due to a treatment-related adverse event (i.e., requiring discontinuation as defined in <a href=\"#S8\">section 8.0</a>, or in the opinion of the site investigator is a treatment-limiting adverse event). This will be evaluated at the individual participant level.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<ol>\n <li>\n Prof. Abraham M. Siika                                 Site Leader/Principal Investigator</li>\n <li>\n Dr. David K. Lagat                                         Sub-investigator</li>\n <li>\n Dr Edith Apondi                                             Sub-investigator</li>\n <li>\n Priscilla Cheruiyot                                        Study Coordinator</li>\n <li>\n Irene Kutto                                                     Study Clinician          </li>\n <li>\n Michael Tanui                                                Study Clinician                      </li>\n <li>\n Agnes Nzioka                                                 Study Clinician</li>\n <li>\n Betty Meli                                                       Study Clinician</li>\n <li>\n Chris Sande Mboya                                       Study Nurse</li>\n <li>\n Allan Sudoi                                                     Regulatory Affairs Coordinator</li>\n <li>\n Viola Kirui                                                       Quality Assurance/Control officer</li>\n <li>\n Cecilia Chebet                                                Recruitment officer</li>\n <li>\n Julie Choge                                                     Recruitment officer</li>\n <li>\n Amina Msuo Shali                                         Recruitment officer</li>\n <li>\n Martha Mokaya                                             Data manger</li>\n <li>\n Wilson Ekiru                                                  Assistant data manger</li>\n <li>\n Kennedy Kenina                                            Assistant data manger           </li>\n <li>\n Simon W. Njuguna                                        Pharmacist of record</li>\n <li>\n Beatrice Jakait                                               Backup pharmacist</li>\n <li>\n Salina Cherutich                                            Pharmaceutical technologist</li>\n <li>\n Peter Rutto                                                    Phlebotomist</li>\n <li>\n Millicent Orido                                              AMPATH Reference Lab</li>\n <li>\n Ibrahim Daud                                               AMPATH Reference Lab</li>\n <li>\n Alice Mudogo                                               AMPATH Reference Lab</li>\n <li>\n Ronald Odero                                              KEMRI CDC Lab, Kisumu</li>\n <li>\n Wilfred Murithi                                              KEMRI CDC Lab, Kisumu</li>\n</ol>\n
      • other_details_explanation<p>\n The outcome of this trial will have major public health implications for areas of the world with high burdens of MDR-TB. The sponsor Country (US) does not fall in this category.</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n Moi Teaching and Referral Hospital/Moi University Institutional Research and Ethics Committee (IREC). Approval granted on January 31 2019 for the Eldoret site.</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration96 weeks for each participating HHC and index case
      • 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_comparatorIsoniazid
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states8
      • number_of_sites2
      • multi_country_listBotswana, Brazil , Haiti , India , Kenya , Peru , South Africa , and Thailand
      • data_monitoring_committeeYes
      • total_enrolment_per_site70 index cases and 280 household contacts
      • total_participants_worldwide1726 index cases and 3452 house hold contacts
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornYes
      • population_infant_and_toddlerYes
      • population_childrenYes
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenYes
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameAbraham
      • investigator1_middle_nameMosigisi
      • investigator1_family_nameSiika
      • investigator1_qualificationMBChB, MMed, MSc
      • investigator1_professional_addressP O Box 4606-30100
      • investigator1_telephone+254721280785
      • investigator1_emailabrahamsiika@gmail.com
      • organisations_transferred_No
      • number_participants70 index cases and 280 household contacts
      • notification
      • approval_date30-09-2019
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted03-03-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-09-03 12:54:30
      • created2019-02-20 08:33:12
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id472
        • application_id761
        • given_nameAbraham
        • middle_nameMosigisi
        • family_nameSiika
        • qualificationMBChB, MMed, MSc
        • professional_addressP O Box 4606-30100
        • telephone+254721280785
        • emailabrahamsiika@gmail.com
        • created2019-02-20 08:49:11
        • modified2020-03-03 15:59:36
    • SiteDetail(array)
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        • id598
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        • county_id27
        • site_nameMoi University Clinical Research Centre
        • physical_addressChandaria Cancer and Chronic Diseases Centre at MTRH
        • contact_detailsP O Box 4606-30100
        • contact_personAllan Sudoi
        • site_capacity(null)
        • misc(null)
        • created2019-02-20 08:49:11
        • modified2020-03-03 15:59:36
        • County(array)
          • id27
          • county_nameUasin Gishu
          • created2012-06-15 10:25:15
          • modified2012-06-15 10:25:15
      • 1(array)
        • id599
        • application_id761
        • county_id35
        • site_nameKEMRI Walter Reed Project
        • physical_addressKericho County Hospital Grounds
        • contact_details0722941525
        • contact_personMary Lelgo
        • site_capacity(null)
        • misc(null)
        • created2019-02-20 09:28:16
        • modified2020-03-03 15:59:36
        • County(array)
          • id35
          • county_nameKericho
          • created2012-06-15 10:26:16
          • modified2012-06-15 10:26:16
    • Sponsor(array)
      • 0(array)
        • id368
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        • sponsorNational Institute of Allergy and Infectious Diseases/National Institute of Child Health and Human Development
        • sponsor_typeOthers
        • contact_personGavin Churchyard, MBBCh, MMed, FRCP, FCP(SA), PhD
        • addressPostnet Suite 300, Private Bag X30500, Houghton, 2041 SOUTH AFRICA
        • telephone_number+27 (0) 10 590 1306
        • fax_number+27 (0) 86 613 3718
        • cell_number+27 (0) 10 590 1306
        • email_addressgchurchyard@auruminstitute.org
        • created2019-02-20 08:49:11
        • modified2020-03-03 15:59:36
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    • Application(array)
      • id21
      • user_id21
      • trial_status_id5
      • abstract_of_study<p style=\"margin-left:108.0pt;\">\n <u>DESIGN</u>                      A5278s/AMC 074 is designed to assess the direction and magnitude of pharmacokinetic (PK) interactions between the antiretroviral agents efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) and the Kaposi’s sarcoma (KS) chemotherapy agents etoposide (ET), vincristine (VCR), and pegylated liposomal doxorubicin (PLD).  This substudy will coenroll a subset of participants randomized on ACTG parent studies A5263 and A5264 for PK sampling on no more than two occasions.  Estimates of participant-specific PK parameters for the parent study agents, obtained by maximum a posteriori (MAP) Bayesian estimation, will be compared to historical control data (KS agents) or estimates obtained for participants on A5264 Arm 1A (antiretroviral agents).</p>\n<p style=\"margin-left:144.0pt;\">\n  </p>\n<p style=\"margin-left:108.0pt;\">\n <u>DURATION</u>                One or two day PK visit(s)</p>\n<p style=\"margin-left:108.0pt;\">\n  </p>\n<ul>\n <li>\n Participants in Arm 1A of A5264 who enter A5264 Step 2 (Arm 2A) may have two PK visits</li>\n</ul>\n<p style=\"margin-left:126.0pt;\">\n  </p>\n<p style=\"margin-left:108.0pt;\">\n  </p>\n<p style=\"margin-left:144.0pt;\">\n <u>SAMPLE SIZE</u>            A5263: 45 participants who complete the PK blood draw visit; 15 participants in each A5263 arm. Participants enrolled who do not complete the PK visit will be replaced.</p>\n<p style=\"margin-left:144.0pt;\">\n A5264: 60 participants who complete the PK blood draw; 30 participants in each A5264 arm. Participants enrolled who do not complete the PK visit will be replaced.</p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n <u>POPULATION</u>            HIV-1 infected men and women enrolled in A5263 or A5264</p>\n
      • study_title<p>\n <strong>A5278 - Pharmacology Substudies of A5263 and A5264</strong></p>\n
      • laymans_summary<p style=\"margin-left:36.0pt;\">\n A5278s/AMC 074 will investigate the potential for drug-drug interactions among agents used for the chemotherapy of KS when given with the ART regimen, EFV/TDF/FTC.  These investigations will occur as a <strong>substudy</strong> to the parent protocols A5263 and A5264.  In A5263, the primary question to be evaluated is whether KS chemotherapy with ET, BV, and PLD and ART with EFV/TDF/FTC given concomitantly affects the PK characteristics of each other when compared with historical controls (when examining the PK of KS agents) and PK parameters obtained from participants randomized on A5264 to Arm 1A (ARV agents). In A5264, the primary question of whether co administration of ET with EFV/TDF/FTC alters the PK of ET when compared with historical controls will be addressed as well.  Additionally, the question of whether the PK of EFV/TDF/FTC is altered in the presence of ET will be investigated in a direct comparison of participants who are randomized to receive initially only the ART regimen, or the ART regimen and ET. PK samples will be collected using a sparse sampling strategy at one specified study day when the participants are receiving concomitant therapy. PK data analysis strategies using nonlinear mixed effects modeling and Bayesian-estimation will be used to obtain estimates of individual and population PK parameters for statistical comparisons. To date, no PK evaluations of these KS and ART regimens have been performed. Therefore, this substudy will provide the first PK data for these agents when used in combination. </p>\n
      • short_titlePK Substudy of A5263 and A5264
      • protocol_noECCT/12/07/03
      • version_noVersion 1.0
      • date_of_protocol25-08-2010
      • study_drugco-formulated EFV/TDF/FTC vs ET, VCR and Paclitaxel
      • disease_conditionAIDS-KS (Kaposi’s sarcoma )
      • 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_nameEtoposide, Paclitaxel, Vincristine
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressaksudoi@hotmail.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_addendum1
      • 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_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist0
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantAllan K Sudoi
      • declaration_date122-02-2013
      • declaration_principal_investigatorAbraham M Siika, MBChB, MMed, Msc - Site Principal Investigator
      • declaration_date222-02-2013
      • placebo_presentNo
      • study_objectives<h2>\n Primary Objectives</h2>\n<p>\n  </p>\n<p style=\"margin-left:36.0pt;\">\n The overall objective of ACTG 5278s/AMC074 is to investigate the potential for drug-drug interactions among agents used for the chemotherapy of KS and co-formulated EFV/TDF/FTC. </p>\n<p>\n  </p>\n<p>\n To investigate the effects of the concomitant EFV/TDF/FTC antiretroviral regimen on ET, VCR, and <strong>PTX</strong> PK in A5263, and assess these concentrations relative to historical controls (which do not include CYP3A inducers such as EFV).</p>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<p>\n To investigate the effects of the KS chemotherapy used in Arms A, B, and C of A5263 on the PK of EFV regimen and assess these concentrations relative to historical controls.</p>\n<p>\n  </p>\n<p>\n To investigate the effects of the concomitant EFV/TDF/FTC antiretroviral regimen on ET in A5264 Arm 1B, and assess these concentrations relative to historical controls.</p>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<p>\n To investigate the effects of ET on the PK parameters of EFV, TDF, and FTC, by comparing PK parameters obtained in A5264 without ET (Arm 1A) versus with ET (Arm 1B).</p>\n<p>\n  </p>\n<h2>\n 1.2       Secondary Objectives</h2>\n<p>\n  </p>\n<p style=\"margin-left:72.0pt;\">\n 1.2.1    To investigate exposure-response relationships between EFV, TDF, and FTC PK parameters and markers of response (including adverse reactions) to HIV and KS treatment, and to investigate exposure-response relationships between ET, VCR, and <strong>PTX</strong> PK parameters and markers of response (including adverse reactions) to KS treatment.</p>\n<p>\n  </p>\n<p style=\"margin-left:72.0pt;\">\n 1.2.2    To compare the effects of the EFV/TDF/FTC antiretroviral regimen in<br />\n A5264 on ET PK when ET is initiated at the same time as EFV/TDF/FTC (Arm 1B) to ET PK when ET treatment is delayed (Arm 2A).</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:72.0pt;\">\n 1.2.3    To investigate the effects of ET on EFV, TDF, and FTC PK through within-subject comparisons of EFV, TDF, and FTC  PK parameters, among participants randomized to A5264 Arm 1A who go on to provide PK samples on Arm 2A.</p>\n<p>\n  </p>\n<p>\n 1.2.4    To investigate the effects of the KS chemotherapy used in Arms A, B, and C of A5263 on the PK of TDF and FTC by comparing PK parameters obtained in A5263 Arms A, B and C with those obtained in A5264 Arm 1A.</p>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n This is found in section 4.0 of the protocol  under SELECTION AND ENROLLMENT OF PARTICIPANTS</p>\n<p>\n 4.1       Inclusion Criteria Step 1</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.1    Current enrollment in Arms 1A, 1B, or 1C of A5263 or Arms 1A or 1B of A5264.</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.2    Current use of EFV/TDF/FTC.</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.3    Ability and willingness of participant or legal guardian/representative to provide informed consent</p>\n<p>\n 4.2       Inclusion Criteria Step 2</p>\n<p style=\"margin-left:36.0pt;\">\n 4.2.1    Current enrollment in Step 2 of A5264.</p>\n<p style=\"margin-left:36.0pt;\">\n 4.2.2    Current use of EFV/TDF/FTC.</p>\n
      • principal_exclusion_criteria<p>\n The exclusion criteria of the parent studies will be applied. These will be attached separately to the application</p>\n
      • primary_end_points<p>\n The endpoints are located in section 9.2 of the protocol as follows:</p>\n<p>\n 9.2       Endpoints</p>\n<p>\n 9.2.1    Primary Endpoints</p>\n<p style=\"margin-left:115.2pt;\">\n 9.2.1.1    A5263 Chemotherapeutics</p>\n<p style=\"margin-left:115.2pt;\">\n <u>ET</u>: Subject-specific estimates of apparent oral clearance (CL/F) for ET obtained by applying maximum a posteriori (MAP) Bayesian estimation (as described in Section 10.2) to concentrations in plasma samples collected from participants randomized to Arm A of A5263, on day 6 (±1) of the first ET cycle, prior to and approximately 1 and 4h after the dose. </p>\n<p style=\"margin-left:115.2pt;\">\n <u>VCR:</u>  Subject-specific estimates of systemic clearance (CL) for VCR obtained by applying MAP Bayesian estimation (as described in Section 10.4) to concentrations in plasma samples collected from participants randomized to Arm B of A5263, on the BV dosing day (day 1) of the first or second BV cycle, prior to, at the end of, and 4h after the end of the IV infusion of BV (administered over a 3-5 min period).  (BLM is primarily eliminated by renal excretion.  BLM also undergoes hydrolysis by BLM hydrolase. Therefore, BLM is expected to neither alter nor be altered by concomitant EFV/TDF/FTC.)</p>\n<p style=\"margin-left:115.2pt;\">\n <u>PLD:</u>  Subject-specific estimates of C_max estimated as observed concentrations of PLD in plasma samples collected from participants randomized to Arm C of A5263, during the first or second PLD cycle, 5 minutes prior to the end of the PLD infusion (under the assumption that the maximum concentration occurs at this time).</p>\n<p style=\"margin-left:115.2pt;\">\n 9.2.1.2    A5263 ART</p>\n<p style=\"margin-left:115.2pt;\">\n For Arm A, estimated subject-specific EFV AUCs obtained by applying MAP Bayesian estimation (as described in Section 10.1) to concentrations in plasma samples collected from participants randomized to each of the 3 arms of A5263, on day 6 (±1) of the first ET cycle, approximately 12 h (within 10 and 20 h) after the EFV/TDF/FTC dose taken the evening before, and approximately 1 and 4 hours after the first blood draw for PK.  For Arms B and C, the day of PK sampling is the dosing day (day 1) of the first or second cycle of BV and PLD, respectively. (If PK visit is day 1 of the first cycle, participants must have taken EFC/TDF/FTC for at least 3 days prior to the PK visit.)</p>\n<p style=\"margin-left:115.2pt;\">\n 9.2.1.3    A5264 Chemotherapeutic</p>\n<p style=\"margin-left:115.2pt;\">\n Subject-specific estimates of ET CL/F obtained by applying MAP Bayesian estimation (as described in Section 10.2) to concentrations in plasma samples collected from participants randomized to Arm 1B of A5264, on day 6 (±1) of the first ET cycle, prior to and approximately 1 and 4 h after the first ET dose. </p>\n<ol>\n <li value=\"NaN\">\n A5264 ART</li>\n</ol>\n<p style=\"margin-left:115.2pt;\">\n Estimated subject-specific EFV, TDF and FTC AUCs obtained by applying MAP Bayesian estimation (as described in Section 10.1) to concentrations in plasma samples collected from participants of A5264, approximately 12 h (within 10 and 20 h) after the EFV/TDF/FTC dose taken the evening before, and approximately 1 and 4 h after the first blood draw for PK samples. For participants randomized to Arm 1A (delayed ET), PK samples will be collected on day 6 (±1) after the start of the ART regimen.  For participants randomized to Arm 1B (immediate ET) or enrolling in Arm 2A, PK samples will be collected on day 6 (±1) of the first ET cycle (and day 6 (±1) after the start of the ART regimen).</p>\n<p>\n 9.2.2    Secondary Endpoints</p>\n<p style=\"margin-left:115.2pt;\">\n 9.2.2.1    For participants on all arms of the two parent studies, subject-specific estimates of EFV, TDF, and FTC AUCs and plasma HIV-1 RNA and KS response markers at week 48.</p>\n<p style=\"margin-left:115.2pt;\">\n 9.2.2.2    Subject-specific estimates of ET CL/F obtained for participants on Arms 1B and 2A of A5264, as described in 9.2.1.3 above.</p>\n<p style=\"margin-left:115.2pt;\">\n 9.2.2.3    Subject-specific estimates of EFV AUC (as described in 9.2.1.2 above) and TDF and FTC AUCs (as described in 9.2.2.4 below) for participants on Arm 1A A5264 who also underwent PK sampling in A5264 Step 2 (Arm 2A).</p>\n<p style=\"margin-left:115.2pt;\">\n 9.2.2.4    Estimated subject-specific TDF and FTC AUC for participants on A5263 Arms A, B, and C as described in Section 10.1.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety0
      • scope_efficacy0
      • scope_pharmacokinetic1
      • 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_controlledNo
      • site_capacity(null)
      • staff_numbers<p>\n Abraham M. Siika MBChB, MMed, MS- Site Leader/ Principal Investigator</p>\n<p>\n Naftali Busakhala - MBChB, MMed- Investigator</p>\n<p>\n Evangeline Njiru - MBChB, MMed- Investigator</p>\n<p>\n Charles Kwobah, MBChB- Medical Officer</p>\n<p>\n Mercy Karoney  MBChB- Medical Officer</p>\n<p>\n Simon Wachira Njuguna, B Pharm, MPSK - Pharmacist of Record</p>\n<p>\n Kipruto Kirwa, BSc, MPH, PhD- Quality Manager</p>\n<p>\n Priscilla Cheruiyot, BScN, MPH- Site Coordinator</p>\n<p>\n Martha Mokaya, BSc, MBA- Data Manager</p>\n<p>\n Wilson Lokitala Ekiru, BSc IT- Assistant Data Manager</p>\n<p>\n Agnes M. Nzioka, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Betty Meli, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Michael Tanui, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Julie Choge -  Recruitment Officer</p>\n<p>\n Dorothy Mwimali -  Recruitment Officer</p>\n<p>\n Cecilia Chebet, Dip Counselling - Recruitment Officer</p>\n<p>\n Beatrice Jakait, B Pharm- Back-up Pharmacist</p>\n<p>\n Zipporah Sambili, Dip Pharm- Back-up Pharmaceutical Technologist</p>\n<p>\n Chris Sande, KHRCN- Study Nurse</p>\n
      • other_details_explanation<p style=\"margin-left:14.2pt;\">\n This is a substudy of A5263 and A5264 studies which are conducted in Resource Limited Settings.</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n  Moi Teaching and Referral Hospital/Moi University Institutional Research and Ethics Committee (IREC). Approval date June 7, 2012. The approval is for MUCRC site only</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_durationOne or two day PK visit(s)
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states7 (seven)
      • number_of_sites2
      • multi_country_listKenya\n\nMalawi\n\nSouth Africa\n\nUganda\n\nBrazil\n\nPeru\n\nZimbabwe
      • data_monitoring_committeeNo
      • total_enrolment_per_site15 participants at Eldoret. Information in other sites not immediately available
      • total_participants_worldwide105
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameN/A
      • investigator1_middle_name
      • investigator1_family_nameN/A
      • investigator1_qualificationN/A
      • investigator1_professional_addressN/A
      • investigator1_telephoneN/A
      • investigator1_emailabrahamsiika@gmail.com
      • organisations_transferred_No
      • number_participants15 participants at the Eldoret Site
      • notification
      • approval_date25-08-2010
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted11-08-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
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      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2020-08-11 11:26:33
      • created2013-02-06 16:25:42
      • total_sites(null)
      • ecitizen_invoice(null)
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        • id24
        • application_id21
        • given_nameAbraham
        • middle_nameMosigisi
        • family_nameSiika
        • qualificationMBChB, MMed, MSc
        • professional_addressP O Box, 4606-30100, Eldoret
        • telephone254721280785
        • emailambarahamsiika@gmail.com
        • created2013-02-20 16:30:08
        • modified2020-08-11 11:26:33
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        • contact_details+254 53 2060850
        • contact_personAllan Sudoi
        • site_capacity(null)
        • misc(null)
        • created2013-02-20 16:30:08
        • modified2020-08-11 11:26:33
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          • id27
          • county_nameUasin Gishu
          • created2012-06-15 10:25:15
          • modified2012-06-15 10:25:15
      • 1(array)
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        • application_id21
        • county_id35
        • site_nameKEMRI Walter Reed Project
        • physical_addressKericho District Hospital Grounds
        • contact_details0713603225
        • contact_personHellen Ngeno
        • site_capacity(null)
        • misc(null)
        • created2013-02-20 16:52:06
        • modified2020-08-11 11:26:33
        • County(array)
          • id35
          • county_nameKericho
          • created2012-06-15 10:26:16
          • modified2012-06-15 10:26:16
    • Sponsor(array)
      • 0(array)
        • id18
        • application_id21
        • sponsorThe National Institute of Allergy and Infectious Diseases (NIAID) and The National Institute of Dental and Craniofacial Research (NIDCR)
        • sponsor_typeOthers
        • contact_person
        • address9000 Rockville Pike Bethesda, Maryland 20892
        • telephone_number301-496-4000
        • fax_number
        • cell_number301-496-4000
        • email_addressNIHinfo@od.nih.gov
        • created2013-02-20 16:30:08
        • modified2020-08-11 11:26:33
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