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  • 1Recruiting
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• applications(array)
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    • Application(array)
      • id389
      • user_id263
      • trial_status_id5
      • abstract_of_study<p>\n The trial is being conducted as an effectiveness trial with the objective of the experimental intervention being registered for the indication “prevention of postpartum haemorrhage” by drug regulatory authorities if it is shown to be non-inferior or superior to the gold standard control, oxytocin. For this purpose a primary endpoint of blood loss 500 mL or more or use of additional uterotonics is considered appropriate. For the purpose of evaluating clinical effectiveness and for inclusion of the experimental intervention in future WHO guidelines and the Model List of Essential Medicines, the more substantive endpoint of blood loss 1000 mL or more is considered appropriate. The blood loss of 1000 mL or more was considered as one of the three critical endpoints (together with blood transfusion and maternal death) for the earlier 2007 WHO recommendations for PPH prevention where outcomes were rated by an independent panel. Since the two primary endpoints serve independent objectives, the Type I error rate for multiplicity of endpoints was not adjusted. </p>\n<p>\n <u><strong>The trial has two primary objectives:</strong></u></p>\n<p>\n (1) To evaluate non-inferiority of carbetocin RTS 100 μg IM versus oxytocin 10 IU IM after vaginal delivery in the prevention of the composite endpoint “blood loss of 500 mL or more or the use of additional uterotonics” at one hour and up to two hours for women who continue to bleed after one hour.</p>\n<p>\n (2) To evaluate non-inferiority of carbetocin RTS 100 µg IM versus oxytocin 10 IU IM in the prevention of sPPH (≥1000 mL blood loss) at one hour and up to two hours for women who continue to bleed after one hour.</p>\n<p>\n <u><strong>For both objectives the hypotheses are:</strong></u></p>\n<p>\n i) Carbetocin RTS 100 μg/ml IM is non-inferior to oxytocin 10IU IM in terms of the proportion of women with blood loss ≥500 mL or use of additional uterotonic drugs after vaginal delivery within a non-inferiority margin of 1.16 on the relative risk scale (objective (1)), and the proportion of women with blood loss ≥1000 mL after vaginal delivery within a non-inferiority margin of 1.23 on the relative risk scale (objective (2)).</p>\n<p>\n <em>Justification</em>: In the conventional superiority trial, the aim is to determine whether one intervention is superior to another, for example, whether an uterotonic is superior to nothing. By contrast, in a non-inferiority trial, the aim is to determine whether an alternative intervention with certain advantages is similar to a gold standard. Oxytocin 10 IU (IM or IV) represents the gold standard management strategy for reducing blood loss in the third stage of labour. The advantages of carbetocin RTS are being more heat-stable than oxytocin and having a longer half-life. In order to evaluate the effectiveness of carbetocin RTS, which has these advantages, it has to be compared to oxytocin to assess whether it is non-inferior to it in efficacy.</p>\n<p>\n ii) Carbetocin RTS 100 μg IM is superior to oxytocin 10 IU IM in terms of the proportion of women with blood loss ≥500 mL or use of additional uterotonic drugs (objective (1)), and in terms of the proportion of women with blood loss ≥1000 mL after vaginal delivery (objective (2)). For each of the two primary endpoints, superiority will be tested if non-inferiority has been demonstrated.</p>\n<div>\n  </div>\n<div>\n <u>Rationale</u>: Superiority of the new treatment for the primary outcome would be an additional</div>\n<div>\n benefit. If carbetocin is demonstrated to be superior to oxytocin in efficacy, it would be the</div>\n<div>\n preferred option.</div>\n
      • study_title<p>\n A phase III, randomized, double-blind, active, controlled, multinational, multicentre,  non-inferiority trial using Carbetocin room temperature stable (RTS) for the prevention of postpartum haemorrhage during the third stage of labour in women delivering vaginally.</p>\n
      • laymans_summary<p>\n PPH is the leading cause of maternal mortality in low-income countries and it contributes to nearly a quarter of maternal deaths globally. PPH is a significant contributor to severe maternal morbidity and long term disability, as well as to a number of other severe maternal conditions, generally associated with more substantial blood loss, including shock and organ dysfunction2-4. Improving health care for women during childbirth in order to prevent and treat PPH is an essential step towards the achievement of the United Nations Millennium Development Goals.</p>\n<p>\n Despite oxytocin being a well-known and extensively studied, there is limited information on its stability at tropical temperatures, mainly at extreme climate conditions and storage under refrigeration is recommended, however carbetocin RTS is a promising intervention for reducing PPH particularly in settings where cold storage is difficult to achieve and maintain.</p>\n<p>\n Merck for Mothers is a 10-year initiative focused on creating a world where no woman has to die from complications of pregnancy and childbirth. Two of its priority areas are postpartum haemorrhage (PPH) and hypertensive disorders of pregnancy.</p>\n<p>\n carbetocin RTS is a promising intervention for reducing PPH particularly in settings where cold storage is difficult to achieve and maintain. An international technical consultation was convened and it was agreed to proceed with a randomized controlled trial to evaluate the effectiveness of carbetocin RTS compared to oxytocin when used intramuscularly. This was based on four considerations:</p>\n<p>\n (i) frequent concerns and documentation of the quality of oxytocin and its stability in some developing countries;</p>\n<p>\n (ii) the potential advantage of carbetocin RTS due to its longer half-life (than oxytocin) especially when administered intramuscularly in addition to its heat stability;</p>\n<p>\n (iii) research will be funded by Merck for Mothers and conducted by WHO independently in terms of the management, analysis and publication of the research results</p>\n<p>\n (iv) if non-inferior to oxytocin, carbetocin RTS formulation will be made available in high-burden countries at an accessible public sector price comparable to the current oxytocin price based on a signed memorandum of understanding between WHO, Ferring and Merck.</p>\n<p>\n  </p>\n
      • short_titleA phase III, non-inferiority trial using Carbetocin room temperature stable (RTS) for the prevention of postpartum haemorrhage during the third stage of labour in women delivering
      • protocol_noECCT/15/03/01
      • version_noVersion 1.1
      • date_of_protocol08-12-2014
      • study_drugCarbetocin RTS 100 μg and oxytocin 10 IU.
      • disease_conditionPostpartum haemorrhage
      • 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_nameWomen will receive a single intramuscular dose of either oxytocin or carbetocin immediately after the birth of the baby
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameOxytocin
      • comparator_registeredYes
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressbianca.hibbert@quintiles.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_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi0
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantBianca Hibbert
      • declaration_date105-03-2015
      • declaration_principal_investigatorProfessor Zahida Qureshi
      • declaration_date205-03-2015
      • placebo_presentNo
      • study_objectives<ul>\n <li>\n <strong>To evaluate non-inferiority of carbetocin RTS 100 μg IM versus oxytocin 10 IU IM after vaginal delivery in the prevention of the composite endpoint “blood loss of 500 mL or more or the use of additional uterotonics” at one hour and up to two hours for women who continue to bleed after one hour.</strong></li>\n <li>\n <strong>To evaluate non-inferiority of carbetocin RTS 100 μg IM versus oxytocin 10 IU IM in the prevention of sPPH (≥1000 mL blood loss) at one hour and up to two hours for women who continue to bleed after one hour</strong></li>\n</ul>\n<p>\n  </p>\n
      • principal_inclusion_criteria<div>\n <strong>To be eligible for inclusion into this trial, the women must fulfill all the following criteria:</strong></div>\n<div>\n  </div>\n<div>\n 1. Be expected to deliver vaginally</div>\n<div>\n 2. Have a cervical dilatation equal to or less than 6cm</div>\n<div>\n 3. Have a known singleton pregnancy</div>\n<div>\n 4. Provide written informed consent before any trial-related procedures are carried out.</div>\n
      • principal_exclusion_criteria<div>\n <strong>Women are not eligible for this trial if they fulfill any of the following exclusion criteria:</strong></div>\n<div>\n  </div>\n<div>\n 1. Are in an advanced first stage of labour (>6 cm cervical dilatation) or too distressed to understand, confirm and give informed consent regardless of cervical dilatation</div>\n<div>\n 2. Are non-emancipated minors (as per local regulations) without a guardian</div>\n<div>\n 3. Have been scheduled for a planned caesarean section</div>\n<div>\n 4. The birth is considered an abortion according to local guidelines</div>\n<div>\n 5. Have known allergies to carbetocin, other oxytocin homologues or excipients in the medicinal products used in the trial</div>\n<div>\n 6. Have serious cardiovascular disorders</div>\n<div>\n 7. Are not capable of giving consent due to other health problems such as obstetric emergencies (e.g. antepartum haemorrhage) or mental disorder</div>\n
      • primary_end_points<p>\n (1) To evaluate non-inferiority of carbetocin RTS 100 μg IM versus oxytocin 10 IU IM after vaginal delivery in the prevention of the composite endpoint “blood loss of 500 mL or more or the use of additional uterotonics” at one hour and up to two hours for women who continue to bleed after one hour.</p>\n<p>\n (2) To evaluate non-inferiority of carbetocin RTS 100 µg IM versus oxytocin 10 IU IM in the prevention of sPPH (≥1000 mL blood loss) at one hour and up to two hours for women who continue to bleed after one hour. </p>\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_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n The Kenyatta National Hospital labour ward has 40 full time nurse/midwives. The Hospital it a Tertiary referral site where approximately 13,000 deliveries are conducted and the Caesarean sections rate is around 35%. There is 24 hour theatre coverage , one theatre is for emergencies is functional 24 hours and the second one for elective surgeries is operational Monday to Friday 8am to 5pm. Both theatres are in labour ward. The hospital has a High dependency unit and an ICU.</p>\n<p>\n There is full time consultant coverage with the postgraduates being first on call.</p>\n<p>\n The study will employ one Project coordinator who will be a midwife and will oversee the running of the project and supervise the six midwives (research midwives )we will employ to work in labour ward on shift duty to carry out the recruitment for patients and  delivery as per study protocol and data collection.</p>\n<p>\n In addition a Data entry clerk will be employed for data entry. Prof. Zahida P Qureshi will be overall incharge and Dr Osoti will assist.</p>\n
      • other_details_explanation<p>\n This study is being conducted in developing countries where the PPH incidence and the need for a heat stable treatment for PPH are high. The only exceptions are UK and Singapore which were included for registration purposes.</p>\n
      • other_details_regulatory_notapproved<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n <tbody>\n <tr>\n <td style=\"width:210px;\">\n <p>\n <strong>Countries </strong></p>\n </td>\n <td style=\"width:409px;\">\n <p>\n <strong> Competent Authority  Name and Address </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:210px;\">\n South Africa</td>\n <td style=\"width:210px;\">\n <p>\n The Registrar    </p>\n Medicines Control Council<br />\n Hallmark Building<br />\n PRETORIA<br />\n 0001</td>\n </tr>\n <tr>\n <td style=\"width:210px;\">\n <p>\n UK</p>\n </td>\n <td style=\"width:409px;\">\n <p>\n Information Processing Unit<br />\n Area 6<br />\n MHRA<br />\n 151 Buckingham Palace Road<br />\n Victoria<br />\n SW1W 9SZ</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:210px;\">\n <p>\n Uganda</p>\n </td>\n <td style=\"width:409px;\">\n <p>\n Uganda National Council For Science And Technology (UNCST) Research</p>\n <p>\n Uganda National Council for Science & Technology, Plot 6 Kimera Road Ntida, Kampala</p>\n <p>\n Uganda</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:210px;\">\n <p>\n Nigeria</p>\n </td>\n <td style=\"width:409px;\">\n <p>\n National Agency for Food and Drug Administration and Control (NAFDAC)</p>\n <p>\n Plot 2032, Olusegun Obasanjo Way, Wuse Zone 7-Abuja FCT Nigeria.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:210px;\">\n <p>\n Egypt</p>\n </td>\n <td style=\"width:409px;\">\n <p>\n Ministry of Health - Central Directorate for Research & Health Development (The new administrative building – floor 7)</p>\n <p>\n 3 Magles El Shaab St.</p>\n <p>\n Cairo.</p>\n <p>\n P.O.: 11516</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:210px;\">\n <p>\n India</p>\n </td>\n <td style=\"width:409px;\">\n <p>\n Drugs Controller General (India),</p>\n <p>\n Directorate General of Health Services</p>\n <p>\n FDA Bhavan</p>\n <p>\n Kotla Road</p>\n <p>\n New Delhi</p>\n <p>\n 110002</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:210px;\">\n <p>\n Singapore</p>\n </td>\n <td style=\"width:409px;\">\n <p>\n Health Sciences Authority</p>\n <p>\n 11 Outram Road<br />\n Singapore</p>\n <p>\n 169078</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:210px;\">\n <p>\n Thailand</p>\n </td>\n <td style=\"width:409px;\">\n <p>\n Food and Drug Administration Ministry of Public Health</p>\n <p>\n Thiwanon Road</p>\n <p>\n Nonthaburi</p>\n <p>\n 11000</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:210px;\">\n <p>\n Argentina</p>\n </td>\n <td style=\"width:409px;\">\n <p>\n MOH –ANMAT</p>\n <p>\n Avenida de Mayo 869 (C1084AAD)</p>\n <p>\n Ciudad Autónoma de Buenos Aires</p>\n <p>\n Argentina</p>\n <p>\n  </p>\n <p>\n And</p>\n <p>\n  </p>\n <p>\n Regional MOH.- Santa Fe province</p>\n <p>\n Bv. Pellegrini 3100, 1er. P – Santa Fe  (3000) Santa Fe Argentina</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:210px;height:61px;\">\n <p>\n Brazil</p>\n </td>\n <td style=\"width:409px;height:61px;\">\n <h5>\n ANVISA – Agência Nacional de Vigilância Sanitária</h5>\n <p>\n COPEC - Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos</p>\n <p>\n Setor de Indústria e Abastecimento (SIA)</p>\n <p>\n Trecho 5, Área Especial 57, 71205-050 – Brasília – DF – Brazil</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_regulatory_approved<p>\n Applications for only South Africa, UK, Nigeria and Egypt have been submitted. And no approvals. There were submissions prior to the Quintiles involvement, e.g. in India, and some other countries, but with the previous protocol, without ICFs etc. Some EC approvals were received, but need to be amended with the current submission to be valid.</p>\n
      • other_details_regulatory_rejected<p>\n No approvals or rejections received as yet.</p>\n
      • other_details_regulatory_halted<h3 style=\"color:blue;\">\n <span dir=\"rtl\"><span style=\"color:#000000;\"><tt><span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\">Not applicable</span></span></tt></span></span></h3>\n
      • estimated_durationThe total study duration will be approximately 24 months.
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherYes
      • design_controlled_specifymultinational, multicentre, noninferiority trial
      • design_controlled_comparatorCarbetocin RTS
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherYes
      • design_controlled_medicinal_specifyoxytocin
      • single_site_member_stateYes
      • location_of_areaKenyatta National Hospital
      • single_site_physical_addressKenyatta National Hospital, Nairobi, Kenya
      • single_site_contact_personProf. Zahida P Qureshi
      • single_site_telephoneDepartment 2726300 Ext. 43372 or 2726360
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states11
      • number_of_sites
      • multi_country_listArgentina, Brazil, Egypt, India, Kenya, Nigeria, Singapore, South Africa, Thailand, Uganda and the United Kingdom.
      • data_monitoring_committeeYes
      • total_enrolment_per_site4000 participants
      • total_participants_worldwideApproximately 30\'000 women delivering vaginally will be recruited in this trial.
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male0
      • subjects_healthyNo
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenYes
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameZahida
      • investigator1_middle_name
      • investigator1_family_name Qureshi
      • investigator1_qualificationMasters of Medicine in Obstetrics and Gynecology, Bachelor of Medicine and Bachelor of Surgery
      • investigator1_professional_addressKenyatta National Hospital
      • investigator1_telephoneDepartment 2726300 Ext. 43372 or 2726360 or 0733 605140
      • investigator1_emailzahida@qureshi.co.ke
      • organisations_transferred_Yes
      • number_participantsIn Kenya, approximately 4000 participants will be taking part in the study.
      • notification<p>\n WHO is the directing and coordinating authority for health within the United Nations system. It is responsible for providing leadership on global health matters, shaping the health research agenda, setting norms and standards, articulating evidence-based policy options, providing technical support to countries and monitoring and assessing health trends.</p>\n
      • approval_date27-07-2015
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted26-06-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<p>\n The result of this trial indicate that carbetocin and oxytocin have similar efficacy profiles in the prevention of PPH.  The co-primary objective for blood loss of 500mL or more or use of additional uterotonics was met with carbetocin demontrating non-inferiority compared with oxytocin. However, the co primary objective for blood loss of 1000mL with carbetocion demonstrating non-inferiority compared with oxytocin was not met. Although the upper limit of 95% CI for co-primary outcome blood loss of 1000mL or more was just above the margin of non-inferiority, most likely values for RR were below the margin, suggesting that the trial was slightly underpowered to show non-inferiority for this outcome.  The overall AE data are consistant with the established safety profiles and show minimal differences between carbetocin and oxytocin.  BAsed on the overall efficacy and safety profiles, carbetocin and oxytocin appear to offer cimilar treatment outcomes</p>\n<p>\n The date of global end of trial was 07 March 2018. The Global end of trial is defined as the date the final clinical database lock.</p>\n
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2020-06-26 12:23:55
      • created2015-02-16 10:14:01
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id264
        • application_id389
        • given_nameZahida
        • middle_name
        • family_name Qureshi
        • qualificationMasters of Medicine in Obstetrics and Gynecology, Bachelor of Medicine and Bachelor of Surgery
        • professional_addressKenyatta National Hospital
        • telephoneDepartment 2726300 Ext. 43372 or 2726360 or 0733 605140
        • emailzahida@qureshi.co.ke
        • created2015-02-16 10:29:22
        • modified2020-06-26 12:23:55
    • SiteDetail(array)
      • 0(array)
        • id316
        • application_id389
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2015-02-16 10:29:22
        • modified2020-06-26 12:23:55
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id203
        • application_id389
        • sponsorWorld Health Organization
        • sponsor_typeOthers
        • contact_personDr A. Metin Gülmezoglu
        • addressDepartment of Reproductive Health & Research, Avenue Appia 20, 1211 Geneva 27, Switzerland
        • telephone_number+41-22-7913417
        • fax_number+41-22-7914171
        • cell_number+41-22-7913417
        • email_addressgulmezoglum@who.int
        • created2015-02-16 10:29:22
        • modified2020-06-26 12:23:55
  • 1(array)
    • Application(array)
      • 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)
      • id387
      • user_id32
      • trial_status_id5
      • abstract_of_study<div>\n  </div>\n<div>\n Short Title: IVERMAL study</div>\n<div>\n  </div>\n<div>\n Background and rationale: In western Kenya the prevalence of malaria in <5 year olds has fallen from 70% in 1997 to 40% in 2008, where it has now stagnated. Innovative approaches are needed to continue towards elimination. Ivermectin is a broad spectrum antiparasitic endectocide widely used for the control of onchocerciasis and lymphatic filariasis at a dose of 150-200 mcg/kg. Ivermectin at this dose has a potent, but short-lived effect for 6-11 days on mosquito survival, egg-laying, and parasite sporogony. Higher doses are needed to prolong its mosquitocidal effects. Regulatory studies have shown ivermectin is very well tolerated and safe even up to 2,000 mcg/kg. We will conduct dose finding studies to evaluate the transmission blocking effect of high-dose ivermectin to define the optimal dose for future use of ivermectin in combination with artemisinin-based combination therapy (ACT) for mass drug administration (MDA) for malaria in Kenya. This study explores a research question of global relevance. A prolonged transmission blocking effect of ivermectin could have substantial consequences for malaria control in the next decades. We expect the results to inform the national regulator in Kenya, national malaria control programs in malaria endemic countries, to inform WHO guidelines, and to contribute to the regulatory process.</div>\n<div>\n  </div>\n<div>\n Primary objective: To determine the safety and efficacy of ivermectin 0, 300, 600 mcg/kg/day for 3 days, when provided with a standard 3-day course of dihydroartemisinin-piperaquine (DP) for uncomplicated malaria, on 14-day mosquito survival after feeding experiment performed at 7 days after treatment.</div>\n<div>\n Hypothesis: High dose ivermectin at 600 mcg/kg daily for 3 days is well tolerated and safe and will have a longer lasting mosquitocidal effect and a greater potential impact on malaria transmission.</div>\n<div>\n  </div>\n<div>\n Overview Study Design: Double-blind placebo-controlled, parallel-group, 3-arm, superiority trial to determine the effect of different doses of ivermectin on mosquito survival. The unit of randomization will be the patient, and the unit of analysis will be the mosquito. The primary endpoint will be mosquito survival 14 days after a feed on blood from a patient who has started ivermectin 7 days earlier (i.e. about 5 days after the last dose of ivermectin with a 3-day regimen administering ivermectin at 0, 24, and 48 hours [days 0, 1 and 2]). Because mosquito feeding involves approximately 100 mosquitoes per feed, the study will use a cluster randomized design with the patient as the cluster unit. The study will have a nested rich pharmacokinetic component in the first 12 patients per study arm, and a sparse sampling population pharmacokinetic component in the remaining patients. The study will also compare the potential modifying effect of the method of feeding by comparing the mosquitocidal effect of ivermectin with membrane versus direct skin feeding.</div>\n<div>\n Sites: The study will be conducted in the Provincial Hospital in Kisumu, western Kenya recently renamed to the Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH). Dependent on the recruitment rate, enrolment will be expanded to up to 3 other hospitals in Kisumu and Siaya counties.</div>\n<div>\n Study Population: Adults with uncomplicated falciparum malaria attending out-patient clinics.</div>\n<div>\n  </div>\n<div>\n Study Interventions: 1. Dihydroartemisinin-piperaquine (DP) alone, DP plus ivermectin 0 mcg/kg/day for 3 days (“placebo” arm); 2. DP plus ivermectin 300 mcg/kg/day plus 300 mcg/kg/day ivermectin-placebo for 3 days (“300 mcg/kg” arm); 3. DP plus ivermectin 600 mcg/kg/day (“600 mcg/kg” arm).</div>\n<div>\n Outcome Measures: Primary efficacy outcome: Mosquito survival: Survival of mosquitoes at 14 days after feeding on blood taking from study participants who started the 3-day ivermectin and DP regimen 7 days earlier. Primary safety outcome measure: Mydriasis quantitated by pupillometry. Key secondary safety outcome: QTc(F) prolongation by ECG.</div>\n<div>\n  </div>\n<div>\n Follow-up procedures: Treatment visits on day 1 and 2. Post-treatment follow-up at day 2 (+4 hours after last dose of ivermectin), days 7, 10, 14, 21, and 28.</div>\n<div>\n Sample size: Main trial: 141 participants (47 per arm); Rich pharmacokinetic study: 36 participants (12 per arm); direct feeding vs membrane feeding 27 participants (9 per arm, day 7 post ivermectin only).</div>\n<div>\n  </div>\n<div>\n Data Analysis: Primary outcomes will be summarised by number (%) of events and analysed using a Generalized Estimating Equations (GEE) model with binomial distribution and log link function that includes treatment as a single predictor taking the cluster design into account, which will generate risk ratios together with their 95% confidence intervals of having a primary endpoint between two active dose groups and the placebo group. Exchangeable covariance structure will be used. The primary endpoint analysis will be based on the ITT population.</div>\n<div>\n  </div>\n<div>\n Partner institutions: KEMRI and CDC Collaboration, Kisumu, western Kenya; Kenya Ministry of Health, Liverpool School of Tropical Medicine; US Centers for Disease Control and Prevention</div>\n<div>\n  </div>\n<div>\n Funding: Malaria Eradication Scientific Alliance (MESA) which is funded through a grant from the Bill and Melinda Gates Foundation.</div>\n
      • study_title<p>\n <font face=\"Arial, sans-serif\"><span style=\"line-height: 18.3999996185303px;\"><b>Efficacy and safety of high-dose Ivermectin for reducing malaria transmission: A dose finding study</b></span></font></p>\n
      • laymans_summary<p>\n --</p>\n
      • short_titleIVERMAL study
      • protocol_noECCT/15/02/03
      • version_no1.4
      • date_of_protocol27-01-2015
      • study_drugIvermectin
      • disease_conditionMalaria
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameIvermectin
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresstsang@kemricdc.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd0
      • applicant_prev_data1
      • applicant_stability_data0
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter0
      • applicant_detailed_budget1
      • applicant_indemnity_pi0
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist0
      • statistical_analysis_plan1
      • applicant_contractual_agreement0
      • declaration_applicantTony Sang
      • declaration_date116-02-2015
      • declaration_principal_investigatorMenno Smit
      • declaration_date216-02-2015
      • placebo_presentYes
      • study_objectives<div>\n The overall aim of the study is to compare the effect of 3-day courses with ivermectin 0, 300, 600 mcg/kg/day when given in combination with standard 3-day course of dihydroartemisinin-piperaquine, on mosquito survival.</div>\n<div>\n  </div>\n<div>\n PRIMARY OBJECTIVE</div>\n<div>\n  </div>\n<div>\n To determine the safety and efficacy of ivermectin 0, 300, 600 mcg/kg/day for 3 days, when provided with a standard 3-day course of dihydroartemisinin-piperaquine (DP) for uncomplicated malaria, on 14-day mosquito survival after feeding experiment performed at 7 days after treatment (i.e. 5 days after the last dose of ivermectin).</div>\n<div>\n  </div>\n<div>\n SECONDARY OBJECTIVES</div>\n<div>\n  </div>\n<div>\n 1. To determine the effect of different doses of ivermectin on oocyst and sporozoite rates.</div>\n<div>\n 2. To determine the effect of different doses of ivermectin on other ectoparasites (e.g. head lice, scabies).</div>\n<div>\n 3. To determine the pharmacokinetic profile of the different ivermectin regimens</div>\n<div>\n 4. To determine if ivermectin interacts with the pharmacokinetics of piperaquine</div>\n<div>\n 5. To determine whether the addition of ivermectin to DP interacts with the ability of DP to clear asexual and sexual stage parasites</div>\n<div>\n 6. To determine the role of genetic variants of CYP3A4 activity in metabolizing ivermectin</div>\n<div>\n 7. To determine the effect of direct feeding versus membrane feeding on mosquito surviv</div>\n
      • principal_inclusion_criteria<div>\n •<span class=\"Apple-tab-span\" style=\"white-space: pre;\"> </span>Asymptomatic, uncomplicated Plasmodium falciparum infection</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Positive malaria microscopy or malaria RDT (pLDH)</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Age: 18-50 years</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Provide written informed consent</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Agree to be able to travel to clinic on days: 1, 2, 7, 10, 14, 21, and 28</div>\n<div>\n  </div>\n<div>\n  </div>\n<p>\n  </p>\n
      • principal_exclusion_criteria<div>\n  </div>\n<p>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Signs or symptoms of severe malaria</p>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Unable to provide written informed consent</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>For women: pregnancy or lactation</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Hypersensitivity to ivermectin or DP</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Qtc > 460 ms on ECG</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Body Mass Index (BMI) below 16 or above 32 kg/m2</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Haemoglobin concentration below 9 g/dL</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Taken ivermectin in the last month</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Taken dihydroartemisinin-piperaquine in the last 12 weeks</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Loa loa as assessed by travel history to Angola, Cameroon, Chad, Central African Republic, Congo, DR Congo, Equatorial Guinea, Ethiopia, Gabon, Nigeria and Sudan</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>History and/or symptoms indicating chronic illness</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Current use of tuberculosis or anti-retroviral medication</div>\n<div>\n •<span class=\"Apple-tab-span\" style=\"white-space:pre\"> </span>Previously enrolled in the same study</div>\n<div>\n  </div>\n
      • primary_end_points<ul>\n <li>\n Mosquito survival: Survival of mosquitoes at 14 days after feeding on blood taking from study participants who started the 3-day ivermectin and DP regimen 7 days earlier</li>\n</ul>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic1
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<div>\n Study Coordinator, Menno Smit</div>\n<div>\n Project manager, Elizabeth Nyothach</div>\n<div>\n Pharmacist, Tony Sang</div>\n<div>\n Regulatory Officer, Juliana Kisakye</div>\n<div>\n Clinical Officer 1, name TBC</div>\n<div>\n Clinical Officer 2, name TBC</div>\n<div>\n Clinical Officer 3, name TBC</div>\n<div>\n Microscopist 1, name TBC</div>\n<div>\n Microscopist 2, name TBC</div>\n<div>\n Phlebotomist 1, name TBC</div>\n<div>\n Laboratory technician 1, TBC</div>\n<div>\n Entomology laboratory assistant 1, TBC</div>\n<div>\n Entomology laboratory assistant 2, TBC</div>\n<div>\n Data manager, TBC</div>\n<div>\n Data clerk, TBC</div>\n<div>\n  </div>\n<div>\n The study will be conducted in the Provincial Hospital in Kisumu, western Kenya recently renamed to the Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH). JOOTRH is a major tertiary care hospital with self-contained paediatric, medical, and obstetric wards, as well as an intensive care unit with mechanical ventilators and telemetry capabilities. Almost 25,000 outpatients are treated for clinical malaria at JOOTRH annually, of which one-third are laboratory confirmed. Approximately 20% of these patients are 18-50 years old. On a daily basis around 4.6 adults (18–50 years old) test positive for malaria in JOOTRH’s outpatient clinic.</div>\n<div>\n  </div>\n
      • other_details_explanation<p>\n The study involves patients with malaria.</p>\n
      • other_details_regulatory_notapproved<p>\n None</p>\n
      • other_details_regulatory_approved<div style=\"margin-left: 40px;\">\n KEMRI  SSC- 12 Feb 2015</div>\n<div style=\"margin-left: 40px;\">\n  </div>\n<div style=\"margin-left: 40px;\">\n Liverpool School of Tropical Medicine  -   23-Jan-2015</div>\n<div>\n  </div>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n None</p>\n
      • estimated_duration4-6 months
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorPlacebo
      • design_controlled_other_medicinalNo
      • design_controlled_placeboYes
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sitesOne main site and three potential expansion sites
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_siteJaramogi Oginga Odinga Teaching & Referral Hospital : 0-141\nKisumu District Hospital : 0-141\nSiaya District Hospital : 0-141\nV District Hospital: 0-141
      • total_participants_worldwide141
      • 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_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameMenno
      • investigator1_middle_nameRoderick
      • investigator1_family_nameSmit
      • investigator1_qualificationMD, MPH
      • investigator1_professional_addressKEMRI/CDC, P.O. Box 1578, Kisumu 40100, Kenya
      • investigator1_telephone+254 703 991513
      • investigator1_emailmenno.smit@liverpool.ac.uk
      • organisations_transferred_Yes
      • number_participants141
      • notification
      • approval_date26-03-2015
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted26-01-2021
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe study has now been approved
      • final_report<div>\n <strong>Summary</strong></div>\n<div>\n Background Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150–200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 μg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment.</div>\n<div>\n  </div>\n<div>\n <strong>Methods</strong> We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18–50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs ≥21 kg/m²; women: <23 vs ≥23 kg/m²), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353.</div>\n<div>\n  </div>\n<div>\n <strong>Findings</strong> Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 μg/kg per day risk ratio [RR] 2·26, 95% CI 1·93–2·65, p<0·0001; hazard ratio [HR] 6·32,</div>\n<div>\n 4·61–8·67, p<0·0001; ivermectin 300 μg/kg per day RR 2·18, 1·86–2·57, p<0·0001; HR 4·21, 3·06–5·79, p<0·0001). Mosquito mortality remained significantly increased 28 days post treatment (ivermectin 600 μg/kg per day RR 1·23, 1·01–1·50, p=0·0374; and ivermectin 300 μg/kg per day 1·21, 1·01–1·44, p=0·0337). Five (11%) of 45 patients receiving ivermectin 600 μg/kg per day, two (4%) of 48 patients receiving ivermectin 300 μg/kg per day, and none of 46 patients receiving placebo had one or more treatment-related adverse events.</div>\n<div>\n  </div>\n<div>\n <strong>Interpretation </strong>Ivermectin at both doses assessed was well tolerated and reduced mosquito survival for at least 28 days</div>\n<div>\n after treatment. Ivermectin 300 μg/kg per day for 3 days provided a good balance between efficacy and tolerability, and</div>\n<div>\n this drug shows promise as a potential new tool for malaria elimination.</div>\n
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2021-01-26 12:43:18
      • created2015-02-13 17:23:59
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id261
        • application_id387
        • given_nameMenno
        • middle_nameRoderick
        • family_nameSmit
        • qualificationMD, MPH
        • professional_addressKEMRI/CDC, P.O. Box 1578, Kisumu 40100, Kenya
        • telephone+254 703 991513
        • emailmenno.smit@liverpool.ac.uk
        • created2015-02-13 17:33:17
        • modified2021-01-26 12:43:18
    • SiteDetail(array)
      • 0(array)
        • id314
        • application_id387
        • county_id42
        • site_nameJaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH)
        • physical_addressKakamega Road, Kisumu, Kenya
        • contact_detailsKEMRI/CDC-CRC, P.O. Box 1578, Kisumu 40100, Kenya
        • contact_personMenno Smit
        • site_capacity(null)
        • misc(null)
        • created2015-02-13 17:33:17
        • modified2021-01-26 12:43:18
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 1(array)
        • id318
        • application_id387
        • county_id42
        • site_nameKisumu District Hospital (KDH),
        • physical_addressKisumu
        • contact_detailsP. O. Box 4685, Kisumu
        • contact_personMenno Smit
        • site_capacity(null)
        • misc(null)
        • created2015-02-17 17:10:55
        • modified2021-01-26 12:43:18
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 2(array)
        • id319
        • application_id387
        • county_id41
        • site_nameSiaya District Hospital
        • physical_addressSiaya
        • contact_detailsP. O. Box 144, Siaya
        • contact_personMenno Smit
        • site_capacity(null)
        • misc(null)
        • created2015-02-17 17:10:55
        • modified2021-01-26 12:43:18
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 3(array)
        • id320
        • application_id387
        • county_id38
        • site_nameVihiga District Hospital
        • physical_addressVihiga
        • contact_detailsP.O. Box 1069, Vihiga
        • contact_personMenno Smit
        • site_capacity(null)
        • misc(null)
        • created2015-02-17 17:10:55
        • modified2021-01-26 12:43:18
        • County(array)
          • id38
          • county_nameVihiga
          • created2012-06-15 10:26:37
          • modified2012-06-15 10:26:37
    • Sponsor(array)
      • 0(array)
        • id201
        • application_id387
        • sponsorLiverpool School of Tropical Medicine
        • sponsor_typeResearch Institution
        • contact_personMenno Smit
        • addressKEMRI/CDC, P.O. Box 1578, Kisumu 40100, Kenya
        • telephone_number+254 703 991513
        • fax_number
        • cell_number+254 703 991513
        • email_addressmenno.smit@liverpool.ac.uk
        • created2015-02-13 17:33:17
        • modified2021-01-26 12:43:18
  • 3(array)
    • Application(array)
      • id343
      • user_id32
      • trial_status_id7
      • abstract_of_study<div>\n Artemether-Iumefantrine (AL) was adopted as first-line antimalarial therapy in Kenya in 2006, and dihydroartemisinin-piperaquine (OP) as the second-line therapy in 2010. In order to monitor the efficacy and potential development of resistance of Plasmodium falciparum parasites to these two drugs, we will conduct in-vivo studies to monitor the efficacy of these antimalarial therapies.</div>\n<div>\n  </div>\n<div>\n A standardized World Health Organization (WHO) in-vivo efficacy study will be conducted in western Kenya among children 6-59 months of age with symptomatic, uncomplicated malaria visiting the out-patient department of hospitals and/or clinics in western Kenya.</div>\n<div>\n  </div>\n<div>\n Every two years, 350 children will be randomly aSSigned to be treated with either AL or DP. Clinical, parasitologic, and hematologic parameters will be monitored over a 42-day follow-up period. Molecular analysis will be conducted to determine the frequency of markers of antimalarial resistance, and to differentiate recrudescence from reinfection. Results from this antimalarial drug efficacy study will be used to assist the Kenya national malaria control program (NMCP) in evaluating the national malaria treatment policy.</div>\n
      • study_title<div>\n Open label randomized study evaluating the in vivo efficacies of Artemether-lumefantrine and Dihydroartemisinin-piperaquine in the treatment of uncomplicated Plasmodium falciparum malaria in children under five years of age in western Kenya.</div>\n
      • laymans_summary<div>\n Artemether-Iumefantrine (AL) was adopted as first-line antimalarial therapy in Kenya in 2006, and dihydroartemisinin-piperaquine (OP) as the second-line therapy in 2010. In order to monitor the efficacy and potential development of resistance of Plasmodium falciparum parasites to these two drugs, we will conduct in-vivo studies to monitor the efficacy of these antimalarial therapies.</div>\n<div>\n  </div>\n<div>\n A standardized World Health Organization (WHO) in-vivo efficacy study will be conducted in western Kenya among children 6-59 months of age with symptomatic, uncomplicated malaria visiting the out-patient department of hospitals and/or clinics in western Kenya.</div>\n<div>\n  </div>\n<div>\n Every two years, 350 children will be randomly aSSigned to be treated with either AL or DP. Clinical, parasitologic, and hematologic parameters will be monitored over a 42-day follow-up period. Molecular analysis will be conducted to determine the frequency of markers of antimalarial resistance, and to differentiate recrudescence from reinfection. Results from this antimalarial drug efficacy study will be used to assist the Kenya national malaria control program (NMCP) in evaluating the national malaria treatment policy.</div>\n<div>\n  </div>\n
      • short_titleIn vivo efficacies of AL and DP
      • protocol_noECCT/15/01/05
      • version_no3.0
      • date_of_protocol24-09-2014
      • study_drugArtemether-Lumefantrine & Dihydroartemisinin-Piperaquine
      • disease_conditionMalaria
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameArtemether-Lumefantrine & Dihydroartemisinin-Piperaquine
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresstsang@kemricdc.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd0
      • applicant_prev_data1
      • applicant_stability_data0
      • applicant_analysis_cert0
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter0
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african0
      • applicant_hard_copies(null)
      • applicant_signed_checklist0
      • statistical_analysis_plan0
      • applicant_contractual_agreement0
      • declaration_applicantDr Tony Sang
      • declaration_date130-01-2015
      • declaration_principal_investigatorDr Aaron Samuels, Principle Investigator
      • declaration_date230-01-2015
      • placebo_presentNo
      • study_objectives<div>\n <strong>Objectives</strong></div>\n<div>\n  </div>\n<div>\n i.<span style=\"white-space:pre\"> </span>To measure the clinical and parasitological efficacy of AL and DP among patients aged 6–59 months with symptomatic, uncomplicated P. falciparum malaria,</div>\n<div style=\"margin-left: 40px;\">\n a.<span style=\"white-space:pre\"> </span>Primary efficacy endpoint:  PCR-corrected parasitemia by day 42, the adequate clinical and parsitological response (ACPR)</div>\n<div style=\"margin-left: 40px;\">\n b.<span style=\"white-space:pre\"> </span>Secondary efficacy endpoints:  Determine the proportion of children with early treatment failure (ETF) and  late treatment failure (LTF) by determining the presence of parasitemia on days 3, 7, 14, 28, 35, and 42</div>\n<div style=\"margin-left: 40px;\">\n c.<span style=\"white-space:pre\"> </span>Should funds permit: Assess for delayed parasite clearance and late recrudescence of infection by additionally sampling children with infection densities of ≥10,000 parasites per microliter at 6, 12, 24, and 36 hours post-treatment</div>\n<div>\n ii.<span style=\"white-space:pre\"> </span>To determine the frequency of existing molecular markers for drug resistance and identify new molecular markers</div>\n<div>\n iii.<span style=\"white-space:pre\"> </span>Evaluate drug concentration levels at day 7</div>\n<div>\n iv.<span style=\"white-space:pre\"> </span>Evaluate duration of malaria HRP2/pLDH RDT positivity after appropriate treatment with AL and DP </div>\n<div>\n  </div>\n
      • principal_inclusion_criteria<ol>\n <li>\n Age 6-59 months</li>\n <li>\n Weight ~ 5.0 kg</li>\n <li>\n Axillary temperature ~ 37.52 C or history of fever in the past 24 hours</li>\n <li>\n Hemoglobin ~7 grams/deciliter at enrolment</li>\n <li>\n Slide-confirmed mono-infection with P. jalciparum, with asexual parasitemia (2,000-200,000 asexual parasites/~I)</li>\n <li>\n live within the catchment boundaries of the study site</li>\n <li>\n Ability to swallow oral medication</li>\n <li>\n Ability and willingness to comply with the protocol for the duration of the study</li>\n <li>\n Ability and willingness to comply with the study visit schedule on days 2, 3, 7, 14, 21, 28, 35, and 42</li>\n <li>\n Parent or caregiver has access to a phone so that study staff may contact them during study period for visit reminders</li>\n <li>\n Parent/guardian provides written informed consent</li>\n</ol>\n<div>\n Sub-study inclusion and exclusion criteria - Identical to the main study except:</div>\n<ol>\n <li>\n Parasite density ~10,000 to S200,000</li>\n <li>\n Willingness to be hospitalized for the first 24 hours after ACT treatment</li>\n <li>\n Willingness to follow-up at 36 hrs post-treatment, and on days 2, 3, 7, 14,21,28,35,42</li>\n</ol>\n
      • principal_exclusion_criteria<ol>\n <li>\n Presence of severe malaria or danger signs, including prostration, alteration in level of consciousness, respiratory distress, convulsions, and jaundice</li>\n <li>\n Severe malnutrition according to WHO child growth standards</li>\n <li>\n Known hypersensitivity to any of the drugs being tested</li>\n <li>\n Use of antimalarials or other drugs with antimalarial activity in the last 2 weeks</li>\n <li>\n General clinical condition necessitates hospitalization</li>\n <li>\n Evidence of concomitant infections at the time of presentation</li>\n <li>\n Plan to travel or leave the area within the next 3 months</li>\n <li>\n Have previously been enrolled in this study</li>\n</ol>\n
      • primary_end_points<ul>\n <li>\n treatment failure,</li>\n <li>\n completion of the follow-up period without treatment failure,</li>\n <li>\n loss to follow-up, withdrawal from study (voluntary or involuntary, and protocol violation). loss to follow-up occurs when, despite all reasonable effort, an enrolled patient who does not attend the scheduled visits cannot be found within 3 days oftheir scheduled visit.</li>\n</ul>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety0
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<table border=\"1\" cellpadding=\"1\" cellspacing=\"1\" style=\"width: 500px;\">\n <tbody>\n <tr>\n <td>\n <strong>Cadre</strong></td>\n <td>\n <strong>Name & Qualification</strong></td>\n </tr>\n <tr>\n <td>\n PI</td>\n <td>\n Aaron Samuels, MD, MSH</td>\n </tr>\n <tr>\n <td>\n PI</td>\n <td>\n Simon Kariuki, PhD</td>\n </tr>\n <tr>\n <td>\n Co-Investigator</td>\n <td>\n Nelli Westercamp, PhD, MPH</td>\n </tr>\n <tr>\n <td>\n Co-Investigator</td>\n <td>\n Meghna Desai, PhD, MPH</td>\n </tr>\n <tr>\n <td>\n Co-Investigator/Lab Manager</td>\n <td>\n Kephas Otieno, MSc,</td>\n </tr>\n <tr>\n <td>\n Pharmacist</td>\n <td>\n Tony Sang, BPharm</td>\n </tr>\n <tr>\n <td>\n Lead Study Nurse</td>\n <td>\n Mary Owidhi</td>\n </tr>\n <tr>\n <td>\n 3 Clinical Officers</td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n 3 Nurses</td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n 1 Quality Control Officer</td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n 3 Laboratory Technologists</td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n 2 field workers</td>\n <td>\n  </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n Kenya Medical research Institute ERC approved this protocol on 06-Oct-2014</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration6 months
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindYes
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherYes
      • design_controlled_specifyTreatment allocation will be blinded only to the microscopists reading the blood films.
      • design_controlled_comparatorParticipants will be rand
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherYes
      • design_controlled_medicinal_specifyParticipants will be randomised to either receive Artemether-Lumefantrine or Dihydroartemisinin-Piperaquine
      • single_site_member_stateYes
      • location_of_areaSiaya District Hospital
      • single_site_physical_addressSiaya
      • single_site_contact_personSimon Kariuki
      • single_site_telephone0725 389246
      • multiple_sites_member_stateNo
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites
      • multi_country_list
      • data_monitoring_committeeNo
      • total_enrolment_per_site350 participants in total every two years
      • total_participants_worldwide350 participants every two years
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenYes
      • population_adolescentNo
      • population_above_18No
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyChildren under 5 will be enrolled upon consent given by parent or guardian
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameAaron
      • investigator1_middle_name
      • investigator1_family_nameSamuels
      • investigator1_qualificationMD, MHS(CDC)
      • investigator1_professional_address1600 Clifton Road NE, MIS A06 Atlanta, Georgia 30329
      • investigator1_telephone+1 (404) 718-4779 or 0727 037873
      • investigator1_emailiyp2@cdc.gov
      • organisations_transferred_No
      • number_participants350 participants every two years
      • notification
      • approval_date03-03-2015
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted02-10-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe study has been approved
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2020-10-02 13:12:43
      • created2014-10-29 10:01:58
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id237
        • application_id343
        • given_nameAAron
        • middle_name
        • family_nameSamuels
        • qualificationMD, MHS(CDC)
        • professional_address1600 Clifton Road NE, MIS A06 Atlanta, Georgia 30329
        • telephone+1 (404) 718-4779 or 0727 037873
        • emailiyp2@cdc.gov
        • created2014-10-29 10:06:39
        • modified2020-10-02 13:12:43
      • 1(array)
        • id238
        • application_id343
        • given_nameSimon
        • middle_name
        • family_nameKariuki
        • qualificationPhD
        • professional_address1578-40100 Kisumu, Kenya
        • telephone0725 389 246
        • emailskariuki@kemricdc.org
        • created2014-10-29 10:13:28
        • modified2020-10-02 13:12:43
    • SiteDetail(array)
      • 0(array)
        • id290
        • application_id343
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2014-10-29 10:06:39
        • modified2020-10-02 13:12:43
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id182
        • application_id343
        • sponsorKenya Medical Research Institute
        • sponsor_typeResearch Institution
        • contact_personDr Simion Kariuki
        • address1578-40100 Kisumu Kenya
        • telephone_number+254 57 2022902/29
        • fax_number
        • cell_number+254 725 389 246
        • email_addressskariuki@kemricdc.org
        • created2014-10-29 10:06:39
        • modified2020-10-02 13:12:43
  • 4(array)
    • Application(array)
      • id379
      • user_id72
      • trial_status_id5
      • abstract_of_study<table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:599px;\" width=\"599\">\n <tbody>\n <tr>\n <td style=\"width:20%;height:106px;\">\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\"><strong>Design:</strong></span></p>\n </td>\n <td style=\"width:80%;height:106px;\">\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\">This study, which shall be conducted in two phases, will examine procedural and clinical outcomes, as well as participant and provider acceptability, of adaptations of the Shang Ring technique for male circumcision that would simplify its use.</span></p>\n <p style=\"margin-left:.25in;\">\n <span style=\"font-family:verdana,geneva,sans-serif;\">·         Phase I will explore use of the no-flip technique with historical data from standard Shang Ring circumcisions in Africa used as the comparison group. Men will be randomized to Shang Ring removal at 7 days vs. being followed to observe for spontaneous detachment,</span></p>\n <p style=\"margin-left:.25in;\">\n <span style=\"font-family:verdana,geneva,sans-serif;\">·         Phase II will be a randomized trial comparing use of topical vs. injectable anesthesia.</span></p>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:149px;height:63px;\">\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\"><strong>Population:</strong></span></p>\n </td>\n <td style=\"width:450px;height:63px;\">\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\">The study population will include Kenyan men and boys ages 10 years and older seeking circumcision at a study sits. A total of 230 participants will be recruited into Phase I and 345 into Phase II. Because of the possibility that boys and men could have different outcomes, we will recruit participants equally in two age groups in both phases; 10-15 and >15 years old.</span></p>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:149px;height:126px;\">\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\"><strong>Duration:</strong></span></p>\n </td>\n <td style=\"width:450px;height:126px;\">\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\">Approximately 8 months for completion through follow-up of the two phases of the study (exact timing will depend on recruitment rate). In the first phase, participants shall be followed-up at 7, 14, 21, 28, 35, and 42 days post circumcision, although study participation will end once complete wound healing has been documented. In the second phase, participants shall be followed up at 7 and 42 days post-circumcision. In both phases men will be followed beyond 42 days if necessary to document complete wound healing.</span></p>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:149px;height:63px;\">\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\"><strong>Primary Objectives & </strong></span></p>\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\"><strong>Endpoints:</strong></span></p>\n </td>\n <td style=\"width:450px;height:63px;\">\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\">Phase I: Assess safety of the no-flip technique for Shang Ring circumcision by determining the rate of moderate and severe adverse events (AE) following use of the no-flip technique. </span></p>\n <p>\n  </p>\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\">Phase II: Assess pain experienced during the Shang Ring circumcision procedure with topical vs. injectable anesthesia. The outcome metric would be maximum pain experienced during the Shang Ring circumcision, assessed using the visual analogue scale (VAS) score, reported immediately after completion of the procedure.</span></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:149px;height:20px;\">\n <p>\n  </p>\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\"><strong>Sites:</strong></span></p>\n </td>\n <td style=\"width:450px;height:20px;\">\n <p>\n  </p>\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\">Homa Bay County Hospital, Homa Bay County, Kenya</span></p>\n <p>\n <span style=\"font-family:verdana,geneva,sans-serif;\">Vipingo Health Center, Kilifi County, Kenya</span></p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • study_title<h2>\n <span style=\"font-size:12px;\"><span style=\"font-family:verdana,geneva,sans-serif;\">Simplifying the Shang Ring Technique for Circumcision of Men and Boys</span></span></h2>\n
      • laymans_summary(null)
      • short_titleSimplifying ShangRing Circumcision for Men and Boys
      • protocol_noECCT/15/01/03
      • version_no4
      • date_of_protocol09-01-2015
      • study_drugN/A
      • disease_conditionN/A
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device1
      • product_type_chemical_name
      • product_type_medical_device_nameShang Ring Device
      • comparator(null)
      • comparator_name(null)
      • comparator_registered(null)
      • comparator_countries(null)
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressqawori@engenderhealth.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_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_applicantQuentin Awori
      • declaration_date127-01-2015
      • declaration_principal_investigatorMark Barone - Principal investigator
      • declaration_date227-01-2015
      • placebo_presentNo
      • study_objectives(null)
      • principal_inclusion_criteria<ol>\n <li>\n Aged 10 years and older;</li>\n <li>\n Uncircumcised upon clinical examination;</li>\n <li>\n In good general health;</li>\n <li>\n Free of genital ulcerations or other visible signs of STI upon clinical examination;</li>\n <li>\n Participant and parent or legally acceptable representative (LAR) as applicable must be able to understand study procedures and requirements of study participation;</li>\n <li>\n Freely consents to participate in the study and signs a written informed consent form if 18 years of age or greater</li>\n <li>\n Accompanied by the parent/LAR, who freely consents and signs an informed consent form for participation of the child into the study for participants less than 18 years old;</li>\n <li>\n Assent from participant less than 18 years old who understand study procedure;</li>\n <li>\n Participant must agree to return to the study site for the full schedule of follow-up visits after his circumcision (or as appropriate the Parent or LAR must agree to bring the participant);</li>\n <li>\n Participant and parent/LAR as appropriate must agree to provide the study staff with an address, phone number, or other locator information while participating in the research study.</li>\n</ol>\n
      • principal_exclusion_criteria<ol>\n <li>\n Has a known allergy or sensitivity to lidocaine or other local anesthesia;</li>\n <li>\n Takes a medication that would be a contraindication for elective surgery, such as an anticoagulant or steroid;</li>\n <li>\n Has known bleeding/clotting disorder (e.g. hemophilia);</li>\n <li>\n Has any congenital genitourinary abnormality;</li>\n <li>\n Has an active genital infection, anatomic abnormality or other condition (e.g. diabetes or sickle cell anemia), which in the opinion of the surgeon, prevents the man from undergoing a circumcision as part of this study; or,</li>\n <li>\n Is currently participating in another biomedical research study. </li>\n</ol>\n
      • primary_end_points<p>\n <u><strong>Phase I of study</strong></u></p>\n<p>\n Assess safety of the no-flip technique for Shang Ring circumcision by determining the rate of moderate and severe adverse events (AE) following use of the no-flip technique.  </p>\n<p>\n <strong><u>Phase II of study</u></strong></p>\n<p>\n Assess pain experienced during the Shang Ring circumcision procedure with topical vs. injectable anesthesia. The outcome metric would be maximum pain experienced during the Shang Ring circumcision, assessed using the visual analogue scale (VAS) score, reported immediately after completion of the procedure.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others1
      • scope_others_specifyAcceptability
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyMedical device in individuals above 10 years of age
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • 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; line-height: 20px;\">\n <u><strong>Homa Bay</strong></u></p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n <strong>Staff at site who will conduct the research</strong></p>\n<ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 10px 25px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n <li>\n Hospital surgeon (Homa bayu)\n <ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 0px 25px;\">\n <li>\n Dr Raymond Simba (Co investigator)- MMED Surg</li>\n </ul>\n </li>\n <li>\n 2 nurses - KRCHN\n <ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 0px 25px;\">\n <li>\n Jairus Oketch</li>\n <li>\n (Still to be recruited)</li>\n </ul>\n </li>\n <li>\n 1 Research Assistant\n <ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 0px 25px;\">\n <li>\n Dan Ouma </li>\n </ul>\n </li>\n <li>\n 1 Lead social mobiliser\n <ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 0px 25px;\">\n <li>\n Nereah Obura</li>\n </ul>\n </li>\n <li>\n Support staff (1)</li>\n</ul>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n <strong>Site & Facility building</strong></p>\n<p style=\"margin: 0px 0px 10px 40px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n Homa bay distirct hospital - VMMC Theatre</p>\n<p style=\"margin-top: 0px; margin-right: 0px; margin-bottom: 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n ================================================</p>\n<p style=\"margin-top: 0px; margin-right: 0px; margin-bottom: 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n <u><strong>Vipingo</strong></u></p>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n <strong>Staff at site who will conduct the research</strong></p>\n<ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 10px 25px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n <li>\n Hospital Clinical Officer in charge\n <ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 0px 25px;\">\n <li>\n Judy Kinya (Local PI)</li>\n </ul>\n </li>\n <li>\n 2 nurses - KRCHN\n <ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 0px 25px;\">\n <li>\n (to be recruited)</li>\n </ul>\n </li>\n <li>\n 1 Research Assistant\n <ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 0px 25px;\">\n <li>\n Millie Oundo </li>\n </ul>\n </li>\n <li>\n 1 Lead social mobiliser\n <ul style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 0px 25px;\">\n <li>\n David Mwamkita</li>\n </ul>\n </li>\n <li>\n Support staff (1)</li>\n</ul>\n<p style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n <strong>Site & Facility building</strong></p>\n<p style=\"margin: 0px 0px 10px 40px; color: rgb(51, 51, 51); font-family: \'Trebuchet MS\', Tahoma, Verdana, Arial, sans-serif; line-height: 20px;\">\n Vipingo Health Center - theatre</p>\n
      • other_details_explanation<p>\n Kenya was the first country where research on the Shang ring as a device for VMMC was conducted (2009). Since then alot of advancement into the use of the device has be gained plus inroads with the ministry of health (VMMC) and various stake holders.</p>\n<p>\n As this study is aimed at further improving the use of the device, Kenya is most suited to provide this environment of advanced research of this kind.</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n Weil Cornell Medical College - 3 Oct 2014</p>\n<p>\n Kenya Medical Research Institute (KEMRI) - 9th Jan 2015</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration3 weeks
      • 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_comparatorRemoval of day 7 group (P
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites2
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_siteNo preset maximum or minimum numbers per site.
      • total_participants_worldwide575
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenYes
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female0
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsNo
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameQuentin
      • investigator1_middle_name
      • investigator1_family_nameAwori
      • investigator1_qualificationMBChB
      • investigator1_professional_addressABC Place, 2nd floor Waiyaki Way, Westlands, Nairobi
      • investigator1_telephone+254 722 912 616
      • investigator1_emailQAwori@engenderhealth.org
      • organisations_transferred_Yes
      • number_participantsPhase I - 230\nPhase II - 345
      • notification
      • approval_date15-04-2015
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted27-01-2015
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe study is now approved
      • final_report<p>\n <strong>Phase 1: Simplifying the ShangRing Technique for Circumcision in Boys and Men: Use of the No-Flip Technique with Randomization to Removal at 7 Days vs. Spontaneous Detachment</strong></p>\n<p>\n Background</p>\n<p>\n Voluntary medical male circumcision is being rolled out to reduce HIV transmission in Sub-Saharan Africa. We assessed safety of the new no-flip ShangRing circumcision technique in males 10 years and older, and determined the clinical course and safety of spontaneous device detachment.</p>\n<p>\n Setting</p>\n<p>\n Two health facilities in Kenya.</p>\n<p>\n Methods</p>\n<p>\n We conducted a case series of no-flip ShangRing circumcision combined with a randomized controlled trial of removal 7 days post-circumcision vs. spontaneous device detachment. The primary outcome was safety of the no-flip technique based on moderate and severe adverse events (AEs). A main secondary outcome was clinical course and safety of spontaneous detachment.</p>\n<p>\n Results</p>\n<p>\n 230 men and boys were circumcised; 114 randomized to 7 day removal and 116 to spontaneous detachment. All circumcisions were successfully completed. There were 6 (5.3%) AEs in the 7-day group and 2 (1.7%) in the spontaneous group; with no significant differences when either were compared to historical data from Africa (p=.07 and p=.79, respectively). There was  no difference in AE rates (p=.169), visit day declared healed (p=.324) or satisfaction (p=.371) between randomization groups. 84 (72.4%) participants in the spontaneous group wore the ShangRing until it detached. The median days to detachment was 14.0 (IQR: 7-21, min-max: 5-35).</p>\n<p>\n Conclusions</p>\n<p>\n The no-flip technique and spontaneous detachment are safe, effective, and acceptable to males 10 years and older. Phimosis and penile adhesions do not limit successful ShangRing circumcision. A single device usable across ages would simplify services, supply chain management, training, and educational materials, and facilitate circumcision scale-up.</p>\n<p>\n <strong>Phase 2: Use of topical versus injectable anaesthesia for ShangRing circumcisions in men and boys in Kenya: Results from a randomized controlled trial</strong></p>\n<div>\n Background</div>\n<div>\n The ShangRing is a disposable, collar clamp circumcision device pre-qualified for use</div>\n<div>\n in men and boys 13 years and above. It has been shown to be faster than conventional</div>\n<div>\n circumcision with comparable adverse event (AE) rates and high client satisfaction.</div>\n<div>\n The fear of pain during circumcision is an important barrier to uptake of voluntary</div>\n<div>\n medical male circumcision (VMMC). Use of topical anesthesia thus presents an</div>\n<div>\n opportunity to address this.</div>\n<div>\n  </div>\n<div>\n Objectives</div>\n<div>\n We sought to evaluate the safety, effectiveness and acceptability of the use of topical</div>\n<div>\n anaesthesia with ShangRing circumcision of men and boys 10 years of age and above.</div>\n<div>\n  </div>\n<div>\n Methods</div>\n<div>\n Participants were randomised 2:1 to receive topical or injectable anaesthesia. All</div>\n<div>\n participants underwent no-flip ShangRing circumcision. The primary outcome measure</div>\n<div>\n was pain. Secondary outcomes included ease of use of topical versus injectable</div>\n<div>\n anaesthesia, AEs and participant satisfaction.</div>\n<div>\n  </div>\n<div>\n Results</div>\n<div>\n Compared to the topical group, participants in the injectable group reported</div>\n<div>\n significantly more pain on administration of the anesthesia and at approximately 20</div>\n<div>\n minutes after the procedure. Sufficient anaesthesia with topical cream was not</div>\n<div>\n achieved in 21 (9.3%) cases and supplementary injectable anaesthesia was required.</div>\n<div>\n The AE rate was significantly (p<.01) lower in the topical (0%) vs. the injectable group</div>\n<div>\n (4.2%). The most common was pain during the post-operative period. All AEs were</div>\n<div>\n managed conservatively and resolved without sequeale. 96.7% of participants were</div>\n<div>\n satisfied with the appearance of the healed penis and 100% would recommend the</div>\n<div>\n ShangRing to others. All seven male circumcision providers involved in the study</div>\n<div>\n preferred topical to injectable anaesthesia.</div>\n<div>\n  </div>\n<div>\n Conclusions</div>\n<div>\n Our results demonstrate the safety, improved clinical experience, effectiveness, and</div>\n<div>\n acceptability of the use of topical anaesthesia in ShangRing circumcision using the noflip</div>\n<div>\n technique. Topical anaesthesia is an important alternative and has the potential to</div>\n<div>\n increase demand for VMMC while decreasing the risk of needlestick injuries.</div>\n
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2018-10-10 18:29:03
      • created2015-01-19 09:07:49
      • total_sites(null)
      • ecitizen_invoice(null)
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      • 0(array)
        • id257
        • application_id379
        • given_nameMark
        • middle_name
        • family_nameBarone
        • qualificationDVM, MS
        • professional_address440 Ninth Avenue, 12th Floor, New York, New York
        • telephone+1 212 561 8084
        • emailmbarone@engenderhealth.org
        • created2015-01-19 10:00:27
        • modified2015-01-27 18:25:09
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        • application_id379
        • county_id43
        • site_nameHoma Bay Level IV hospital
        • physical_addressHoma Bay town,
        • contact_details0723 886 261
        • contact_personDr. Raymond Otieno
        • site_capacity(null)
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        • created2015-01-19 10:00:27
        • modified2015-01-27 18:25:09
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          • created2012-06-15 10:27:10
          • modified2012-06-15 10:27:10
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        • application_id379
        • county_id3
        • site_nameVipingo Health Centre
        • physical_addressVipingo
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        • contact_personJudy Kinya
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        • misc(null)
        • created2015-01-19 11:11:35
        • modified2015-01-27 18:25:09
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          • created2012-05-31 16:15:49
          • modified2012-05-31 16:15:49
    • Sponsor(array)
      • 0(array)
        • id195
        • application_id379
        • sponsorEngenderHealth
        • sponsor_type(null)
        • contact_personMark Barone
        • address440 Ninth Avenue, New york
        • telephone_number+1 (206) 709-3100
        • fax_number
        • cell_number+1 (206) 709-3100
        • email_addressmbarone@engenderhealth.org
        • created2015-01-19 10:00:27
        • modified2015-01-27 18:25:09
      • 1(array)
        • id196
        • application_id379
        • sponsorWeill Cornell Medical College
        • sponsor_type(null)
        • contact_personProf. Phillip Li
        • address1300 York Avenue . New York, NY 10065
        • telephone_number+1 (212) 746-5454
        • fax_number
        • cell_number+1 646 341 0033
        • email_addresspsli@med.cornell.edu
        • created2015-01-19 11:48:26
        • modified2015-01-27 18:25:09
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PHP Environment

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