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• trial_statuses(array)
  • 1Recruiting
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• applications(array)
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    • Application(array)
      • id1565
      • user_id667
      • trial_status_id2
      • abstract_of_study<p>\n <strong>Background: </strong>MK-8527 is a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) with potent antiretroviral activity against HIV-1, being developed for the prevention of HIV-1 infection because of its potent antiviral activity, long half-life, and favorable safety profile as demonstrated in early-phase clinical studies. Nonclinical and clinical data indicate that MK-8527 is generally well tolerated. The convenience and discretion of monthly oral administration of MK-8527 may facilitate adherence and access to PrEP for women at high risk for HIV-1 infection, ultimately leading to greater effectiveness for HIV-1 prevention than what is currently observed with daily oral emtricitabine/tenofovir disoproxil (FTC/TDF).</p>\n<p>\n <strong>Objectives: </strong>The primary objective of this study is to evaluate the efficacy, safety, and tolerability of MK-8527 monthly compared to FTC/TDF daily for the prevention of HIV-1 infection as assessed by the incidence rate per year of adjudicated HIV-1 infections and the number of adverse events reported leading to discontinuation of study intervention.</p>\n<p>\n <strong>Methods: </strong>This is a randomized, active-controlled, parallel-group, multisite, double-blind, double-dummy study to evaluate the efficacy and safety of monthly oral MK-8527 in cisgender women (assigned female sex at birth) 16 to 30 years of age, who are at a greater likelihood of HIV-1 exposure. The active comparator for this study will be oral daily FTC/TDF. Approximately 4580 participants from Africa will be randomized and stratified by age in a 1:1 ratio to receive either MK-8527 or FTC/TDF for the duration of the study. Approximately 80% of participants will be ≤25 years of age. Enrolment is competitive, and sites will enrol participants consecutively until the global target sample size is achieved. Our site will enroll upto 150 participants. Participants will be assessed every month till month 24, with an additional follow-up at day 28 and day 42 post-end of treatment.</p>\n<p>\n <strong>Expected results:</strong> The primary hypothesis is that oral monthly MK-8527 is superior to oral daily FTC/TDF with respect to the hazard ratio for HIV-1 infection and the number of adverse events reported leading to discontinuation of the study intervention.</p>\n
      • study_title<p>\n <b style=\"color: rgb(0, 0, 0); font-size: medium;\"><span lang=\"EN-GB\" style=\"font-size: 12pt; font-family: "Times New Roman", serif;\">A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate the Efficacy and Safety of MK-8527 Oral Once-Monthly as HIV-1 Preexposure Prophylaxis in Women.</span></b></p>\n
      • laymans_summary<p>\n HIV remains a major global health challenge, with nearly 40 million people living with the virus and over 1.3 million new infections reported in 2023. Women and girls account for a large share of these infections, especially in sub-Saharan Africa, where young women aged 15–24 are particularly affected—over 3,000 become infected every week in that region alone. To help prevent HIV, medications called PrEP (pre-exposure prophylaxis) are used. These are usually daily pills, but taking a pill every day can be hard for some people. New injectable options are available, but are not widely accessible and may not be preferred by everyone. This study is testing a new HIV prevention pill called MK-8527, which is taken once a month. It may be easier to use and more appealing for women who struggle with daily pills or dislike injections. The study involves over 4,500 HIV-negative cisgender women (assigned female sex at birth) aged 16 to 30 who are at higher risk of HIV infection.</p>\n<p>\n This study will be conducted at the KEMRI-CMR-RCTP Lumumba site in Kisumu County, Kenya. Upto 150 cisgender women (assigned female sex at birth) aged 16 to 30 who are at higher risk of HIV infection will be enrolled at this site. Participants will be randomly assigned to take either MK-8527 once a month or the standard daily PrEP pill. They will attend monthly follow-up visits for HIV testing, health check-ups, and medication monitoring over 24 months, with a short follow-up at day 28 and day 42 after treatment ends. Participants who become pregnant and continue with the study medication will have additional assessments, including blood sample collection. Participants will be recruited from within Kisumu County from HIV testing points, learning institutions, safe spaces, drop-in centres, bars and beaches, and from social media.</p>\n<p>\n If successful, MK-8527 could offer a simpler and more acceptable HIV prevention method for women, especially in areas where HIV rates are high and daily pill-taking is difficult.</p>\n
      • short_titleMK-8527-010
      • protocol_noECCT/25/08/02
      • version_no00
      • date_of_protocol28-04-2025
      • study_drugMK-8527
      • disease_conditionHIV
      • 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_nameMK-8527
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameTenofovir Disoproxil Fumarate + Emtricitabine
      • comparator_registeredYes
      • comparator_countriesKenya, Uganda, Tanzania, South Africa, USA
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressrgreshon@kemri-rctp.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
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      • applicant_financial_declaration1
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      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
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      • applicant_dsmb_charter1
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      • applicant_indemnity_pi1
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      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
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      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantDr. Greshon Rota
      • declaration_date112-08-2025
      • declaration_principal_investigatorProf. Elizabeth Bukusi
      • declaration_date212-08-2025
      • placebo_presentYes
      • study_objectives<p>\n Primary Objectives.</p>\n<p>\n 1. To evaluate the efficacy of MK-8527 qm compared to FTC/TDF qd for the prevention of HIV-1 infection as assessed by the incidence rate per year of adjudicated HIV-1 infections.</p>\n<p>\n 2. To evaluate the safety and tolerability of MK-8527 qm compared to FTC/TDF qd.</p>\n<p>\n Secondary Objectives.</p>\n<p>\n - None</p>\n<p>\n Tertiary/Exploratory Objectives</p>\n<div>\n 1. To evaluate aspects of treatment with MK-8527 qm and FTC/TDF qd on participant-reported outcomes.</div>\n<div>\n <div>\n 2. To evaluate the pharmacokinetics of MK-8527 qm using sparse PK sampling</div>\n <div>\n 3. To evaluate adherence to MK-8527 qm and FTC/TDF qd</div>\n <div>\n 4. To assess association between adherence to MK-8527 qm and efficacy in a nested casecontrol study</div>\n <div>\n 5. To evaluate the impact of MK-8527 qm on renal function compared to FTC/TDF qd as measured by the change from baseline in renal biomarkers at Weeks 24 and 48</div>\n <div>\n 6. To evaluate viral drug resistance in participants who seroconvert to HIV-1</div>\n <div>\n 7. To measure the plasma concentrations of ENG, MPA, and NET among participants who use an ENG-releasing implant or injectable depot MPA or injectable NETEN</div>\n <div>\n 8. To evaluate the PK of MK-8527 in pregnant participants</div>\n <div>\n 9. To evaluate the impact of MK-8527 qm on body weight and body mass index compared to FTC/TDF qd as measured by the change from baseline through Week 48</div>\n <div>\n 10. To explore the relationship between genetic variation and response to the treatment(s) administered, and mechanisms of disease. Variation across the human genome may be analyzed for association with clinical data collected in the study.</div>\n</div>\n<p>\n  </p>\n
      • principal_inclusion_criteria<div>\n <strong>Inclusion Criteria</strong></div>\n<div>\n An individual is eligible for inclusion in the study if the individual meets all of the following criteria:</div>\n<div>\n  </div>\n<div>\n <strong>Type of Participant and Disease Characteristics</strong></div>\n<div>\n 1. Is confirmed HIV-uninfected based on negative HIV-1/HIV-2 test results during screening. Note: Any positive HIV test during the Screening Period will exclude the participant from the study regardless of a negative confirmatory test. Additional testing to confirm suspected HIV infection during screening will be performed in accordance with local guidelines. If HIV infection is confirmed, participants will be referred for appropriate care, as necessary.</div>\n<div>\n 2. Has been sexually active (>2 vaginal intercourse encounters with cisgender male individual(s) within the last 3 months).</div>\n<div>\n  </div>\n<div>\n <strong>Demographics</strong></div>\n<div>\n 3. Was assigned female sex at birth, and is cisgender.</div>\n<div>\n 4. Aged from 16 years to 30 years of age inclusive, at the time of providing the informed consent or assent, as applicable. Note: Enrollment for 16- to 17-year-old participants may begin only after completion and review of the initial safety review results by the eDMC (refer to the section on statistical considerations).</div>\n<div>\n 5. Weighs >35 kg at enrollment.</div>\n<div>\n  </div>\n<div>\n <strong>Assigned Female Sex at Birth</strong></div>\n<div>\n 6. A participant assigned female sex at birth is eligible to participate if not breast/chestfeeding</div>\n<div>\n <div>\n 7. A POCBP is eligible to participate if not pregnant and if a negative highly sensitive pregnancy test (urine or serum), as required by local regulations, has been obtained within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.5. The definition of childbearing potential is in Appendix 5.</div>\n <div>\n  </div>\n <div>\n <strong>Informed Consent</strong></div>\n <div>\n 8. The participant (or participant’s legally acceptable representative) has provided documented informed consent and the participant has provided documented assent, when applicable, for the study.</div>\n <div>\n  </div>\n <div>\n <strong>Additional Categories</strong></div>\n <div>\n 9. Has no plans to travel or relocate away from the site that would interfere with attending monthly on-site visits for the duration of the study.</div>\n <div>\n  </div>\n <div>\n <strong>The following criteria must also be met to enroll in the Contraceptive Implant Injection DDI Substudy:</strong></div>\n <div>\n 10. Is currently using an ENG-releasing implant (ie, Nexplanon or Implanon NXT) or injectable-MPA or injectable-NET-EN or is willing to begin use at the Screening Visit.</div>\n</div>\n<div>\n  </div>\n<div>\n  </div>\n<div>\n  </div>\n
      • principal_exclusion_criteria<div>\n <strong>Exclusion Criteria</strong></div>\n<div>\n An individual must be excluded from the study if the individual meets any of the following criteria:</div>\n<div>\n  </div>\n<div>\n <strong>Medical Conditions</strong></div>\n<div>\n 1. Has hypersensitivity or other contraindication to any component of the study interventions as determined by the investigator.</div>\n<div>\n 2. Has evidence of acute or chronic hepatitis B infection (HBsAg positive).</div>\n<div>\n Note: Participants with isolated HBcAb positivity (HBsAg and HBsAb negative) will beexcluded if HBV DNA is positive.</div>\n<div>\n Note: Participants who do not demonstrate immunity to HBV will be offered HBV vaccination.</div>\n<div>\n 3. Has a history of malignancy within 5 years of screening except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer</div>\n<div>\n <div>\n 4. Has a history or current evidence of any condition (eg, active tuberculosis infection or hepatic cirrhosis), therapy, laboratory abnormality or other circumstance (including substance or alcohol use disorder) that might, in the opinion of the investigator, confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to enroll.</div>\n <div>\n  </div>\n <div>\n <strong>Prior/Concomitant Therapy</strong></div>\n <div>\n 5. Has taken cabotegravir, lenacapavir, or any other long-acting HIV prevention product at any time (past or current use). Note: Prior use of ISL (MK-8591) is permitted.</div>\n <div>\n 6. Is currently receiving or is anticipated to require any prohibited therapies outlined in Section 6.5 from 30 days prior to Day 1 through the study duration (ie, up to 56 ±5 days following the last dose of blinded monthly study intervention). Note: Participants taking or starting tenofovir-based PrEP at screening may continue</div>\n <div>\n their regimen until 24 hours before the blinded monthly dose on Day 1. Dapivirine ring can be removed on Day 1 prior to administration of study intervention.</div>\n <div>\n 7. Has received an HIV vaccine at any time (ie, through past participation in an investigational clinical study) or monoclonal antibodies to HIV within 12 months before Day 1.</div>\n <div>\n  </div>\n <div>\n <strong>Prior/Concurrent Clinical Study Experience</strong></div>\n <div>\n 8. Is currently participating in or has participated in an interventional or prevention clinical study with an investigational compound or device within 30 days prior to Day 1 through the duration of the study. Note: Concurrent participation in observational or noninterventional studies or longitudinal follow-up from interventional studies may be permitted and should be discussed with the Sponsor before enrollment and through study duration.</div>\n <div>\n  </div>\n <div>\n <strong>Diagnostic Assessments</strong></div>\n <div>\n 9. Has exclusionary laboratory values within 45 days prior to Day 1 as listed in Table 1 in the protocol. Note: A single repeat of a laboratory screening test will be allowed for test results that are unexpected, but the repeat test results must be available within the 45-day screening window</div>\n <div>\n  </div>\n <div>\n <div>\n <strong>Other Exclusions</strong></div>\n <div>\n 10. Is expecting to donate eggs at any time during the study. Note: Investigators should provide appropriate guidance to participants regarding egg</div>\n <div>\n donation after completion of the study intervention. It is recommended that all participants refrain from egg donation for at least 56 days following their last dose of</div>\n <div>\n blinded monthly study intervention.</div>\n <div>\n 11. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study.</div>\n </div>\n</div>\n<p>\n  </p>\n
      • primary_end_points<p>\n 1. <strong>Incidence rate of adjudicated </strong>HIV-1 infections at week 48 and week 96.</p>\n<p>\n 2. Adverse events and Adverse events leading to discontinuation of study intervention measured from the time of intervention randomization through 56 days after cessation of double-blind monthly study intervention</p>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
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      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Refer to sections 1,6, 7, and 8 of the site specific addendum attached. </p>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n National Drug Authority Uganda.(NDA). Date Unknown.</p>\n<p>\n South African Health Products Regulatory Authority (SAHPRA). Date Unknown.</p>\n<p>\n  </p>\n
      • other_details_regulatory_approved<p>\n None. Study in review.</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration27 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_comparatorTDF/FTC
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states3
      • number_of_sites4
      • multi_country_listKenya, South Africa, and Uganda
      • data_monitoring_committeeYes
      • total_enrolment_per_siteMinimum 150, Maximum 300)
      • total_participants_worldwide4580
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male0
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameElizabeth
      • investigator1_middle_nameAnne
      • investigator1_family_nameBukusi
      • investigator1_qualificationMBChB, M.Med (ObGyn), MPH, PhD, PGD (Research Ethics), MBE (Research Ethics)
      • investigator1_professional_addressKEMRI-CMR-RCTP KEMRI CIS Building Ondiek Road, Lumumba Sub-County Hospital P.O. Box 614-40100 Kisumu, Kenya
      • investigator1_telephone+254 733 617 503
      • investigator1_emailebukusi@rctp.or.ke
      • organisations_transferred_Yes
      • number_participantsMinimum 600, Maximum 1200
      • notification
      • approval_date21-11-2025
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted11-09-2025
      • is_child0
      • unsubmitted1
      • initial_date_submitted18-08-2025
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments have been addressed.
      • final_report(null)
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      • quantity_imported(null)
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      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-11-21 05:13:46
      • created2025-06-30 15:58:56
      • total_sites1
      • ecitizen_invoice379287
    • InvestigatorContact(array)
      • 0(array)
        • id1346
        • application_id1565
        • given_nameElizabeth
        • middle_nameAnne
        • family_nameBukusi
        • qualificationMBChB, M.Med (ObGyn), MPH, PhD, PGD (Research Ethics), MBE (Research Ethics)
        • professional_addressKEMRI-CMR-RCTP KEMRI CIS Building Ondiek Road, Lumumba Sub-County Hospital P.O. Box 614-40100 Kisumu, Kenya
        • telephone+254 733 617 503
        • emailebukusi@rctp.or.ke
        • created2025-08-12 06:49:34
        • modified2025-09-11 14:27:19
    • SiteDetail(array)
      • 0(array)
        • id1981
        • application_id1565
        • county_id42
        • site_nameKEMRI CMR RCTP
        • physical_addressKEMRI CIS Building Ondiek Road, Lumumba Sub-County Hospital P.O. Box 614-40100 Kisumu, Kenya
        • contact_detailsTelephone: 0202600017, P.O. Box 614-40100 Kisumu, Kenya
        • contact_personDr Victor Omollo
        • site_capacity(null)
        • misc(null)
        • created2025-08-12 06:49:34
        • modified2025-09-11 14:27:19
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
    • Sponsor(array)
      • 0(array)
        • id861
        • application_id1565
        • sponsorMerck Sharp & Dohme LLC
        • sponsor_typeIndustry
        • contact_personSusan Vaz
        • addressMSD Office Address: 117 16th Road, Midrand, 1685, Gauteng, South Africa Private Bag 3, Halfway House, 1685, Gauteng, South Africa
        • telephone_number+27 79 510 3445
        • fax_number
        • cell_number+27 74 688 8319
        • email_addresssusan.vaz@msd.com
        • created2025-08-12 06:49:34
        • modified2025-09-11 14:27:19
  • 1(array)
    • Application(array)
      • id1563
      • user_id127
      • trial_status_id2
      • abstract_of_study<h1>\n Abstract</h1>\n<p>\n <strong>Background:</strong><br />\n HIV-1 infection remains a persistent global epidemic. In 2023, 39.9 million people were living with HIV, with 1.3 million new infections reported globally. Women and girls accounted for 44% of new HIV infections globally, and in sub-Saharan Africa, they represented 62%. Approximately 4000 adolescent girls and young women aged 15–24 became infected every week, with 3100 of these cases in sub-Saharan Africa. HIV requires lifelong treatment and poses multiple health risks, creating a growing healthcare burden. While WHO-recommended daily oral PrEP, including FTC/TDF and FTC/TAF, is effective, its success depends heavily on strict adherence—often a challenge in high-risk populations. Recently approved injectable PrEP like cabotegravir has improved efficacy but faces access and acceptability barriers. Thus, a long-acting oral PrEP alternative like MK-8527 could address these limitations. The trial tests the efficacy of MK-8527 administered once monthly (qm) compared to FTC/TDF administered once daily (qd) for the prevention of HIV-1 infection, as measured by the annual incidence rate of adjudicated HIV-1 infections. Additionally, the study evaluates the safety and tolerability of MK-8527 qm in comparison to FTC/TDF qd.</p>\n<p>\n <strong>Methodology:</strong><br />\n This Phase 3 randomized, double-blind, active-controlled clinical trial compares once-monthly oral MK-8527 to once-daily FTC/TDF for HIV-1 pre-exposure prophylaxis in cisgender women aged 16–30 at risk of HIV infection. Approximately 4580 participants will be enrolled and followed for up to 24 months, with a 28-day follow-up. Participants will be randomized to receive either MK-8527 or FTC/TDF under blinded design. The primary endpoint is the incidence rate of adjudicated HIV-1 infections.</p>\n<p>\n <strong>Outcomes:</strong><br />\n An interim analysis will occur after ≥24 primary endpoint cases are accrued. MK-8527's long intracellular half-life supports a monthly dosing strategy aimed at improving adherence and acceptability among women. This study may lead to a more practical and preferred HIV prevention option for women at high risk, especially in low-resource and high-burden settings.</p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n
      • study_title<p style=\"margin-left:6.2pt;\">\n A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate the Efficacy and Safety of MK-8527 Oral Once-Monthly as HIV-1 Preexposure</p>\n<p style=\"margin-left:6.2pt;\">\n Prophylaxis in Women</p>\n<p style=\"margin-left:6.2pt;\">\n  </p>\n
      • laymans_summary<h1>\n  Lay Summary</h1>\n<p>\n HIV remains a major global health problem.  Around 40 million people are living with the virus, and more than 1.3 million new cases were reported in 2023. Women and girls make up a large number of these cases, especially in sub-Saharan Africa. In this region, young women aged 15 to 24 are hit the hardest, with over 3,000 new infections happening each week.</p>\n<p>\n To help prevent HIV, medications called PrEP (pre-exposure prophylaxis) are used. These are usually taken as daily pills, but taking a pill every day can be difficult  for some people.  Injections are now available as another option, but they aren’t easy for everyone to get and some people might not like them.</p>\n<p>\n This study is testing a new HIV prevention pill called <strong>MK-8527</strong>, which is taken <strong>once a month</strong><strong>.</strong> It may be easier to use and more attractive for women who find it hard to take a pill every day, or don’t like getting injections. The study involves over 4,500 HIV-negative cisgender women (assigned female sex at birth and identify as a woman) aged 16 to 30, who have a higher chance of getting HIV infection.</p>\n<p>\n <strong>Methods:</strong><br />\n Participants in the study will be randomly placed into one of two groups:  one will take the monthly pill (MK-8527)  , and the other will take  the standard daily PrEP pill (FTC/TDF). They will come in once a month for 24 months for HIV tests, health check-ups, and to track how the medicine is working, with a short follow-up after treatment ends.<br />\n If a participant becomes pregnant and decides to keep taking the study medicine, she will have some extra health checks, including blood sample tests.</p>\n<p>\n  <strong>Outcome:</strong><br />\n If successful, MK-8527 could provide an easier and more preferred way for women to prevent HIV—especially in places where HIV is common and taking a pill every day is hard</p>\n
      • short_titleMK-8527 as HIV-1 PrEP in Women
      • protocol_noECCT/25/08/01
      • version_no0.00
      • date_of_protocol28-04-2025
      • study_drugMK-8527
      • disease_conditionHIV-1
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameMK8527 (Investigational)
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameFTC/TDF (Emtricitabine/Tenofovir Disoproxil Fumarate)
      • comparator_registeredYES
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressmaricianah@gmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantDr. Maricianah Onono
      • declaration_date112-08-2025
      • declaration_principal_investigatorProf. Elizabeth Bukusi
      • declaration_date212-08-2025
      • placebo_presentYes
      • study_objectives<p>\n <strong>Primary Objectives:</strong></p>\n<p>\n 1. To evaluate the efficacy of MK-8527 qm compared to FTC/TDF qd for the prevention of HIV-1 infection as assessed by the incidence rate per year of adjudicated HIV-1 infections. Hypothesis: MK-8527</p>\n<p>\n  2. To evaluate the safety and tolerability of MK-8527 qm compared to FTC/TDF qd.</p>\n<p>\n  </p>\n<p>\n <strong>Tertiary Objectives:</strong></p>\n<ol>\n <li>\n  To evaluate aspects of treatment with MK-8527 qm and FTC/TDF qd on participant-reported outcomes.</li>\n <li>\n  To evaluate the pharmacokinetics of MK-8527 qm using sparse PK sampling</li>\n <li>\n To assess association between adherence to MK-8527 qm and efficacy in a nested case control study</li>\n <li>\n To evaluate adherence to MK-8527 qm and FTC/TDF qd</li>\n <li>\n To evaluate the impact of MK-8527 qm on renal function compared to FTC/TDF qd as measured by the change from baseline in renal biomarkers at Weeks 24 and 48</li>\n <li>\n To evaluate viral drug resistance in participants who seroconvert to HIV-1</li>\n <li>\n To measure the plasma concentrations of ENG, MPA, and NET among participants who use an ENG-releasing implant or injectable depot MPA or injectable NET EN</li>\n <li>\n To evaluate the PK of MK-8527 in pregnant participants</li>\n <li>\n To evaluate the impact of MK-8527 qm on body weight and body mass index compared to FTC/TDF qd as measured by the change from baseline through Week48</li>\n <li>\n To explore the relationship between genetic variation and response to the treatment(s) administered, and mechanisms of disease. Variation across the human genome may be analyzed for association with clinical data collected in the study.</li>\n</ol>\n
      • principal_inclusion_criteria<h2>\n Inclusion</h2>\n<p>\n The site will consider a participant eligible for inclusion in the study if the individual meets all of the following criteria:</p>\n<p>\n  </p>\n<p>\n <strong>Type of Participant and Disease Characteristics</strong></p>\n<p>\n 1. Is confirmed HIV-uninfected based on negative HIV-1/HIV-2 test results during screening.</p>\n<p>\n <em>Note: Any positive HIV test during the Screening Period will exclude the participant from the study regardless of a negative confirmatory test. Additional testing to confirm suspected HIV infection during screening will be performed in accordance with local guidelines. If HIV infection is confirmed, participants will be referred for appropriate care, as necessary.</em></p>\n<p>\n 2. Has been sexually active (≥2 vaginal intercourse encounters with cisgender male individual(s) within the last 3 months).</p>\n<p>\n <strong>Demographics</strong></p>\n<p>\n 3. Was assigned female sex at birth, and is cisgender.</p>\n<p>\n 4. Aged from 16 years to 30 years of age inclusive, at the time of providing the informed consent or assent, as applicable.</p>\n<p>\n <em>(Note: Enrolment for 16- to 17-year-old participants may begin only after completion and review of the initial safety review results by the eDMC (as indicated in section 9 of the protocol on statistical considerations).</em></p>\n<p>\n 5. Weighs ≥35 kg at enrolment.</p>\n<p>\n  </p>\n<p>\n <strong>Assigned Female Sex at Birth</strong></p>\n<p>\n 6. A participant assigned female sex at birth is eligible to participate if not breast/chestfeeding.</p>\n<p>\n 7. A POCBP is eligible to participate if not pregnant and if a negative highly sensitive pregnancy test (urine or serum), as required by local regulations, has been obtained within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. </p>\n
      • principal_exclusion_criteria<h3>\n Exclusion Criteria</h3>\n<p>\n The site will exclude and individual from the study if they meet any of the following criteria:</p>\n<p>\n  </p>\n<p>\n <strong>Medical Conditions</strong>:</p>\n<p>\n 1. Has hypersensitivity or other contraindication to any component of the study interventions as determined by the investigator.</p>\n<p>\n  2. Has evidence of acute or chronic hepatitis B infection (HBsAg positive<em>). </em></p>\n<p>\n <em>  Note: Participants with isolated HBcAb positivity (HBsAg and HBsAb negative) will be excluded if HBV DNA is positive.</em></p>\n<p>\n <em>Note: Participants who do not demonstrate immunity to HBV will be offered HBV vaccination.</em></p>\n<p>\n 3. Has a history of malignancy within 5 years of screening except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer.</p>\n<p>\n 4. Has a history or current evidence of any condition (eg, active tuberculosis infection or hepatic cirrhosis), therapy, laboratory abnormality or other circumstance (including substance or alcohol use disorder) that might, in the opinion of the investigator, confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to enroll.</p>\n<p>\n  </p>\n<p>\n <strong>Prior/Concomitant Therapy</strong></p>\n<p>\n 5. Has taken cabotegravir, lenacapavir, or any other long-acting HIV prevention product at any time (past or current use). Note: Prior use of ISL (MK-8591) is permitted.</p>\n<p>\n 6. Is currently receiving or is anticipated to require any prohibited therapies as outlined in Section 6.5 of the global protocol (from 30 days prior to Day 1 through the study duration (ie, up to 56 ±5 days following the last dose of blinded monthly study intervention).</p>\n<p>\n <em>Note: Participants taking or starting tenofovir-based PrEP at screening may continue their regimen until 24 hours before the blinded monthly dose on Day 1. Dapivirine ring can be removed on Day 1 prior to administration of study intervention.</em></p>\n<p>\n 7. Has received an HIV vaccine at any time (ie, through past participation in an investigational clinical study) or monoclonal antibodies to HIV within 12 months before Day 1.</p>\n<p>\n  </p>\n<p>\n <strong>Prior/Concurrent Clinical Study Experience</strong></p>\n<p>\n 8. Is currently participating in or has participated in an interventional or prevention clinical study with an investigational compound or device within 30 days prior to Day 1 through the duration of the study.</p>\n<p>\n <em>Note: Concurrent participation in observational or noninterventional studies or longitudinal follow-up from interventional studies may be permitted and should be discussed with the Sponsor before enrollment and through study duration</em>.</p>\n<p>\n  </p>\n<p>\n <strong>Diagnostic Assessments</strong></p>\n<p>\n 9. Has exclusionary laboratory values within 45 days prior to Day 1 as listed in the laboratory exclusion criteria on below.<img alt=\"\" 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\" /></p>\n<p>\n <em>Note: A single repeat of a laboratory screening test will be allowed for test results that are unexpected, but the repeat test results must be available within the 45-day screening window.</em></p>\n<p>\n            </p>\n
      • primary_end_points<p>\n  1. Adjudicated HIV-1 infection</p>\n<p>\n  2. Adverse Events</p>\n<p>\n 3. Adverse events-Adverse events leading to discontinuation of study intervention</p>\n
      • scope_diagnosis0
      • scope_prophylaxis1
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">The sites have infrastructure that includes adequate study space, laboratory equipment, experienced staff who have been involved in a number of phase 2 and 3 trials. The staff also have experience in contraceptive counselling, clinical assessment, HIV care and counselling and thus the study takes advantage of this existing infrastructure.</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">The study will be coordinated by:</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">1. Prof. Elizabeth Bukusi MBChB, MMed, MPH, PhD</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">2. Dr. Maricianah Onono MBChB, Msc, PhD, MMed</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">3. Prof. Nelly Mugo MBChB, MMed, MPH, PhD</span></p>\n<p>\n <span style=\"font-family:arial,helvetica,sans-serif;\">4. Dr. Irene Inwani MBChB, MMed, MPH</span></p>\n
      • other_details_explanation<p>\n <span style=\"font-size:12px;\">Kenya continues to face a significant HIV burden, particularly among women of reproductive age, who account for a large proportion of new infections. Conducting this trial in Kenya allows for the <span style=\"color: rgb(0, 0, 0); font-family: arial, sans-serif; font-variant-ligatures: no-contextual;\">addressing of a critical public health priority through an innovative intervention that aligns with national HIV prevention strategies and </span>for the evaluation of MK-8527, a once-monthly oral PrEP candidate, in a high-risk population where its impact could be most meaningful. The study will generate locally relevant data, support public health efforts, and leverage Kenya’s strong research infrastructure to address a critical unmet need in HIV prevention.</span></p>\n
      • other_details_regulatory_notapproved<p>\n Kenya Medical Research Institute- Scientific Ethics Research Unit (SERU) </p>\n<p>\n Date of application: 26th June 2025</p>\n
      • other_details_regulatory_approved<p>\n None</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n Not Applicable</p>\n
      • estimated_duration24 months
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorFTC/TDF
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states3
      • number_of_sites4
      • multi_country_listKenya, South Africa and Uganda
      • data_monitoring_committeeYes
      • total_enrolment_per_site150 - 600\n
      • total_participants_worldwide4580
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male0
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenYes
      • subjects_nursing_womenYes
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyAdolescents 16 and 17 years old
      • subjects_othersYes
      • subjects_others_specifyInfants born of consenting pregnant and breast feeding participants who consent to the sub studies
      • investigator1_given_nameElizabeth
      • investigator1_middle_nameAnne
      • investigator1_family_nameBukusi
      • investigator1_qualificationMBChB, M.Med (ObGyn), MPH, PhD , PGD(Research Ethics). MBE (Research Ethics)
      • investigator1_professional_addressCenter for Microbiology Research, KEMRI, Box 19464, post code 00202, Nairobi
      • investigator1_telephoneTel mobile 254 733617503/ 720617503 Fax 254 20 2737658 (Nairobi) 254 57 2021945 (Kisumu) Land line 254 20 6751748(Nairobi) 254 57 2021036 (Kisumu)
      • investigator1_emailebukusi@rctp.or.ke
      • organisations_transferred_Yes
      • number_participants1000
      • notification
      • approval_date21-11-2025
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted11-09-2025
      • is_child0
      • unsubmitted1
      • initial_date_submitted12-08-2025
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments have been addressed.
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-11-21 05:43:56
      • created2025-06-25 20:14:16
      • total_sites1
      • ecitizen_invoice382691
    • InvestigatorContact(array)
      • 0(array)
        • id1311
        • application_id1563
        • given_nameMaricianah
        • middle_name
        • family_nameOnono
        • qualificationMBChB, MSc, PhD, MMed
        • professional_addressBox 19669-40123
        • telephone0732390992
        • emailmaricianah@gmail.com
        • created2025-06-25 20:33:51
        • modified2025-09-11 17:56:24
    • SiteDetail(array)
      • 0(array)
        • id1947
        • application_id1563
        • county_id42
        • site_nameKEMRI-RCTP KISUMU
        • physical_addressCIS Building, Lumumba Subcounty Hospital
        • contact_detailsTel mobile 254 733617503/ 720617503 Fax 254 20 2737658 (Nairobi) 254 57 2021945 (Kisumu) Land line 254 20 6751748(Nairobi) 254 57 2021036 (Kisumu)
        • contact_personProf Elizabeth Anne Bukusi
        • site_capacity(null)
        • misc(null)
        • created2025-06-25 20:33:51
        • modified2025-09-11 17:56:24
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 1(array)
        • id1949
        • application_id1563
        • county_id42
        • site_nameKargeno Research and Policy Hub KEMRI-CMR KISUMU
        • physical_addressStreet Address: Karume Road / Jairo Street Junction, Opposite Administration Police (AP) line Dispensary, Kisumu
        • contact_detailsBox 19669-40123; Tel 0732390992
        • contact_personDr Maricianah Onono
        • site_capacity(null)
        • misc(null)
        • created2025-06-30 12:47:49
        • modified2025-09-11 17:56:24
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 2(array)
        • id1950
        • application_id1563
        • county_id22
        • site_nameKEMRI-PHRD, Thika
        • physical_addressSection 9 OAU, Near Thika Nursing Home, Thika
        • contact_detailsP.O.BOX 54840-00200, Nairobi, Kenya Tel:0723914057
        • contact_personProf. Nelly Rwamba Mugo
        • site_capacity(null)
        • misc(null)
        • created2025-06-30 12:47:49
        • modified2025-09-11 17:56:24
        • County(array)
          • id22
          • county_nameKiambu
          • created2012-06-15 10:24:37
          • modified2012-06-15 10:24:37
      • 3(array)
        • id1951
        • application_id1563
        • county_id43
        • site_nameUW KNH - Rachuonyo County Hospital
        • physical_addressRachuonyo County Referral Hospital
        • contact_detailsP.O.BOX 42-40222, Oyugis,Kenya, Tel: +254722608483
        • contact_personDr. Irene Inwani
        • site_capacity(null)
        • misc(null)
        • created2025-06-30 12:47:49
        • modified2025-09-11 17:56:24
        • County(array)
          • id43
          • county_nameHoma Bay
          • created2012-06-15 10:27:10
          • modified2012-06-15 10:27:10
    • Sponsor(array)
      • 0(array)
        • id849
        • application_id1563
        • sponsorMerck Sharp & Dohme LLC
        • sponsor_typeIndustry
        • contact_personSue Bailey
        • addressMSD (Pty) Ltd, South Africa 117 16th Road, Midrand, 1685, Gauteng, South Africa
        • telephone_number+27116553307
        • fax_number
        • cell_number+27116553307
        • email_addresssue.bailey@msd.com
        • created2025-06-25 20:33:51
        • modified2025-09-11 17:56:24
  • 2(array)
    • Application(array)
      • id1519
      • user_id966
      • trial_status_id(null)
      • abstract_of_study<p>\n Each year around 15 million newborns are born prematurely and among this, 1 million die. Prematurity contributes to the leading cause of death for neonatal and under-five child mortality. The most common cause of death for preterm infants is respiratory distress syndrome (RDS). Management options for RDS include continuous positive airway positive pressure (CPAP), mechanical ventilation, and surfactant administration. Surfactant is recommended and is on the essential drug list by the World Health Organization (WHO). Though it is recommended by WHO, the cost of surfactant is not affordable for most low- or middle-income countries (LMICs). Additionally, the method of administration utilizing laryngoscopy is challenging in LMICs with limited skilled health workers. Less invasive and less technically challenging methods of surfactant administration are required to strengthen surfactant delivery. Administration via supraglottic airway device is a newer method that is both less invasive to the patient as well as less technically challenging for the health worker. The study aims to evaluate the comparative effectiveness of surfactant administered via a supraglottic airway device (SALSA) compared to surfactant administered via endotracheal tube placed under direct laryngoscopy with rapid extubation (InSurE). The design will be unblinded, multi-centre, randomized controlled trial (RCT). Te reserch question is 'Is surfactant administered via the SALSA method non-inferior (10% margin) to surfactant administered via the InSurE method for the primary outcome of survival to 72 hours without receiving or reaching criteria for mechanical ventilation?'  the study population is Preterm infants (gestational age 28 0/7 -36 6/7 weeks) born in the study hospitals with birthweight ≥ 1000 grams and a clinical diagnosis of RDS who meet surfactant criteria within 24 hours from birth: Downes’ score of 4 or greater, CPAP ≥ 6 cmH20 and FiO2 ≥ 0.4 to maintain saturation 90-95% for at least 30 minutes. The study sites will be St Paul’s Hospital Millennium Medical College in Ethiopia, Kenyatta National Hospital in Kenya, and Lagos State University Teaching Hospital in Nigeria. All are government academic tertiary hospitals with neonatal intensive care units with the ability to provide CPAP with blended oxygen, surfactant and mechanical ventilation. The intervention is Surfactant administration using supraglottic airway device (SALSA) while the control will be  Surfactant administration using Intubation, Surfactant administration, and Extubation (InSurE).</p>\n
      • study_title<p>\n Randomized Controlled Trial of Surfactant Administered via Supraglottic Airway Device (SALSA) Compared to Endotracheal Tube (InSurE) on Survival without Mechanical Ventilation in Preterm Neonates with Respiratory Distress Syndrome in Sub-Saharan Africa</p>\n
      • laymans_summary<div>\n Respiratory Distress Syndrome is the leading cause of mortality in preterm neonates globally, especially in LMICs. Evidence-based therapies for RDS include oxygen, CPAP, surfactant, and mechanical ventilation. The standard of care for preterm infants with RDS treated with CPAP therapy and oxygen is to utilize surfactant when CPAP has been optimized but an infant remains in respiratory failure. The goal of surfactant therapy is to prevent the need for mechanical ventilation or death due to respiratory failure, and it has been proven to be an effective therapy since the 1990s. In many LMICs, however, the use of surfactant is limited due to cost and availability, even though surfactant remains on the WHO’s list of essential medications. Historically, administration of surfactant has also required highly skilled providers, using techniques of direct laryngoscopy to place catheters or tubes for surfactant administration through the vocal cords of preterm infants to administer the medication directly into the lungs. Newer techniques utilizing supraglottic airway devices for surfactant administration have proven to be effective in delivering the medication to the upper airway with distribution to lungs via positive pressure breaths. However, studies on SALSA in preterm infants have been limited by available supraglottic airway device sizes. There are approximately 25 different supraglottic or laryngeal mask devices available in current clinical practice. Manufacturer’s recommendations vary, however most size 1 device are recommended for infants 2-5kg and > 34 weeks, although size 1 devices have been used in clinical trials in smaller infants. Supraglottic airway devices from one manufacturer are now available in clinical practice in size 0 and 0.5, appropriate for infants weighing < 2000 grams.</div>\n<div>\n Currently, the standard of care, way to give surfactant requires laryngoscopy. This is where a clinician looks directly into the baby’s airway using a laryngoscope (a metal device with light that holds the airway open) and then inserts a tube through the vocal cords, after the tube placement is checked for being in the airway or windpipe surfactant will be delivered. This method is very effective, but is challenging to learn, and may take more than one attempt even for experienced clinicians. Also, during laryngoscopy, some babies may briefly have a drop in their heart rate or oxygen levels.</div>\n<div>\n Supraglottic airways are a different type of device, made from a soft plastic, shaped to fit into the mouth and form a seal over the airway opening(windpipe), without passing through the vocal cords. They can be inserted without using a metal laryngoscope, they may be easier for clinicians to use and more comfortable for babies. Supraglottic airway devices are used for surfactant administration in some settings. Our study aims to compare their safety and effectiveness as compared to the above standard of care.</div>\n<div>\n Kenyatta National Hospital neonatal unit will participate in this proposed trial with an aim to evaluate the comparative effectiveness of surfactant administered via a supraglottic airway device (SALSA) compared to surfactant administered via endotracheal tube placed under direct laryngoscopy rapid extubation (InSurE). This will be a non-blinded randomized controlled trial.</div>\n
      • short_titleSASI
      • protocol_noECCT/25/07/06
      • version_no4.2
      • date_of_protocol27-03-2025
      • study_drugsurfactant administered via a supraglottic airway device (SALSA) compared to surfactant administered via endotracheal tube placed under direct laryngoscopy rapid extubation (InSurE
      • disease_conditionRespiratory Distress Syndrome
      • 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_namelaryngeal Mask Airway
      • comparatorYes
      • comparator_nameSurfactant via InSurE (utilizing ETT)
      • comparator_registeredYes
      • comparator_countriesEndotracheal tubes are registered in numerous countries worldwide such as North America (US, Canada, Mexico), Europe (Germany, Italy, France, UK, Spain, and other European nations), Asia-Pacific (Japan, China, India, Australia, South Korea, and the rest of the region), and LAMEA (Brazil, Saudi Arabia, South Africa, and the rest of the region). They are available and marketed in Kenya.
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressmail4chomba@gmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicant0721612393
      • declaration_date128-02-2025
      • declaration_principal_investigatorDr Mary Waiyego, National Site Investigator- Kenya- Neonatologist
      • declaration_date228-02-2025
      • placebo_presentNo
      • study_objectives<p>\n To evaluate the comparative effectiveness of surfactant administered via a supraglottic airway device (SALSA) compared to surfactant administered via endotracheal tube placed under direct laryngoscopy with rapid extubation (InSurE).</p>\n
      • principal_inclusion_criteria<div>\n Gestational age 28 0/7 -36 6/7 weeks</div>\n<div>\n Birthweight 1000 grams or greater</div>\n<div>\n Inborn</div>\n<div>\n Spontaneously breathing</div>\n<div>\n Clinical diagnosis of RDS and meeting surfactant criteria within 24 hours from birth</div>\n<div>\n Downes’ score of 4 or greater</div>\n<div>\n CPAP ≥ 6 cmH20 and FiO2 ≥ 0.4 to maintain saturations 90-95%</div>\n<div>\n CPAP optimized and safety check complete</div>\n
      • principal_exclusion_criteria<div>\n Previous treatment with surfactant or mechanical ventilation via an endotracheal tube</div>\n<div>\n Urgent need for intubation and mechanical ventilation as determined by the treating clinician</div>\n<div>\n Known pneumothorax</div>\n<div>\n Major congenital anomaly of lungs, heart or airway</div>\n<div>\n Apgar < 3 at 5 minutes</div>\n<div>\n Intent to limit care based on palliative or comfort care</div>\n
      • primary_end_points<div>\n Survival without receiving or reaching criteria for mechanical ventilation at 72 hours post randomization</div>\n<ul>\n <li>\n Mechanical ventilation criteria: patient met criteria for 3rd surfactant dose (first two doses given via randomized method, SALSA or InSurE), apnea not responding to effective positive pressure ventilation for 1 minute or clinician discretion due to vital sign or clinical instability</li>\n</ul>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety0
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyNon- Inferiority
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<div>\n The study will be conducted in the Newborn Unit of Kenyatta National hospital, a public tertiary hospital that receives referrals from within and outside Kenya in the Eastern and Central African regions. The newborn unit is located at the pediatric specialized units on the first floor.</div>\n<div>\n The KNH newborn unit admits, on average, 150 neonates per month. About 13% of neonates admitted to the NBU have very low birth weight (1000-1499 grams), with 85% of these neonates being admitted on their day of birth. The average length of stay is 9.7 days, and the median is 10.8 days. The NBU has a 60-bed capacity, though average bed occupancy is about 150%. The newborn unit staff includes 5 neonatologists, 2 neonatology fellows, and 12-15 pediatrician trainees. Eight nurses work in mixed shifts, with an average of 13 on duty at any time. Total nurses- 88, Nursing ratios NICU -1:3, HBU-1:10, General Nursery-1:13. Primary reasons for admissions to the KNH newborn unit include intrapartum-related complications, respiratory distress syndrome, neonatal sepsis, low birthweight, and neonatal jaundice.</div>\n<div>\n The study will be  led by Dr Mary Waiyego- neonatologist (Site  Principal Investigator) , Dr Phillip Mule, a pharmacist, Dr Miriam Weru- Neonatologist and study doctor with experience in airway management, Dorothy Chomba- Study Coordinator, six study nurses with experience in research data collection , a data clerk with experience in data entry and unit airway management team.  </div>\n
      • other_details_explanation<p>\n The study is multi country and it will be implimented in Ethiopia at  St Paul\'s Hospital Millennium Medical College.</p>\n
      • other_details_regulatory_notapproved<p>\n Kenya -</p>\n<ul>\n <li>\n National Commission for Science technology and Innovation</li>\n <li>\n Pharmacy Poisons Board</li>\n</ul>\n<p>\n  </p>\n<div style=\"margin: 0px; font-family: Aptos, Aptos_EmbeddedFont, Aptos_MSFontService, Calibri, Helvetica, sans-serif; font-size: 12pt; color: rgb(0, 0, 0);\">\n  <b>For Ethiopia </b></div>\n<div style=\"margin: 0px; font-family: Aptos, Aptos_EmbeddedFont, Aptos_MSFontService, Calibri, Helvetica, sans-serif; font-size: 12pt; color: rgb(0, 0, 0);\">\n  </div>\n<div style=\"margin: 0px; font-family: Aptos, Aptos_EmbeddedFont, Aptos_MSFontService, Calibri, Helvetica, sans-serif; font-size: 12pt; color: rgb(0, 0, 0);\">\n Ethics Committee -St. Paul\'s hospital Milennium Medical College IRB </div>\n<div style=\"margin: 0px; font-family: Aptos, Aptos_EmbeddedFont, Aptos_MSFontService, Calibri, Helvetica, sans-serif; font-size: 12pt; color: rgb(0, 0, 0);\">\n                                  The National Research Ethics Review Board (NRERB)</div>\n<div style=\"margin: 0px; font-family: Aptos, Aptos_EmbeddedFont, Aptos_MSFontService, Calibri, Helvetica, sans-serif; font-size: 12pt; color: rgb(0, 0, 0);\">\n  </div>\n<div style=\"margin: 0px; font-family: Aptos, Aptos_EmbeddedFont, Aptos_MSFontService, Calibri, Helvetica, sans-serif; font-size: 12pt; color: rgb(0, 0, 0);\">\n Regulatory Authority -Ethiopian Food and Drug Authority (EFDA )</div>\n<div style=\"margin: 0px; font-family: Aptos, Aptos_EmbeddedFont, Aptos_MSFontService, Calibri, Helvetica, sans-serif; font-size: 12pt; color: rgb(0, 0, 0);\">\n  </div>\n<div style=\"margin: 0px; font-family: Aptos, Aptos_EmbeddedFont, Aptos_MSFontService, Calibri, Helvetica, sans-serif; font-size: 12pt; color: rgb(0, 0, 0);\">\n <div style=\"font-size: 12pt;\">\n <b>For Nigeria </b></div>\n <div style=\"font-size: 12pt;\">\n  </div>\n <div style=\"font-size: 12pt;\">\n <span style=\"font-size: 12pt;\">Ethics Committee</span> -Lagos State University Teaching Hospital Health Research Ethics Committee</div>\n <div style=\"margin: 1em 0px; font-size: 12pt;\">\n <span style=\"font-size: 12pt;\">Regulatory Authority </span> -National Agency for Food and Drug Administration and Control (NAFDAC)</div>\n</div>\n<p>\n  </p>\n
      • other_details_regulatory_approved<p>\n Kenyatta National Hospital - University of Nairobi Research Ethics Review Committtee</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n None</p>\n
      • estimated_duration2 years
      • design_controlled_randomisedYes
      • design_controlled_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_comparatorSurfactant via InSurE
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKenyatta national Hospital
      • single_site_physical_addressHospital Road
      • single_site_contact_personDr Mary Waiyego
      • single_site_telephone0721612393
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states3
      • number_of_sites
      • multi_country_listNigeria\nEthiopia\nKenya
      • data_monitoring_committeeYes
      • total_enrolment_per_site280 (Kenyatta National Hospital will be the only site in Kenya)
      • total_participants_worldwide612 participants
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornYes
      • population_newbornYes
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18No
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationYes
      • subjects_incapable_consentYes
      • subjects_specifyPreterm infants (gestational age 28 0/7 -36 6/7 weeks) born in the study hospitals with birthweight of above 1000 grams and a clinical diagnosis of RDS who meet surfactant criteria within 24 hours from birth: Downes score of 4 or greater, CPAP of >= 6 cmH20 and FiO2 >=0.4 to maintain saturation 90-95% for at least 30 minutes
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameMary
      • investigator1_middle_nameWaiyego
      • investigator1_family_nameKariuki
      • investigator1_qualificationMBChB, M.Med, CPSA
      • investigator1_professional_addressP.O. Box 20723-00202 Nairobi
      • investigator1_telephone0721612393
      • investigator1_emailwaiyegomary99@gmail.com
      • organisations_transferred_Yes
      • number_participants280 participants
      • notification<p>\n None</p>\n
      • approval_date31-10-2025
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted22-09-2025
      • is_child0
      • unsubmitted1
      • initial_date_submitted29-07-2025
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments have been addressed.
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-10-31 15:49:16
      • created2025-02-20 13:23:33
      • total_sites3
      • ecitizen_invoice376519
    • InvestigatorContact(array)
      • 0(array)
        • id1234
        • application_id1519
        • given_nameMary
        • middle_nameWaiyego
        • family_nameKariuki
        • qualificationMBChB,M.Med,CPSA
        • professional_addressP.O. Box 20723-00202 Nairobi
        • telephone0721612393
        • emailwaiyegomary99@gmail.com
        • created2025-02-20 13:23:33
        • modified2025-09-22 13:12:59
    • SiteDetail(array)
      • 0(array)
        • id1848
        • application_id1519
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2025-02-20 13:44:11
        • modified2025-09-22 13:12:59
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id812
        • application_id1519
        • sponsor St Paul\'s Hospital Millennium Medical College
        • sponsor_typeOthers
        • contact_personMahlet Abayneh Gizaw
        • addressAddis Ababa, Ethiopia
        • telephone_number+251911171340
        • fax_number
        • cell_number+251911171340
        • email_addressmahlet.abayneh@sphmmc.edu.et
        • created2025-02-20 13:44:11
        • modified2025-09-22 13:12:59
  • 3(array)
    • Application(array)
      • id1570
      • user_id263
      • trial_status_id2
      • abstract_of_study<p>\n This is a Phase 4, non-randomized, open-label, multicenter, multicountry, rollover study in participants living with HIV-1 infection who were treated in the parent studies with CAB LA + RPV LA given intramuscularly on a Q4W or Q8W dosing schedule. Final dosing information for children <12 years of age with a body weight <35 kg will be included via a protocol amendment once the data from the IMPAACT 2036 (CRAYON) study become available. This rollover study will be conducted primarily to enable continued access to CAB LA + RPV LA and also to collect long-term safety and tolerability data as specified in the Schedule of Activities in participants who completed the parent studies and who at the time of rollover, experience and are expected to continue to experience clinical benefit from the regimen, and have no other access to locally available CAB LA + RPV LA.</p>\n
      • study_title<p>\n A Phase 4, Open-Label, Rollover Study to Provide Continued Access to Cabotegravir Long-acting Injection and Rilpivirine Long-acting Injection to Participants Living with Human Immunodeficiency Virus Type 1 (HIV-1) Infection Who Participated in Longacting Combination Therapy Studie</p>\n
      • laymans_summary<p>\n Cabotegravir (CAB) is a potent integrase strand transfer inhibitor (INSTI) with attributes allowing formulation and delivery as a long-acting (LA) parenteral product. Rilpivirine (RPV), also formulated as a LA product, is a diarylpyrimidine derivative and a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity against wild type HIV-1 and select NNRTI-resistant mutants. The combination of CAB LA and RPV LA has been shown in clinical trials in virologically suppressed adults living with HIV to be safe, well-tolerated and efficacious as a complete injectable antiretroviral regimen. This study enables continued CAB LA + RPV LA access to participants who were included in the clinical development studies for CAB LA + RPV LA (IMPAACT 2017 [MOCHA], IMPAACT 2036 [CRAYON], IMPAACT 2040 [CREATE], TMC278LAHTX3002 [CARES], TMC278LAHTX3005 [IMPALA], in the following sections referred to as the parent studies) and who continue to benefit clinically from the regimen but do not have access to locally available CAB LA + RPV LA to continue treatment. The rollover study will be reviewed periodically to evaluate other access options.</p>\n
      • short_titleCabotegravir + Rilpivirine Lon
      • protocol_noECCT/25/07/05
      • version_noOriginal, 12 January 2024
      • date_of_protocol12-01-2024
      • study_drugCAB LA + RPV LA
      • disease_conditionHIV-1 infection
      • 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_nameTMC278 (rilpivirine)
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressamina.salim@iqvia.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantElizabeth Chirchir
      • declaration_date116-07-2025
      • declaration_principal_investigatorDr Loice Achieng
      • declaration_date216-07-2025
      • placebo_presentNo
      • study_objectives<p>\n <u><strong>Primary Objective      </strong></u>                                                                                                                       </p>\n<p>\n The primary objective of the study is to provide continued CAB LA + RPV LA access to participants who were enrolled and treated with CAB LA + RPV LA in the parent studies, and who, at the time of roll-over, experience and are expected to continue to experience clinical benefit from this treatment.                                            <strong><u> </u></strong></p>\n<p>\n <strong><u>Secondary Objective  </u> </strong>                                                                                                                     </p>\n<p>\n The secondary objective is to assess the long-term safety and tolerability of CAB LA + RPV LA by evaluating the incidence of serious adverse events (SAEs), pregnancies, adverse events (AEs) leading to discontinuation of CABLA +RPV LA, and AEs considered to be related to the study intervention</p>\n
      • principal_inclusion_criteria<p>\n <u><strong>Inclusion Criteria</strong></u></p>\n<p>\n 1.Participants (or their legally acceptable representative) must sign an ICF indicating that they understand the purpose of, and procedures required for the study and are willing to participate in the study. Assent is also required of children capable of understanding the nature of the study (in keeping with local regulations) as described in Section 10.2.3.                                                                                                                                                                                           </p>\n<p>\n 2. Participants living with HIV-1 infection who were treated with CAB LA + RPV LA in any of the following parent studies: TMC278LAHTX3002 (CARES), TMC278LAHTX3005 (IMPALA), IMPAACT 2017 (MOCHA), IMPAACT 2036 (CRAYON), IMPAACT 2040 (CREATE), and completed the protocol-defined treatment period.                                                                                                                                                                                                                               </p>\n<p>\n 3. Has benefited clinically from treatment with CAB LA + RPV LA in the opinion of the investigator and will continue to benefit clinically from this intervention.                  4. Must be able and willing to comply with the rollover protocol requirements. 5. Participant’s general medical condition, in the opinion of the investigator, does not interfere with participation in this study</p>\n
      • principal_exclusion_criteria<p>\n <strong><u>Exclusion Criteria</u>                                                                                                                          </strong></p>\n<p>\n <strong>  1.</strong>Participants using disallowed concomitant treatment (see Section 6.9).                                       </p>\n<p>\n <strong>2. </strong>Participants who were withdrawn from the previous parent study with CAB LA + RPV LA that they were participating in prior to this rollover study, based on any of the mandatory withdrawal criteria. </p>\n
      • primary_end_points<p>\n Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use1
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<p>\n <b><span lang=\"EN-US\" new=\"\" style=\"font-size: 12pt; line-height: 103%; font-family: \" times=\"\">SITE DESCRIPTION</span></b></p>\n<p>\n <strong>Description of KNH CCC</strong></p>\n<p>\n <span style=\"font-size:12px;\"><span style=\"font-family: arial, helvetica, sans-serif;\">Kenyatta National Hospital Comprehensive Care Centre (CCC) was established in December 2002 as the pioneer care and treatment centre for HIV/AIDS. The Centre was established with the support of the USAID/FHI/KNH cooperative agreement with the main objective of mitigating the effects of HIV/AIDS nationally by participating in the national HIV/AIDS response. Since 2005, services and expansion of the Centre have been supported by Center for Disease Prevention and Control (CDC) through the University of Nairobi, AIDS Care and Treatment Services (ACTS), Partnership for Advanced Care and Treatment – Centre of Excellence (PACT - CoE) and Centers’ of Excellence - HIV Medicine (CoEHM) Programs, and the Center for International Health, Education, and Biosecurity (CIHEB) - Kenya. It has evolved over time to be a centre of excellence for ambulatory HIV medicine in the country dealing with both complicated referral patients and stable patients.</span></span></p>\n<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\"><b><span lang=\"EN-US\" style=\"line-height: 103%;\"> </span></b></span></span><strong>KNH Site Staff for IMPALA Rollover Study</strong></p>\n<p>\n  </p>\n<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n <tbody>\n <tr>\n <td style=\"width:150px;\">\n <p>\n Name</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n Role</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n Qualifications</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n Experience</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:150px;\">\n <p>\n Joseph Nkuranga</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n Study Coordinator</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n MBChB, MSc Epidemiology</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n >15 years HIV clinical care, >5 years in clinical trials</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:150px;\">\n <p>\n Agatha Theuri</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n Study Clinician</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n Dip Clinical Medicine, BSc PH</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n >10 years HIV clinical care, >5 years in clinical trials</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:150px;\">\n <p>\n Elizabeth Kamau</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n Study Nurse</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n KRCHN, BScN</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n >15 years HIV clinical care, >5 years in clinical trials</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:150px;\">\n <p>\n Zian Muikamba</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n Study Physician</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n MBChB, MMed</p>\n </td>\n <td style=\"width:150px;\">\n <p>\n 10 years clinical care, 1 year in research</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\">The CCC offers a one-stop-shop approach in the management of HIV/AIDS. In order to achieve this goal, a multidisciplinary team with different specializations in HIV/AIDS management runs the centre. This team consists of Consultants, Medical Specialists, Medical Officers, Registered Clinical Officers, Pharmacists and Pharmaceutical Technologists, Counsellors, Laboratory Staff, Nursing Officers, Nutritionists and social workers among others.</span></span></p>\n<div>\n <span style=\"font-family:arial,helvetica,sans-serif;\"><span style=\"font-size:11px;\">T</span></span><span style=\"font-size:12px;\">he CCC currently serves an average of 150-200 patients per day. There are 3 co-investigators in the IMPALA Study who are based at the site and 2 site-based study staff (study nurse/counsellor and study clinical officer) have been engaged and are currently working at the CCC. With the experience of the staff working in the CCC and the high number of patients including those with history of sub-optimal adherence to treatment and/or care, the KNH Comprehensive Care Centre is best suited to undertake this research study.</span></div>\n<div>\n <span font-size:=\"\" new=\"\" style=\"font-family: \" times=\"\">Services offered at the Comprehensive Care Centre .</span></div>\n<div>\n <p>\n <strong>The services offered at the Comprehensive Care Centre include the following:</strong></p>\n <ul>\n <li>\n Diagnosis and Treatment of opportunistic infections and other HIV/AIDS related co-morbidities</li>\n <li>\n Anti-Retroviral Therapy both 1st line; 2nd line and 3rd line regimens as per the WHO guidelines</li>\n <li>\n Laboratory monitoring and evaluation of the patients - The centre has an ISO 15189:2012 standard accredited laboratory which has equipment that can do the following analytical procedures:\n <ol style=\"list-style-type:lower-alpha;\">\n <li>\n Flow Cytometry</li>\n <li>\n Hematology</li>\n <li>\n Chemistry</li>\n <li>\n TB Diagnosis</li>\n <li>\n HIV EID</li>\n <li>\n HIV Viral Load</li>\n </ol>\n </li>\n <li>\n Research: Since its inception the centre has actively been involved in research which has informed HIV/AIDS national policy. Some of the research conducted in the facility by both the University of Nairobi and Kenyatta National Hospital in collaboration with international partners include:\n <ul>\n <li>\n A clinical trial with almost 400 participants at the site to determine the efficacy of a switch to DTG-based ART from the standard PI/r-based ART for PLHIV on second-line ART</li>\n <li>\n A clinical trial with over 300 participants evaluating the effectiveness of switching older PLHIV on first-line ART to bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF)</li>\n <li>\n Effectiveness of Non-nucleoside Reverse-Transcriptase Inhibitor-Based Antiretroviral Therapy in Women Previously Exposed to a Single Intrapartum Dose of Nevirapine:  A Multi-country, Prospective Cohort Study</li>\n <li>\n Optimizing Pediatric HAART Study</li>\n <li>\n Evaluation of the Kenya ARV scale-up program:  Surveillance for emergence of antiretroviral resistant genotypes among treatment experienced patients</li>\n <li>\n Treatment outcomes of HIV infected adolescents attending a National Referral Hospital in Kenya:</li>\n <li>\n Trends, treatment outcomes and determinants of attrition among adult patients in care in a large tertiary HIV clinic in Nairobi Kenya</li>\n <li>\n Predicted HIV-1 co receptor usage among Kenya patients shows a high tendency for subtype d to be CXCR4 tropic</li>\n </ul>\n </li>\n <li>\n Training of undergraduate and postgraduate students in the departments of Clinical Medicine and Therapeutics and Pediatrics and Child Health at the University of Nairobi</li>\n <li>\n Adherence Counseling</li>\n <li>\n Nutritional Counseling</li>\n <li>\n Social Work Support</li>\n <li>\n Physiotherapy services</li>\n <li>\n Supportive Counseling</li>\n </ul>\n</div>\n<p>\n  </p>\n
      • other_details_explanation<p>\n <span font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">This is a Phase 4, non-randomized, open-label, multicenter, multicountry, rollover study in participants living with HIV-1 infection who were treated in the parent studies.Based on the number of participants in the parent studies, a maximum of 710 participants (adults, adolescents and children) are expected to potentially rollover into the current study for continued access to CAB LA + RPV LA from study centers in Botswana, Kenya, South Africa, Uganda and Thailand.</span></p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong style=\"font-weight: bold;\">Regulatory Authority:</strong></p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <u><strong>Botswana Medicines & Regulatory Authority</strong></u></p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong style=\"font-weight: bold;\">Country:</strong> Botswana</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong style=\"font-weight: bold;\">Dates of Approval:</strong> <strong>18 June 2024.</strong></p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong style=\"font-weight: bold;\">Sites:2</strong></p>\n<ol font-size:=\"\" style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 10px 25px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <li style=\"line-height: 20px;\">\n Gaborone CRS, Botswana Harvard AIDS Institute Partnership.</li>\n <li style=\"line-height: 20px;\">\n Princess Marina Hospital Grounds & Botswana, Molepolole Princess Marina Hospital Grounds, Gaborone, Botswana</li>\n</ol>\n<p style=\"line-height: 20px;\">\n <strong><u>National Drug Authority(NDA)</u></strong></p>\n<p style=\"line-height: 20px;\">\n <strong>Country :</strong>Uganda</p>\n<p style=\"line-height: 20px;\">\n <strong>Dates of Approval:24 Oct 2024</strong></p>\n<p style=\"line-height: 20px;\">\n <strong>Sites: 6</strong></p>\n<p style=\"line-height: 20px;\">\n Dr Henry Mugerwa-Site CC8-UG10001_JCRS-Lubowa                                                                                                                                         </p>\n<p style=\"line-height: 20px;\">\n Dr Noela Owarwo-Site CC8-UG10002_IDI                                                                                                                                           </p>\n<p style=\"line-height: 20px;\">\n Dr Ibraham Yawe Site CC8-UG10004_JCRC-FortPortal                                                                                                                                     </p>\n<p style=\"line-height: 20px;\">\n Dr Violet Korutaro Site CC8-UG10005_Baylor-Uganda CRS                                                                                                                               </p>\n<p style=\"line-height: 20px;\">\n Dr Maxensia Owor-Site CC8-UG10006-MUHJU                                                                                                                                                                </p>\n<p style=\"line-height: 20px;\">\n Dr Eugene Ruzagira_Site CC8-UG10007-UVRI-MRC-</p>\n<p style=\"line-height: 20px;\">\n  </p>\n<p>\n  </p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration48 Months
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states5
      • number_of_sites5
      • multi_country_listBotswana, Kenya, South Africa, Uganda and Thailand.
      • data_monitoring_committeeNo
      • total_enrolment_per_site40
      • total_participants_worldwide710 participants
      • 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_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifyMinors
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_name Reena
      • investigator1_middle_name
      • investigator1_family_nameShah
      • investigator1_qualificationMBBS
      • investigator1_professional_addressAga Khan University Hospital
      • investigator1_telephone+254 735338003
      • investigator1_emailreena.shah@aku.edu
      • organisations_transferred_Yes
      • number_participants250
      • notification<p style=\"margin: 0px 0px 10px 22.5pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <em>Please find below sponsor information regarding Cabotegravir-related files submission status sent on email as per sponsor request.</em></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; font-size: 12.5px;\">\n <li style=\"line-height: 20px;\">\n <em>Submission done by GSK on 21 Oct 2024</em></li>\n <li style=\"line-height: 20px;\">\n <em>Sender: Marwa Mohammed</em></li>\n <li style=\"line-height: 20px;\">\n <em>Subject: Janssen rollover study - TMC278LAHTX4002 (Cabotegravir)</em></li>\n</ul>\n
      • approval_date31-10-2025
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted13-10-2025
      • is_child0
      • unsubmitted1
      • initial_date_submitted19-09-2025
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments have been addressed.
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-10-31 15:23:04
      • created2025-07-03 12:22:53
      • total_sites5
      • ecitizen_invoice379871
    • InvestigatorContact(array)
      • 0(array)
        • id1321
        • application_id1570
        • given_nameLoice
        • middle_nameAchieng
        • family_nameOmbajo
        • qualificationMBChB, M.Med, DLSHTM MSc, (ID), FRCP
        • professional_addressKenyatta National Hospital
        • telephone0722576984
        • emailloisea@uonbi.ac.ke
        • created2025-07-03 12:28:45
        • modified2025-10-13 15:53:52
    • SiteDetail(array)
      • 0(array)
        • id1956
        • application_id1570
        • county_id47
        • site_nameAga Khan University Hospital
        • physical_address3Rd Parklands Avenue, Limuru Rd,
        • contact_details3Rd Parklands Avenue, Limuru Rd,
        • contact_personProf Reena Shah
        • site_capacity(null)
        • misc(null)
        • created2025-07-03 12:28:45
        • modified2025-10-13 15:53:52
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 1(array)
        • id1961
        • application_id1570
        • county_id28
        • site_nameMoi University Clinical Research Centre
        • physical_addressMoi University Clinical Research Centre
        • contact_detailsP.O. Box 4606, 30100
        • contact_personProf Abraham Mosigisi Siika
        • site_capacity(null)
        • misc(null)
        • created2025-07-08 13:18:49
        • modified2025-10-13 15:53:52
        • County(array)
          • id28
          • county_nameElgeyo/Marakwet
          • created2012-06-15 10:25:27
          • modified2012-06-15 10:25:27
      • 2(array)
        • id1962
        • application_id1570
        • county_id35
        • site_nameKEMRI-WRP
        • physical_addressKEMRI-WRP,Hospital Road,
        • contact_detailsP.O. Box 1357
        • contact_personDr Josphat Kosgei
        • site_capacity(null)
        • misc(null)
        • created2025-07-08 13:18:49
        • modified2025-10-13 15:53:52
        • County(array)
          • id35
          • county_nameKericho
          • created2012-06-15 10:26:16
          • modified2012-06-15 10:26:16
      • 3(array)
        • id1963
        • application_id1570
        • county_id42
        • site_nameUniversity of Nairobi - Jaramogi Oginga Odinga Teaching and Referral Hospital
        • physical_addressJomo Kenyatta Highway
        • contact_detailsPO Box 849-40100,
        • contact_personDr Loice Achieng
        • site_capacity(null)
        • misc(null)
        • created2025-07-08 13:18:49
        • modified2025-10-13 15:53:52
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
    • Sponsor(array)
      • 0(array)
        • id852
        • application_id1570
        • sponsorJanssen Cilag
        • sponsor_typeIndustry
        • contact_personCatherine Michielsens
        • addressTurnhoutseweg 30,2340 Beerse Belgium
        • telephone_number+3214602111
        • fax_number
        • cell_number+3214602111
        • email_addressra-jcisupportoffice@its.jnj.com
        • created2025-07-03 12:28:45
        • modified2025-10-13 15:53:52
  • 4(array)
    • Application(array)
      • id1556
      • user_id799
      • trial_status_id2
      • abstract_of_study<div>\n Increasing antimicrobial resistance (AMR) threatens to undermine the effectiveness of World Health Organization (WHO) recommended antibiotic treatments for neonatal sepsis in most low- and middle-income country (LMIC) settings where disease burden is high. The key threat is multidrug-resistant (MDR) Gram-negative bacteria, where there are limited well established neonatal treatment options and a wide use of meropenem, driving carbapenem resistance. Accumulating data show that these MDR Gram-negative bacteria are now the dominant cause of neonatal sepsis in many high-burden settings. Current WHO guidelines, however, continue to recommend empiric first- and second-line regimens for neonatal sepsis that have remained unchanged for nearly 20 years, despite considerably higher observed rates of AMR. There is therefore an urgent need to re-evaluate guidance for empiric treatment and develop updated first-line empiric and second-line regimens with improved efficacy in the context of increasing MDR sepsis in neonates. It is critically important to directly compare suitable novel regimens, including off-patent drugs with a neonatal licence but not currently widely used for the treatment of neonatal sepsis, to currently recommended and used regimens given the lack of evidence supporting use. Although large pragmatic randomised controlled trials are needed, study designs with either two or multiple arms are not feasible for various reasons, and novel trial designs are crucial to allow for multiple parallel group comparisons from sites randomising different sub-populations of neonates across different sets of clinically relevant regimens for their site and specific sub-population.</div>\n<div>\n  </div>\n<div>\n <div>\n NeoSep1 trial, will test three novel dual combinations of three existing, off-patent drugs, namely fosfomycin + amikacin, flomoxef + amikacin and fosfomycin + flomoxef, and compare these to WHO recommended and other currently used broad spectrum antibiotic combinations. Reflecting that they have been infrequently used in neonatal populations, we will perform a run-in non-randomised pharmacokinetic (PK) study of the fosfomycin and flomoxef when given with amikacin or each other to confirm plasma drug levels at the proposed doses based on other studies and collect safety data (Part 1) before the start of the main randomised trial (Part 2). Part 1 of the NeoSep1 trial aimed to confirm that the recommended doses of fosfomycin and flomoxef, in combination with each other or with amikacin, provided adequate drug exposure and were safe in neonates with suspected sepsis. Three sites participated in Part 1: Kilifi County Hospital (Kenya), (Tygerberg Hospital (South Africa), and Chris Hani Baragwanath Hospital (South Africa). Sixty-five neonates (52 from South Africa; 13 from Kenya) were enrolled March-November 2023; 62 received trial antibiotics. At baseline, 48/62 (77%) were preterm, and 48 (77%) were ≤7 days PNA. The early, middle, and late median concentrations after the first dose were 195, 164 and 98 μg/mL for fosfomycin; and 117, 103 and 50 μg/mL for flomoxef, respectively. Eighteen (29%) neonates had 22 Serious Adverse Events (SAEs), all unrelated to study drugs. Prolonged jaundice occurred in 1 neonate, was possibly related to fosfomycin and flomoxef, and resolved spontaneously. Seven neonates (11.6%; 95%CI: 5.7–22.8) died by day 28 (all unrelated). In this predominately preterm population, fosfomycin and flomoxef exposures shortly after birth were therefore similar to previously published studies, although with substantial variability, supporting the planned dosing for Part 2.</div>\n <div>\n  </div>\n <div>\n In Part 2 of the trial, approximately 3,000 neonates (approximately 600 participants across the 3 sites in Kenya, approximately 200 per site) hospitalised with clinical signs of neonatal sepsis will be randomised across trial sited located in sub-Saharan Africa and Asia, including Kenya and South Africa, to locally relevant first- and second-line antibiotic regimens and followed up for 90 days for safety and efficacy outcomes. In Kenya, 3 sites (Kilifi County Hospital in Kilifi, Coast General Teaching and Referral Hospital in Mombasa, and Mbagathi Hospital in Nairobi) will participate in Part 2. First-line treatment is expected to continue for 7±2 days based on clinician’s judgement of the baby’s condition for babies with culture negative sepsis and 10 days (-3 +4) for culture positive sepsis. If antibiotics are switched to second-line treatment, the total duration of antibiotic treatment including first- and second-line is 14 ±7 days depending on the neonate’s condition. Assessment of safety (Part 1 and 2) and efficacy (Part 2 only) will include blood investigations (C-reactive protein, full blood count, kidney and liver function tests) and clinical assessment using a recovery score respectively. Peri-rectal swabs will be taken at baseline and at the end of treatment to assay carriage of commensal organisms and antimicrobial resistance genes in Part 2. Healthcare-related costs will be measured in Part 2 of the trial. Results obtained from this trial will inform treatment guidelines and improve survival of neonates hospitalised with sepsis.</div>\n</div>\n<p>\n  </p>\n
      • study_title<p>\n <span style=\"color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px; background-color: rgb(249, 249, 249);\">An open-label randomised controlled trial comparing novel combination and currently used antibiotic regimens for the empiric treatment of neonatal sepsis with a run-in confirmatory pharmacokinetic phase.</span></p>\n
      • laymans_summary<p>\n <strong>A study comparing new and currently used antibiotic combinations for treatment of newborn babies hospitalised with infection.</strong></p>\n<div>\n <strong>What is the problem/background?</strong></div>\n<div>\n Babies admitted to hospital with a severe infection of the blood are treated with medicines called “antibiotics.” In many countries, these antibiotics are those recommended by the World Health Organisation (WHO). Other countries use different antibiotics based on local policies but unfortunately these are not always easily available. The use of different antibiotics also varies from baby to baby and between countries and hospitals.</div>\n<div>\n More infections are now being caused by bacteria which are “resistant” to commonly used antibiotics. This means these antibiotics will not kill the bacteria and therefore will not cure the infection. These bacteria are often called multidrug resistant, as they are not killed by most antibiotics. We need to find new ways of treating these infections – using combinations of existing antibiotics is one possibility. Fosfomycin, flomoxef and amikacin are three antibiotics that could be combined into different two drug combinations. Another option is to give stronger antibiotics at the start of treatment. The problem with doing this is that not all babies will need these antibiotics – and the more we use them, the more resistance will develop to these antibiotics. So, using stronger antibiotics in lots of babies now, who don’t need them, may mean that in future we will not be able to use them in any babies who might need them.</div>\n<div>\n  </div>\n<div>\n <strong>What questions are we trying to answer?</strong></div>\n<div>\n The NeoSep1 study will test how well giving fosfomycin and amikacin, OR flomoxef and amikacin OR fosfomycin and flomoxef works to treat babies 28 days old or younger who are in hospital with severe infection of the blood. It will also test how well these new combinations work compared to other antibiotics or combinations of antibiotics that are currently used globally.</div>\n<div>\n  </div>\n<div>\n <strong>Where is the study taking place, how many people does it involve and how are they selected?</strong></div>\n<div>\n The study will take place across sites selected in several countries particularly in low- and middle-income countries (LMICs) including Kenya, and South Africa and other countries in Africa and Southeast Asia. Babies aged 28 days or below hospitalised with severe infection requiring intravenous (IV) antibiotics will be screened at admission to check if they fulfil criteria required for study participation. During screening, clinicians will obtain medical history, perform physical examination, and obtain blood samples for baseline/routine investigations which include full blood count (FBC), kidney function tests, and blood culture. Written informed consent will be obtained from parents/guardians before enrolment. Verbal assent will be obtained from parents/guardians of seriously ill babies, and this will be followed up by written informed consent. In addition to routine investigations at admission, blood samples to measure liver function and C-reactive Protein (CRP), a marker of infection in blood, will be done after obtaining consent. Each of these tests will require about 0.5-1 ml (a few drops) of blood.</div>\n<div>\n We have worked out the right doses of fosfomycin, amikacin and flomoxef to use in an earlier part of this study by measuring levels of these drugs in babies’ blood. We will check how well these three combinations, as well as other antibiotics that are used routinely to treat severe infection in newborn babies, treat bacterial infections and stop babies from dying. Approximately 3000 babies (approximately 600 participants across the 3 sites in Kenya, approximately 200 per site) hospitalised with a severe infection of the blood will be enrolled in several countries in Africa and South East Asia, including Kenya and South Africa. In Kenya, 3 sites i.e., Kilifi County Hospital in Kilifi, Coast General Teaching and Referral Hospital in Mombasa and Mbagathi Hospital in Nairobi will participate.</div>\n<div>\n  </div>\n<div>\n <strong>What does the study involve for those who are in it?</strong></div>\n<div>\n A computer programme will assign antibiotic treatments at random (like the flip of a coin) and babies will generally get antibiotics for about 7-10 days in the first instance (their “first line” treatment). If a baby’s condition gets worse during this time, or doesn’t get better as would be expected, doctors will be able to give them a different antibiotic (also known as “second-line” treatment) to see if they do better with different antibiotics. Which specific second-line antibiotics each baby gets will also be chosen at random from a set of combinations that doctors would use after each first-line treatment. Babies will get different second-line antibiotic treatments to those they already had as first-line.</div>\n<div>\n CRP will be repeated on Days 3 and 7. FBC, kidney and liver function tests will be done at baseline and if abnormal, repeated on Day 3, Day 7, Day 14, end of treatment (if not Day 7 or 14), Day 28, and Day 90 after starting treatment. Blood culture will be repeated in case of clinical deterioration and before switching to second-line antibiotics. Additional safety blood tests or investigations will be performed to investigate symptoms or monitor laboratory test abnormalities as clinically indicated following routine clinical practice. We will collect data on any side-effects from Day 0 to Day 28. Babies will have their bottoms/nappies swabbed or a fresh stool sample collected on Day 0 and at the end of treatment to test presence of bacteria resistant to antibiotics. We will collect information of treatment costs from all parents/guardians (e.g. transport costs, family information such as parental age, education level and data on socio-economic status, and information on clinic and hospital visits) and healthcare providers (e.g. costs of medication and procedures, overhead costs and staff costs). Babies will be followed up for 90 days, with a visit or telephone call 28 and 90 days after entering the study to see if the baby is still doing well.</div>\n<div>\n  </div>\n<div>\n <strong>What are the benefits and risks/costs of the study for those involved?</strong></div>\n<div>\n All babies will receive comprehensive medical care while in the ward (including a daily structured review to check progress) and during follow-up. Additional clinical and nursing staff will be recruited and will undertake study duties and assist in general care in the ward, adding to the staff available. Training will be enhanced for all paediatric ward staff on treatment of sick babies. Following discharge from the ward, parents/guardians will have continued access to the study staff via telephone contact and will be advised to bring their babies to the study clinic for review in case of illness while at home.</div>\n<div>\n Drawing a blood sample carries the risks of damage to the vein and infection. However, the study staff will be trained on careful procedures including cleaning the skin to help prevent these. Blood sample volumes obtained for investigation will be minimal, based the baby’s body weight/percentage total blood volume. Swabs of baby’s bottom are minimally invasive and can be taken in a standardised manner independent of passing stools using a soft swab. The risks of swabbing a baby’s bottom are minimal and our study sites have experience in obtaining these samples. Side effects that may be associated with the antibiotics include changes in the level of salts/sodium in blood following administration of fosfomycin. Babies will be monitored for side effects and treated appropriately in case they occur. Parents/guardians will receive transport reimbursement (during scheduled and unscheduled sick visits) and an out-of-pocket allowance (during scheduled visits) for clinic visits. However, costs related to hospitalisation will not be reimbursed.</div>\n<div>\n  </div>\n<div>\n <strong>How will the study benefit society?</strong></div>\n<div>\n The study will enable us to measure the doses of new antibiotics and confirm optimal doses that can be used to treat babies with infection. We will compare different antibiotic combinations, including new ones and those already used in hospitals to see which ones are safe and the best in treating babies with infection. Knowledge of safe and effective antibiotic combinations in sick babies will help decision-making about the first antibiotics to give babies who have infection when they are admitted to hospital to improve their outcomes. This will also help to minimise chances of development and spread of bacteria that are resistant to the antibiotics in use. Knowledge of how bacteria resistant to antibiotics spreads in hospitalised babies will help in finding ways to prevent emergence and spread of resistance and inform development and use of effective antibiotics. Knowledge of individual and provider healthcare costs will guide policymakers on planning and allocation of limited resources to meet the population’s health needs.</div>\n<div>\n  </div>\n<div>\n <strong>When does the study start and finish?</strong></div>\n<div>\n The first part of the study started as soon as scientific and ethical approval was granted. The study is expected to continue for about 5 years until follow-up of participants is completed and the results are available.</div>\n
      • short_titleNeosep1
      • protocol_noECCT/25/06/02
      • version_no4.0
      • date_of_protocol01-11-2024
      • study_drugAntibiotics of interest are: Fosfomycin, Amikacin and Flomoxef. Other antibiotics are: Ampicillin/ amoxicillin, Benzylpenicillin, Cefotaxime, Ceftazidime, Ceftriaxone, Cloxacillin, Flucloxacillin, Gentamicin, Meropenem, Piperacillin/tazobactam
      • disease_conditionNeonatal Sepsis
      • 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_nameFosfomycin, Amikacin and Flomoxef
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressneosep1@pharmalys.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantKamaljot Hunjan, Main Local Contact - Pharmalys
      • declaration_date103-06-2025
      • declaration_principal_investigatorDr Christina Obiero, National Principal Investigator
      • declaration_date203-06-2025
      • placebo_presentNo
      • study_objectives<p>\n <strong><span font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Primary objectives</span></strong></p>\n<p>\n <span font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">To provide a ranking of eight different clinically relevant antibiotic regimens for first-line empiric and second-line (after lack of response/deterioration) treatment of neonatal sepsis, in terms of 28-day mortality as the primary outcome measure.</span></p>\n<p>\n <strong><span font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Secondary objective(s)</span></strong></p>\n<p>\n <span font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">1. To provide a ranking of clinically relevant antibiotic regimens based on other efficacy and safety secondary outcomes, as well as on health economic measures and the potential selection of resistance at an individual neonate and neonatal unit level.</span></p>\n<div font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">\n 2. To determine efficacy of antibiotic treatment regimen used based on:</div>\n<div font-size:=\"\" style=\"color: rgb(51, 51, 51); margin-left: 40px;\" trebuchet=\"\">\n • Clinical status at days 3, 7, 14 and 28 after randomisation</div>\n<div font-size:=\"\" style=\"color: rgb(51, 51, 51); margin-left: 40px;\" trebuchet=\"\">\n • Clinically appropriate need for additional antibiotics beyond the first randomised treatment</div>\n<div font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">\n <div style=\"margin-left: 40px;\">\n • Clinically appropriate need for additional antibiotics beyond the first randomised and second (for failure) treatment</div>\n <div style=\"margin-left: 40px;\">\n • Cure, defined as clinical improvement and no need for further antibiotic treatment for the original sepsis episode, at test of cure (TOC) visit (day 14 ± 3 days after randomisation).</div>\n <div style=\"margin-left: 40px;\">\n • Length of stay during the index hospitalisation</div>\n <div style=\"margin-left: 40px;\">\n • Systemic antibiotic exposure (days on antibiotics) during the index hospitalisation</div>\n <div style=\"margin-left: 40px;\">\n • 90-day mortality</div>\n <div style=\"margin-left: 40px;\">\n • Change in C-reactive protein from baseline to day 3 and day 7</div>\n <div>\n 3. To collect safety data on different antibiotic treatment regimens</div>\n <div>\n 4. To determine antibiotic resistance development in neonates treated with different first- and second-line antibiotic regimens</div>\n <div>\n 5. To investigate health economic outcomes in neonates treated with different first- and second-line antibiotic regimens</div>\n</div>\n<p>\n  </p>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">1. Currently admitted to hospital</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">2. Aged <span font-size:=\"\" trebuchet=\"\">≤28</span> days (post-natal age)</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">3. Weight <span font-size:=\"\" trebuchet=\"\">≥</span>1000g</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">4. Clinical diagnosis of a new episode of sepsis with two or more of the following clinical signs together with planned treatment with IV antibiotics</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">a. Abnormal temperature (<35.5°C Or ≥38°C)</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">b. Chest indrawing or increase in oxygen requirement or increase of respiratory support</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">c. Abdominal distension</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">d. Difficulty in feeding or feeding intolerance</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">e. Evidence of shock including cold peripheries</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">f. Lethargy, or reduced or no spontaneous movement</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">g. Cyanosis</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">h. Abnormal heart rate (bradycardia <80 bpm; tachycardia >180 bpm)</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">i. Convulsions</span></p>\n<p style=\"margin-left: 40px;\">\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">j. Irritability For making the diagnosis of significant sepsis, the neonate should have no alternative primary explanation for these criteria (such as Hypoxic Ischaemic Encephalopathy, hypothermia, hypoglycemia, prematurity etc)</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">5. At moderate to high risk of death from this episode of sepsis, based on a neonatal sepsis severity score (NeoSep Severity Score) :. This was adapted from the WHO pSBI based scores for the hospital setting and developed using baseline clinical information and subsequent mortality from the NeoOBS study; specifically, a NeoSep Severity Score of 5 or higher at presentation for this episode of sepsis (which may be before formal screening)</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">6. Can receive all potential treatment options on the relevant randomisation list for this neonate at their site, ensuring randomisation is possible (see country-specific appendices)</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">7. IV antibiotics about to be started OR not received more than 24 hours of IV antibiotics for this episode of neonatal sepsis at the point of randomisation</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">8. Parent/guardian willing and able to provide consent (written or, if their neonate is severely ill, verbal consent which must be confirmed by written consent as soon as possible and wherever possible within 48 hours after the first trial specific procedure). Verbal consent allows for administration of first-line antibiotics at no or minimal delay </span></p>\n
      • principal_exclusion_criteria<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">1. A known serious, non-infective co-morbidity anticipated to cause death within this admission (including major congenital abnormalities anticipated to cause death within this admission other than prematurity, e.g. known large ventricular septal defect)</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">2. Previously enrolled in this trial</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">3. Current participation in any other clinical study of an Investigational Medicinal Product (IMP) that is a systemic drug, unless it has received prior approval by the NeoSep1 Trial Management Group (TMG)</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">4. Known contraindication to any of the trial antibiotics on the randomisation list for the relevant neonatal sub-population in that site </span></p>\n
      • primary_end_points<p>\n <strong><span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">PRIMARY END POINT</span></strong></p>\n<ul>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">28-day mortality</span></li>\n</ul>\n<p>\n <strong><span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">SECONDARY ENDPOINTS</span></strong></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Efficacy</span></p>\n<ul>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Clinical status, assessed daily after randomisation through to the earlier of discharge from a trial site or Day 28, using a clinical recovery score based on data from the NeoOBS observational study  </span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Additional systemic antibiotics beyond the first randomised treatment through Day 28</span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Additional systemic antibiotics beyond the first randomised and second (for failure) treatment through Day 28</span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Length of stay during the index hospitalisation</span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Systemic antibiotic exposure (days on antibiotics) during the index hospitalisation</span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">90-day mortality</span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Change in C-reactive protein from baseline to Day 3 and Day 7</span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Re-admission by Day 90 (all-cause)</span></li>\n</ul>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Safety (all graded using combined LMIC relevant adapted DAIDS and NAESS):</span></p>\n<ul>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Grade 3/4 adverse events (AEs) through Day 28</span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">AEs of any grade related to antibiotics through Day 28</span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Modification (including discontinuation) of antibiotics for adverse reactions through Day 28</span></li>\n <li>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51);\" trebuchet=\"\">Neurodevelopment as assessed by the WHO Global Scale for Early Development (GSED) package at Day 28 and Day 90</span></li>\n</ul>\n
      • scope_diagnosis1
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others1
      • scope_others_specify- Health Economics\n- Microbiology
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyPharmacokinetics
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use1
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Please refer to the site specific addendum attached</p>\n
      • other_details_explanation<p>\n <span font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">The choice of the countries participating to this study and specifically Kenya is mainly because the high mortality rate due to neonetal sepsis which is not the case in Switzerland.</span></p>\n
      • other_details_regulatory_notapproved<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">Initial application to GHANA FDA Date of application: 14th January 2025</span></p>\n<p>\n <span font-size:=\"\" style=\"background-color: rgb(249, 249, 249); color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">Initial application to UGANDA NDA Date of application: 19th May 2025</span></p>\n
      • other_details_regulatory_approved<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">Amendment made to SOUTH AFRICA SAPHRA- Date of approval: 07th November 2024 - Number of sites: 02</span></p>\n<p>\n <span background-color:=\"\" font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">Amendment made to KENYA PPB - </span><span font-size:=\"\" style=\"background-color: rgb(249, 249, 249); color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">Date of approval: 06th May 2025 - Number of sites: 1 - New application requested for 2 additional sites</span></p>\n
      • other_details_regulatory_rejected<p>\n Not applicable</p>\n
      • other_details_regulatory_halted<p>\n Not applicable</p>\n
      • estimated_duration4 years
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindNo
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherYes
      • design_controlled_specifyPersonalised RAndomised Controlled Trial (PRACTical), comparing multiple different novel combination and currently used antibiotic regimens, including a Sequential Multiple Assignment Randomised Trial (SMART) design
      • design_controlled_comparatorAmikacin, Gentamicin
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states9 countries
      • number_of_sites3
      • multi_country_list8 sites in Africa have been confirmed in Uganda (2 sites), Kenya (3 sites), Ghana (1 site), and South Africa (2 sites).\n8 sites have been selected in South-East Asia in Bangladesh (2 sites), India (3 sites), Malaysia (1 site), Pakistan (1 site), and Vietnam (1 site).
      • data_monitoring_committeeYes
      • total_enrolment_per_site200 (A minimum of 50 and a maximum of 400 per site will be randomised)
      • total_participants_worldwide3000
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornYes
      • population_newbornYes
      • population_infant_and_toddlerNo
      • population_childrenNo
      • 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_specifyNeonates
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameChristina
      • investigator1_middle_nameWesonga
      • investigator1_family_nameObiero
      • investigator1_qualificationMBCHB, MPH
      • investigator1_professional_addressP.O Box 230-80108 Kilifi, Kenya
      • investigator1_telephone+254 721 889 581
      • investigator1_emailcobiero@kemri-wellcome.org
      • organisations_transferred_Yes
      • number_participants600 across 3 sites (Kilifi County Hospital in Kilifi, Coast General Teaching and Referral Hospital in Mombasa, and Mbagathi Hospital in Nairobi)
      • notification
      • approval_date02-10-2025
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted04-06-2025
      • is_child0
      • unsubmitted1
      • initial_date_submitted04-06-2025
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonFeedback on evaluation comments from applicant satisfactory
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-11-12 16:28:03
      • created2025-05-28 18:52:45
      • total_sites1
      • ecitizen_invoice374418
    • InvestigatorContact(array)
      • 0(array)
        • id1299
        • application_id1556
        • given_nameNayirat
        • middle_nameMohamed
        • family_nameDormohamed
        • qualificationMBCHB, MMed, MPhil
        • professional_addressPO Box 85639-80100, Mombasa, Kenya
        • telephone+254 723311339
        • emailnayiratdor@gmail.com
        • created2025-05-28 20:01:29
        • modified2025-07-07 18:44:05
    • SiteDetail(array)
      • 0(array)
        • id1935
        • application_id1556
        • county_id1
        • site_nameCoast General Teaching and Referral Hospital
        • physical_addressKisauni Road, Mombasa
        • contact_detailsPO Box 90231-80100 Mombasa
        • contact_personNayirat Mohamed Dormohamed
        • site_capacity(null)
        • misc(null)
        • created2025-05-28 20:01:29
        • modified2025-07-07 18:44:05
        • County(array)
          • id1
          • county_nameMombasa
          • created2012-05-31 16:15:11
          • modified2012-07-09 13:06:23
    • Sponsor(array)
      • 0(array)
        • id844
        • application_id1556
        • sponsorGlobal Antibiotic Research and Development Partnership (GARDP)
        • sponsor_typeResearch Institution
        • contact_personSally Ellis
        • addressGlobal Antibiotic Research and Development Partnership (GARDP) 15 Chemin Camille-Vidart 1202 Geneva, Switzerland
        • telephone_number+41 22 5551990
        • fax_number
        • cell_number+44 7727 596296
        • email_addresssellis@gardp.org
        • created2025-05-28 20:01:29
        • modified2025-07-07 18:44:05
• page_options(array)
  • 55
  • 1010
• redir
• $request->data(array)
  • Application(empty)
• $this->validationErrors(array)
  • Permission(empty)
  • Aro(empty)
  • Aco(empty)
  • Application(empty)
  • User(empty)
  • TrialStatus(empty)
  • InvestigatorContact(empty)
  • Sponsor(empty)
  • SiteDetail(empty)
  • County(empty)
• Loaded Helpers(array)
  • 0Html
  • 1Form
  • 2Session
  • 3Text
  • 4Number
  • 5SimpleGraph
  • 6Paginator
  • 7DebugTimer
  • 8Toolbar
  • 9HtmlToolbar

App Constants

CakePHP Constants

PHP Environment

Included Files

Include Paths

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

Included Files

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