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      • abstract_of_study<p>\n Etavopivat (FT-4202) is a potent, selective, orally bioavailable, small-molecule activator of pyruvate kinase-red blood cell (PKR) being developed by Forma Therapeutics, Inc and is intended for use as a treatment for patients with sickle cell disease (SCD). The clinical hypothesis is that PKR activation will reduce the rate of sickle cell polymerization and improve red blood cell (RBC) membrane function, thereby reducing RBC sickling and RBC hemolysis that lead to vascular obstruction and anemia, two hallmarks of SCD pathology.</p>\n<p style=\"margin-left:1.05pt;\">\n This multi -centre phase 1/2, study aims to evaluate the pharmacokinetics and safety of Etavopivat in SCD patients aged 12 years to below 18 years in a single arm, open label study. This study will enroll 50 patients aged 12 years to below 18 years with SCD. ACTU site will enroll at least 15 participants into the study.</p>\n<p style=\"margin-left:1.55pt;\">\n  </p>\n<p style=\"margin-left:1.55pt;\">\n The participants will be seen at the study sites at screening, day 1, week 2, week 4 then approximately every 4 weeks until week 24, then approximately every 8 weeks until week 96, which is the end of treatment. End of study visit will occur 4 weeks after the last full dose with a tolerant window of 1week. Safety will be monitored throughout the study, and PK, QoLs, and clinical outcome measures will be performed at specified visits.   </p>\n<h1>\n 8.       INTRODUCTION</h1>\n<p>\n Currently, therapeutic treatment of SCD is inadequate. Potentially curative therapies, such as bone marrow transplant or gene therapies, are invasive and such high-risk procedures are limited to only a subset of patients. For most patients, treatment involves supportive care for management of vaso-occlusive crisis (VOC) or the use of hydroxyurea (HU), to stimulate production of fetal Hb (HbF) and reduce Hb polymerization. While inducing HbF can be effective therapeutically, HU can be myelosuppressive and is a teratogen (Sampson et al. 2010). Although HU is considered to have an acceptable therapeutic index, the myelosuppressive and teratogenic risks limit its effectiveness (Platt 2008).</p>\n<p>\n Chronic transfusion is another way of preventing stroke recurrence in patients with SCD. However, frequent transfusion is associated with significant co-morbidities, such as secondary hemochromatosis; cardiomyopathy and infections; alloimmunization; social and family burden (Franke 2018). An oral therapy reducing the need for RBC transfusion and the associated iron overload, would therefore address a critical unmet medical need for patients with SCD on chronic transfusions for prevention of stroke recurrence.</p>\n<p>\n  </p>\n<p style=\"margin-left:1.8pt;\">\n FT-4202 is a potent, selective, orally bioavailable, small-molecule activator of pyruvate kinase-red blood cell (PKR). Pyruvate kinase R (PKR) is the isoform of pyruvate kinase expressed in RBCs and is a key enzyme in glycolysis (Zanella et al. 2005). Activation of PKR is proposed to directly target both sickling by reducing deoxy-HbS and hemolysis by improving RBC membrane integrity. Specifically, PKR activation inhibits Hb deoxygenation and sickling by decreasing levels of the glycolytic intermediate 2,3-diphosphoglycerate (2,3-DPG) and increasing O2 affinity of HbS. Furthermore, PKR activation increases adenosine triphosphate (ATP), which has been shown to support overall RBC membrane integrity and stress resilience (Betz et al. 2009), thus potentially decreasing hemolysis. ATP also supports elimination of reactive oxygen species (ROS) which damage RBCs and impair their functionality, and reduces vascular adhesion associated with membrane injuries (Banerjee and Kuypers 2004). The combination of anti-sickling effects, decreased hemolysis, and improved RBC membrane fitness is proposed to reduce the onset and complications of vaso-occlusive events and, in parallel, address the chronic anemia of SCD  </p>\n<p style=\"margin-left:1.8pt;\">\n  </p>\n<p style=\"margin-left:1.55pt;\">\n A First-in-Human (FIH) clinical study (Protocol 4202-HVS-101) entitled “A Randomized, Placebo-controlled, Double Blind, Single Ascending and Multiple Ascending Dose Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of FT-4202 in Adult Healthy Volunteers and Sickle Cell Disease Patients” has completed enrollment. A total of 90 healthy subjects and 42 SCD patients had been enrolled in the study, including 32 healthy subjects and seven SCD patients in the single ascending dose (SAD) cohorts, 48 healthy subjects and three SCD patients in the multiple ascending dose (MAD) cohorts, and 10 subjects in the food effect (FE) cohort. The 42 SCD patients were enrolled 7 in the SAD cohort,14 in the MAD cohort and 15 in the 12-week open label.</p>\n<p>\n For the healthy subject SAD cohorts, a total of 6 (18.8%) subjects were reported with at least one treatment-emergent adverse event (TEAE), including 5 (20.8%) subjects who received FT-4202 and 1 (12.5%) subject who received placebo. No TEAE was reported in more than 1 subject. No treatment-emergent serious adverse events (TESAEs) were reported and there were no TEAEs that led to dose reduction/interruption or discontinuation of study drug.</p>\n<p>\n  </p>\n<p>\n For the healthy subject MAD cohorts, a total of 18 (37.5%) subjects were reported with at least one TEAE, including 15 (41.7%) of subjects who received FT-4202 and 3 (25.0%) subjects who received placebo. The most common TEAE was headache, which was reported in 10 (27.8%) subjects receiving FT-4202 and 2 (16.7%) subjects receiving placebo. For headache TEAEs, there was no apparent relationship between daily FT-4202 exposure and incidence. For subjects receiving FT-4202, all other TEAEs were reported in 1 (2.8%) subject each. No TESAEs were reported and there were no TEAEs that led to dose reduction/interruption or discontinuation of study drug.</p>\n<p>\n  </p>\n<p style=\"margin-left:1.8pt;\">\n For the SCD SAD cohort, TEAEs were reported in 2 (100.0%) patients who received placebo and 2 (40.0%) patients who received Etavopivat. For patients who received Etavopivat, 1 TEAE of transient, mild (Grade 1) palpitations was considered possibly treatment-related and resolved without treatment. For the SCD SAD cohort, no TESAEs were reported, and there were no TEAEs that led to dose reduction/interruption or discontinuation of study drug.</p>\n<p style=\"margin-left:1.8pt;\">\n For the SCD multiple dose cohorts, TEAEs were reported in 7 (87.5%) patients who received Etavopivat in the MAD-1 cohort (300 mg Etavopivat × 14 days), 6 (75.0%) patients who received Etavopivat in the MAD-2 cohort (600 mg of Etavopivat × 14 days), and 14 (93.3%) patients in the 12-week OL cohort. For patients receiving Etavopivat, treatment-related TEAEs were reported in 2 (25.0%) patients in the MAD-1 cohort and 7 (46.7%) patients in the OL cohort. Treatment-emergent SAEs were reported in 1 (12.5%) patient in the MAD-2 cohort and 5 (33.3%) patients in the OL cohort; 1 (6.7%) patient in the OL cohort had a TEAE that led to study discontinuation (SAE of deep vein thrombosis [DVT]). For patients with SCD receiving Etavopivat in the 14-day cohorts, the TEAEs reported in > 1 patient were sickle cell anemia with crisis (MAD-1, n=3 [37.5%]; MAD-2, n=3 [37.5%]), headache (MAD-1, n=3 [37.5%]; MAD-2, n=1 [12.5%]), nausea (MAD-1, n=2 [25.0%]; MAD-2, n=1 [12.5%]), and vomiting (MAD-1, n=1 [12.5%]; MAD-2, n=1 [12.5%]).</p>\n<p style=\"margin-left:1.8pt;\">\n In the 12week OL cohort, the TEAEs reported in > 1 patient were sickle cell anemia with crisis (n=7 [46.7%]); headache (n=4 [26.7%]); and dizziness, nausea, and upper respiratory tract infection (n=2 [13.3%] for each). Six patients receiving Etavopivat in the SCD multiple dose cohorts were reported with TESAEs, including 1 (12.5%) patient in the MAD-2 cohort (1 event of unrelated Grade 3 sickle cell anemia with crisis) and 5 (33.3%) patients in the 12-week OL cohort (2 patients with events of unrelated Grade 3 sickle cell anemia with crisis and single-patient events of ACS [unrelated Grade 3], corona virus infection [unrelated Grade 3], DVT [possibly related Grade 3], non-cardiac chest pain [unrelated Grade 3], and syncope [unrelated Grade 3]).</p>\n<p>\n  </p>\n
      • study_title<p>\n A Single Arm, Open Label, Phase 1/2 Study to Evaluate the Pharmacokinetics and Safety of Etavopivat in Pediatric Patients with Sickle Cell Disease</p>\n
      • laymans_summary<p>\n About 300,000 children are born each year with SCD(Sickle Cell Disease). It affects the red blood cells within the blood that carries the important function of transporting oxygen to all body parts. Normal red blood cells have a regular circular shape and it is maintained that way in the body. For patients with SCD, their red blood cell takes the shape of a sickle when the body is stressed and clogs the blood vessels, leading to early destruction of the deformed sickled red blood cell and damage of the body parts because of lack of oxygen. The abnormality and many other processes make it difficult for the sickled red blood cell to transport oxygen. The lack of oxygen in the body parts can cause severe body pains which is a key presentation of SCD. Potential cure for SCD such as bone marrow transplant and gene treatment are limited by their  high cost and use of advanced medical technology not available in many countries.. About a quarter of patients with SCD develop stroke by the age of 45 years with a very high likelihood of recurrence. Lifelong blood transfusion can be used to prevent stroke recurrence in patients with SCD who have a stroke by reducing the percentage of sickled haemoglobin to below 30 percent. However, this lifelong transfusion has many challenges such as iron overload, heart problems, social and family burden. Currently there are no treatments approved for the reduction of the transfusion burden in these patients and therefore an oral treatment reducing the need for blood transfusion and its associated iron overload will be key in addressing this unmet need for patients on long term transfusion for prevention of stroke. Another drug that prevents initial stroke in patients with SCD is hydroxyurea but is not well tolerated by some patients thus an unmet need still exists. There are other new drugs which are also being developed and what we are proposing is one of them</p>\n
      • short_titleHibiscus Kid\'s Study
      • protocol_noECCT/23/02/01
      • version_no3.0
      • date_of_protocol01-07-2022
      • study_drugEtavopivat
      • disease_conditionSickle Cell Disease
      • 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_nameEtavopivat
      • 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
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      • 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_applicant+245112195624
      • declaration_date101-02-2023
      • declaration_principal_investigatorDr Bernhards Ogutu
      • declaration_date201-02-2023
      • placebo_presentNo
      • study_objectives<p>\n Primary Objectives</p>\n<ul>\n <li>\n To assess the PK of etavopivat in patients with SCD</li>\n <li>\n To assess the safety and tolerability of etavopivat during the 24-week primary treatment period</li>\n</ul>\n<p>\n Secondary Objectives</p>\n<ul>\n <li>\n To assess the safety and tolerability of etavopivat during the 72-week treatment extension period</li>\n <li>\n To assess the effects of etavopivat on hemoglobin (Hb) response</li>\n <li>\n To describe the occurrence of VOCs in enrolled patients</li>\n <li>\n To assess changes in fatigue of patients with SCD taking etavopivat</li>\n <li>\n To assess changes in cerebral blood flow in patients with SCD taking etavopivat</li>\n</ul>\n
      • principal_inclusion_criteria<p>\n Inclusion Criteria</p>\n<p>\n Informed Consent</p>\n<p>\n 1. Patient’s parent, legal guardian, or legal representative has provided documented informed consent and patients have provided age-appropriate assent</p>\n<p>\n  Age</p>\n<p>\n 2. 12 to < 18 years of age</p>\n<p>\n Type of Participant and Disease Characteristics</p>\n<p>\n 3. Patient has confirmed diagnosis of SCD • Documentation of SCD genotype (HbSS, HbSβ0-thalassemia or other sickle cell syndrome variants) based on prior history of laboratory testing. Molecular genotyping is not required. SCD genotype may be determined from the results of Hb electrophoresis, high-performance liquid chromatography (HPLC), or similar testing. Note that Hb electrophoresis is performed by the local laboratory at Screening.</p>\n<p>\n 4. Hemoglobin ≥ 5.5 and < 10.5 g/dL</p>\n<p>\n 5. Adolescent patients with severe SCD, as defined by at least 1 of the following:</p>\n<p>\n • Two or more VOCs in the past 12 months, defined as a previously documented episode of acute chest syndrome (ACS) or acute painful crisis (for which there was no explanation other than VOC) which required prescription or healthcare professional-instructed use of analgesics for moderate to severe pain</p>\n<p>\n • Hospitalization for any SCD-related complication in the last 12 months</p>\n<p>\n • Proteinuria, defined as an albumin:creatinine ratio (ACR) > 100 mg/g on 2 measures (separated by ≥ 1 month) as an indicator of early renal disease</p>\n<p>\n • History of a conditional TCD in the last 12 months, but not currently being treated with chronic transfusion therapy. Conditional TCD is defined as a TAMMV of 170-199 cm/s by TCD or 155-184 cm/s by imaging TCD (TCDi).</p>\n<p>\n 6. For participants taking HU, the dose of HU (mg/kg) must be stable (no more than a 20% change in dosing) for at least 90 days prior to start of study treatment with no anticipated need for dose adjustments during the study, in the opinion of the Investigator</p>\n<p>\n 7. Patients on crizanlizumab or L-glutamine treatment at the time of consent may be eligible if they:</p>\n<p>\n • Have been on a stable dose for ≥ 12 months at the time of consent (ie, no changes to the dose except for changes to weight or for safety reasons)</p>\n<p>\n • For patients on crizanlizumab, have been ≥ 80% compliant with the planned regimen during the 12 months prior to the time of consent.</p>\n<p>\n Sex and Contraceptive Requirements</p>\n<p>\n 8. Patients, who if female and of childbearing potential, are using acceptable methods of contraception and agree not to donate ova from study start to 90 days after the last dose of study drug, and who if male, are willing to use acceptable methods of contraception and agree not to donate sperm, from study start to 90 days after the last dose of study drug.</p>\n
      • principal_exclusion_criteria<p>\n Exclusion Criteria</p>\n<p>\n Medical Conditions</p>\n<p>\n 1. Female who is breast feeding or pregnant</p>\n<p>\n 2. More than 10 VOCs within the 12 months prior to starting study treatment that required a hospital, ER, or clinic visit</p>\n<p>\n 3. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days of Screening</p>\n<p>\n 4. Hepatic dysfunction characterized by alanine aminotransferase (ALT) > 4 × upper limit of normal (ULN) and/or direct bilirubin > 3 × ULN</p>\n<p>\n 5. Patients with clinically significant bacterial, fungal, parasitic, or viral infection requiring systemic therapy</p>\n<p>\n • Patients with acute bacterial, fungal, parasitic, or viral infection requiring systemic therapy should delay screening/enrollment until active therapy has been completed</p>\n<p>\n • Patients with acute viral infections (eg, coronavirus disease 2019 [COVID-19]) should delay screening/enrollment until the acute infection has resolved. Note: Infection prophylaxis is allowed (see concomitant medication restrictions)</p>\n<p>\n 6. Known human immunodeficiency virus (HIV) positivity</p>\n<p>\n 7. Known infection with hepatitis B virus (hepatitis B surface antigen [HepBsAg] and hepatitis B core antibody [HepBcAb] positive)</p>\n<p>\n 8. Active Hepatitis C infection</p>\n<p>\n 9. Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the local laboratory) < 30 mL/min/1.73 m2 or on chronic dialysis</p>\n<p>\n 10. History of malignancy within the past 2 years prior to treatment Day 1 requiring systemic chemotherapy and/or radiation</p>\n<p>\n • Patients with malignancy considered surgically cured are eligible (eg, non-melanoma skin cancer, cancer of the cervix in-situ, ductal carcinoma in situ [stage 1], Grade 1 endometrial cancer)</p>\n<p>\n 11. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to uncontrolled clinically significant arrhythmias and congenital heart disease requiring treatment. Children with well-controlled asthma are not excluded.</p>\n<p>\n 12. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable)</p>\n<p>\n 13. Abnormal TCD in the 12 months prior to starting study treatmen</p>\n<p>\n Prior/Concomitant Therapy</p>\n<p>\n 14. Has chronic daily use of opioid analgesia for any reason (defined as opioid use in the majority of the 30 days prior to starting study treatment)</p>\n<p>\n 15. Patients receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion)</p>\n<p>\n 16. Received any blood products within 30 days of starting study treatment</p>\n<p>\n 17. Receiving or use of concomitant medications that are strong inducers of CYP3A4/5 within 2 weeks of starting study treatment</p>\n<p>\n 18. Use of voxelotor within 28 days prior to starting study treatment or anticipated need for this agent during the study</p>\n<p>\n 19. Receipt of erythropoietin or other hematopoietic growth factor treatment within 28 days of starting study treatment or anticipated need for such agents during the study</p>\n<p>\n 20. Receipt of prior cellular based therapy (eg, hematopoietic cell transplant, gene modification therapy)</p>\n<p>\n 21. Patients who are not taking or are unable to take antimalarial prophylaxis at the time of consent and during the study if they live in areas of endemic malaria where prophylaxis is recommended</p>\n<p>\n Prior/Concurrent Clinical Study Experience</p>\n<p>\n 22. Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of last dose prior to date of informed consent, whichever is longer, or is currently participating in another trial of an investigational agent (or medical device)</p>\n<p>\n Other Exclusions</p>\n<p>\n 23. Inadequate venous access as determined by the Investigator/ site staff.</p>\n<p>\n 24. Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent</p>\n
      • primary_end_points<p>\n • Single-dose: maximum concentration (Cmax), area under the concentration time curve (AUC)0-t, AUC0-inf</p>\n<p>\n • Steady-state etavopivat plasma exposure (Cmax,ss, AUCtau,ss, Cavg,ss, Cmin,ss)</p>\n<p>\n • Estimated using population PK</p>\n<p>\n • Incidence of adverse events (AEs), serious adverse events (SAEs), and AEs related to etavopivat</p>\n<p>\n • Number of premature discontinuations, dose interruptions, and dose reductions</p>\n
      • scope_diagnosis0
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      • scope_others1
      • scope_others_specifyTolerability
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      • staff_numbers<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\"><u><strong>Site # 960 AHERO CLINICAL TRIALS UNIT</strong></u></span></span></p>\n<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\"><strong><span lang=\"EN-US\" style=\"line-height: 148%;\">Study Site </span></strong></span></span></p>\n<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\">The study will be conducted at Ahero Clinical Trials Unit (ACTU), a satellite unit of Centre for Clinical Research of the Kenya Medical Research Institute (KEMRI) and also affiliated to the Center for Research in Therapeutic Sciences (CREATES), Strathmore University. The unit was set up in the year 2008 for the conduct of clinical trials in malaria as the area is within an area of all year transmission of malaria.</span></span><span style=\"font-family: arial, helvetica, sans-serif;\">The site has a well-equipped consultation office with coaches, emergency tray and drugs including oxygen with the ability to manage appropriately medical emergencies. There is also a pharmacy, well equipped laboratory with the ability to perform routine tests and a spacious archive and data entry rooms</span></p>\n<p>\n <strong><span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\">Staffs</span></span></strong></p>\n<p>\n <span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\"><span lang=\"EN-US\" style=\"line-height: 148%;\">The site has 1 PI Dr Bernherads Ogutu, 1 pediatrician  Dr Allan Otieno assisted by 2 medical officers  Dr John Orimbo and Dr Fredrick Olewe. @ Pharmacists Dr. Ruth Wasuna and Dr. Simeon Onyango. A study Coordinator Ms. Cecilia Awino and a number of clinical officers, nurses and laboratory technicians to conduct the clinical trials and offer medical care to research participants.</span></span></span></p>\n<p>\n <u><strong>Site # 961 Kombewa Clinical Research Centre</strong></u></p>\n<p>\n <u><strong>Study Site</strong></u></p>\n<p>\n The study will be conducted at the KCRC and recruitment will occur at the Kombewa County hospital and in the surrounding health facilities. The HDSS (Health Demographic Surveillance System) may be used to locate potential participants. The KEMRI/WRP Kombewa Clinical Research Center (KCRC) is designed for large clinical trials and has a full clinical laboratory including microbiology capability.</p>\n<p>\n KCRC is part of The Walter Reed Project (WRP), which is a 40-year collaboration between the Kenya Medical Research Institute, (KEMRI) and the Walter Reed Army Institute of Research (WRAIR). The US Army Medical Research Unit in Kenya (USAMRU-K) is a WRAIR attachment stationed in Kenya with headquarters in Nairobi and field stations in Kericho and Kisumu. WRP-Kisumu conducts a wide spectrum of field and laboratory work including numerous clinical research trials.</p>\n<p>\n Staffs</p>\n<p>\n The site has 1 PI Dr. Walter Otieno who will be responsible for the overall conduct of the trial at this study site, administrative actions between WRP, Institutional Review Boards, and the sponsor, oversight of field activities and patient care. She contributed to the site protocol development and will contribute to the statistical analysis and writing of the scientific report, 5 associate Investigators, Dr. Jack Hutter, Dr. Janet Oyieko, Dr. Valentine Sing’oei, Dr. Doris Njoroge and Dr. Michal Ohaga who will be responsible for the clinical conduct of the trial, the care provided to patients, oversight of field activities. They will also contribute to the statistical analysis and writing of scientific report(s). 1 Regulatory Affairs oversight Miss Irene Onyango who will be responsible for communication with IRBs and ECs. 1 Clinical Research Coordinator Ms Caroline Laboso who will be responsible for overall study coordination while working in a team environment under the direction of the investigators. Coordinating the recruiting, screening, and enrolling of study volunteers; arranging follow-up visits; completing and ensuring the accuracy of CRFs and regulatory documents; and ensuring the adherence to GCP guidelines. There are also several Clinical Officers, Nurses and Laboratory technologists <span style=\"font-family: arial, helvetica, sans-serif;\">to conduct the clinical trials and offer medical care to research participants</span>.</p>\n<p>\n <u><strong><span style=\"font-size:12px;\"><span style=\"font-family:arial,helvetica,sans-serif;\"><span lang=\"EN-US\" style=\"line-height: 148%;\">Site #  962 </span></span></span>KEMRI-Walter Reed-Kericho</strong></u></p>\n<p>\n <u><strong>Study Site</strong></u></p>\n<p>\n The study will be conducted at KEMRI-Walter Reed-Kericho. The site has a long-standing experience in conducting several studies including clinical trials, ranging from therapeutics that included a study of the safety and impact of broadly neutralizing monoclonal antibody therapy with VRC01 on viremia in acute HIV infection, alone or in combination with antiretroviral therapy (ART), vaccines (HIV, Polio, Ebola, Shigella) and cohort studies. The clinical trials range from phase I to IV with age ranges from birth to the elderly, some of which are randomized double blind, placebo controlled and United States Investigational New Drug (IND)/ Food and Drug Administration (FDA)- regulated.</p>\n<p>\n <u><strong>Staffs</strong></u></p>\n<p>\n The site has 1 PI Dr. Isaac Tsikhutsu who will be responsible for the overall conduct of the trial at these study site administrative actions between Institutional Review Boards, and the sponsor, oversight of field activities and patient care. He contributed to the protocol development and will contribute to the statistical analysis and writing of the scientific report. 4 Sub-Investigators Dr. Fredrick Sawe, Dr. Deborah Langat,Dr. Josphat Kosgey and Dr. Lucy Koech who will be responsible for the clinical conduct of the trial, the care provided to patients, oversight of field activities. They will contribute to the statistical analysis and writing of scientific report(s). 1 study pahrmacist Dr. Faith Riziki will be responsible for handling of IP including receipt, storage, and dispensing. 1 study coordinator Ms Linet Cherono will be responsible for the regulatory activities of the study. Several clinical officers, nurses and laboratory technologists <span style=\"font-family: arial, helvetica, sans-serif;\">to conduct the clinical trials and offer medical care to research participants</span>.</p>\n<p>\n <u><strong>Site # 963 KEMRI: Siaya Clinical Research Annexe</strong></u></p>\n<p>\n <u><strong>Study Site </strong></u></p>\n<p>\n The study will be conducted at the KEMRI CRDR Clinical Research Annexe Siaya  within Siaya County Referral Hospital. KEMRI has a modern research annex at the Siaya County Referral hospital with capacity to conduct phase I to Phase III studies through training and experience.</p>\n<p>\n <u><strong>Staffs</strong></u></p>\n<p>\n Site investigators responsible for day to day running of the project include: I PI Dr Videlis Nduba who will be responsible for the overall conduct of the trial at this study site, administrative actions between site, Institutional Review Boards, and the sponsor, oversight of site activities and clinical care provision to study participants. He will contribute to the writing of the scientific report. 1 Medical Officer Dr Mercy Mwale who will be responsible for the clinical conduct of the trial, the care provided to patients, oversight of study activities at the site. Reviewing potential Study participants for eligibility, supervising Clinical Officers, review of laboratory results, adverse events and serious adverse events surveillance, documentation and reporting, providing first hand clinical care to participants. Data entry, 1 Pharmacist Dr. Ian Mwangi who will be responsible for the  application of import license for Investigational Products, IMP accountability from receipt to storage, cold chain maintenance, preparation and dispensing and accountability logs, and IMP destruction. Supervision of the Pharmaceutical Technologists at each of the study sites, and other 2 Pharm tech, 6 Nurses, 5 Quality Assurance/Quality Control Officers, 2 Clinical Officers, 7 Community Interviewers, 2 Data personnel and 3 Laboratory Personnel <span style=\"font-family: arial, helvetica, sans-serif;\">to conduct the clinical trials and offer medical care to research participants</span>.</p>\n<p>\n  </p>\n
      • other_details_explanation<p>\n <span style=\"color: rgb(51, 62, 72); font-family: sans-serif; font-size: 16px; background-color: rgb(238, 238, 238);\">Forma Therapeutics, Inc. (Sponsor) is initiating Study 4202-HEM-202, titled, “A Single Arm,</span><br style=\"box-sizing: inherit; color: rgb(51, 62, 72); font-family: sans-serif; font-size: 16px;\" />\n <span style=\"color: rgb(51, 62, 72); font-family: sans-serif; font-size: 16px; background-color: rgb(238, 238, 238);\">Open Label, Phase 1/2 Study to Evaluate the Pharmacokinetics and Safety of Etavopivat in Pediatric Patients with Sickle Cell Disease,” outside of the United States, specifically in Canada, UK, Lebanon, Nigeria, Turkey, and Kenya. Studies of etavopivat are ongoing in the United States (US) and globally where there is a consistent interest in etavopivat from sickle cell experts. Although 8 etavopivat clinical studies have been conducted or are currently being conducted in the US (2 of which include adolescent patients), US sites are not currently planned for Study 4202-HEM-202. There are several reasons for this, including that the sickle cell disease population in the US is rare, and sites have exhausted eligible patients with on-going Studies 4202-HEM-201 and 4202-HEM-301. The patient availability in the selected countries has the potential to provide improved therapy to children with sickle cell disease with significant unmet medical need. Depending on enrollment, the Sponsor may expand the conduct of the study to other countries including the US.</span></p>\n
      • other_details_regulatory_notapproved<p>\n National Agency for Food & Drug Administration - Submitted 14Oct2022</p>\n<p>\n T.R. Ministry of Health Turkish Medicines and Medical Devices Agency - Submitted on 19 Sep 2022</p>\n
      • other_details_regulatory_approved<p>\n <span style=\"font-size: 16px;\">Health Canada (the Competent Authority in Canada) - Approved on 30Jun2022</span></p>\n<p>\n <span style=\"font-size: 16px;\">United Kingdom Regulatory Approval was received on 04Nov2022</span></p>\n<p>\n <span style=\"font-size: 16px;\">Healthcare Products Regulatory Agency approved on 04 Nov 2022</span></p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration100 weeks
      • 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_sites4
      • multi_country_listNigeria.\nLebanon.\nUK.\nCanada.\nTurkey
      • data_monitoring_committeeNo
      • total_enrolment_per_site4-6
      • total_participants_worldwide50
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenYes
      • population_adolescentYes
      • 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_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameBernhards
      • investigator1_middle_name
      • investigator1_family_nameOgutu
      • investigator1_qualificationMD, PHD
      • investigator1_professional_addressAhero Clinical Trials Unit P.O Box 2254, Nairobi
      • investigator1_telephone+254733812613
      • investigator1_emailogutu@gmail.com
      • organisations_transferred_Yes
      • number_participants18
      • notification
      • approval_date14-06-2023
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted01-02-2023
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments resolved.
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-03-24 16:12:22
      • created2022-10-31 13:48:25
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id860
        • application_id1182
        • given_nameVidelis
        • middle_name
        • family_nameNduba
        • qualificationMBchB, MPH, PhD
        • professional_addressKenya Medical Research Institute-Centre for Respiratory Disease Research P.O Box 47855-00100
        • telephone+254 724 522 474
        • emailvnduba@gmail.com
        • created2022-11-08 17:55:58
        • modified2023-02-01 17:00:10
      • 1(array)
        • id861
        • application_id1182
        • given_nameWalter
        • middle_name
        • family_nameOtieno
        • qualificationMD, Mmed
        • professional_addressUSAMRU-A/K PO Box 54, Kisumu
        • telephone +254 714481488
        • emailwalter.otieno@usamru-k.org
        • created2022-11-08 18:14:54
        • modified2023-02-01 17:00:10
      • 2(array)
        • id862
        • application_id1182
        • given_nameIsaac
        • middle_name
        • family_name Tsikhutsu
        • qualificationMD, Mmed
        • professional_addressKEMRI-Walter Reed-Kericho PO Box 1357 Kericho
        • telephone +254 722749789
        • emailIsaac.tsikhutsu@usamru-k.org
        • created2022-11-08 18:14:54
        • modified2023-02-01 17:00:10
    • SiteDetail(array)
      • 0(array)
        • id1330
        • application_id1182
        • county_id42
        • site_nameAHERO CLINICAL TRIALS UNIT
        • physical_addressP.O Box 2254
        • contact_details+254733812613
        • contact_personDr Bernhards Ogutu
        • site_capacity(null)
        • misc(null)
        • created2022-11-08 17:55:58
        • modified2023-02-01 17:00:10
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 1(array)
        • id1331
        • application_id1182
        • county_id35
        • site_nameKEMRI-Walter Reed-Kericho
        • physical_addressPO Box 1357 Kericho
        • contact_details +254722749789
        • contact_personDr Isaac Tsikhutsu
        • site_capacity(null)
        • misc(null)
        • created2022-11-08 18:56:37
        • modified2023-02-01 17:00:10
        • County(array)
          • id35
          • county_nameKericho
          • created2012-06-15 10:26:16
          • modified2012-06-15 10:26:16
      • 2(array)
        • id1335
        • application_id1182
        • county_id42
        • site_nameKEMRI: Siaya Clinical Research Annexe
        • physical_address P.O BOX 144-40600 Siaya, Kenya
        • contact_details+254724522474
        • contact_personDr Videlis Nduba
        • site_capacity(null)
        • misc(null)
        • created2022-11-22 09:25:22
        • modified2023-02-01 17:00:10
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 3(array)
        • id1336
        • application_id1182
        • county_id42
        • site_nameKombewa Clinical Research Centre
        • physical_addressNamba Kosea Road,Kombewa
        • contact_details+254714481488
        • contact_personDr Walter Otieno
        • site_capacity(null)
        • misc(null)
        • created2022-11-22 09:34:32
        • modified2023-02-01 17:00:10
        • County(array)
          • id42
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          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
    • Sponsor(array)
      • 0(array)
        • id613
        • application_id1182
        • sponsorForma Therapeutics, Inc
        • sponsor_typeIndustry
        • contact_person
        • address300 North Beacon Street, Suite 501 Watertown, MA 02472
        • telephone_number 617-679-1970
        • fax_number
        • cell_number+1-857-209-2235
        • email_address4202-202Clinical@formarx.com
        • created2022-11-08 17:55:58
        • modified2023-02-01 17:00:10
  • 1(array)
    • Application(array)
      • id1382
      • user_id613
      • trial_status_id6
      • abstract_of_study<p>\n Shigellosis remains a major public health problem around the world; it is one of the leading causes of diarrheal disease in low- and middle-income countries (LMIC), particularly in young children. The Global Burden of Disease study (IHME) estimated that in 2017 Shigella caused approximately 238,000 deaths globally and, with 15.2%, it ranked second with regard to pathogen contributions in global diarrheal deaths. In infants, in LMIC, particularly where healthcare resources are limited, shigellosis can often lead to death. There is presently no widely available vaccine against Shigella. The candidate vaccine, altSonflex1-2-3, has been evaluated for the FTiH in adults in Belgium, and is currently evaluated in a Phase 2 age de-escalation clinical study in Kenya, with the aim of identifying a preferred dose, using a 3-dose vaccinations schedule in infants from 9 months of age (NCT05073003). The current Phase 2 clinical study will evaluate the immunogenicity and safety of an alternative 2-dose vaccination schedule. The candidate vaccine, altSonflex1-2-3, will be administered intramuscularly by study site staff and contains 15 μg (Dose C), 7.5 μg (Dose B), or 3.75 μg (Dose A) of OAg for each antigen component. About 400 9-month old infants will be screened to enroll 200 participants. The results of this study will allow the selection of the most appropriate dose for further vaccine development in infants 9 months of age, which is the main target age group for this vaccine. The study findings will be shared with all authorities having oversight of this protocol including the sponsor, Kenya Medical Research Institute Scientific Ethics Review Unit, Pharmacy and Poisons Board, Walter Reed Army Institute of Research Institutional Review Board and Kenya’s Ministry of Health.</p>\n
      • study_title<p>\n A Phase 2 single-blind, randomized, controlled, single center study to assess the immunogenicity and safety of a 2-dose schedule with GVGH altSonflex1-2-3 vaccine in African infants (H06_02TP)</p>\n
      • laymans_summary<p>\n Lay Title: A study on the safety and immune responses to the GVGH vaccine against shigellosis in infants</p>\n<p>\n Shigellosis is an infectious disease caused by a group of bacteria called Shigella. Shigellosis remains a major public health problem around the world; it is one of the leading causes of diarrheal disease in low- and middle-income countries (LMIC), particularly in young children. The Global Burden of Disease study (IHME) estimated that in 2017 Shigella caused approximately 238,000 deaths globally. In infants, in LMIC, particularly where healthcare resources are limited, shigellosis can often lead to death. There is presently no widely available vaccine against Shigella. Treatment for shigellosis is mainly supportive to keep patients stable. Shigellosis can be treated with antibiotics but many Shigella bacteria no longer respond well to or are resistant to most of the used antibiotics. Thus, a very important way to fight Shigella is through prevention with the use of vaccination.. The aim of the study is to assess how an experimental Shigella vaccine, called altSonflex1-2-3, given in two doses, makes the body to produce proteins that fight off the bacteria causing shigellosis and to assess the side effects the vaccine may cause. Infants who are 9 months old will receive 2 injections of Shigella vaccine or 2 injections of the control vaccines. The benefits of this study include, participants or participants’ parents may gain medical advice about their own or their children’s health status H06_02TP /WRAIR # /KEMRI/SERU/CCR/0327/4829 Kericho Site Specific Addendum Version 2.0 dated 15 Nov 2023 Page 7 of 30 through the medical evaluations and laboratory assessments associated with the study. Vaccines administered as control and not routinely given will be provided free of charge and can provide protection against Salmonella Typhi, diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and disease caused by Haemophilus influenzae type b. The infants who will be assigned to receive the shigella vaccine will receive THYPIBEV vaccine after the study is completed as a benefit. The results of this study will allow the selection of the most appropriate dose for further vaccine development in infants 9 months of age, which is the main target age group for this vaccine.</p>\n
      • short_titleH06_02TP
      • protocol_noECCT/24/02/08
      • version_no1
      • date_of_protocol19-12-2022
      • study_drugShigella 4-component generalized modules for membrane antigens vaccine (altSonflex1-2-3)
      • disease_conditionShigellosis
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines1
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressKericho.DRS@usamru-k.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_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_applicant+254 110 122
      • declaration_date127-02-2024
      • declaration_principal_investigatorJOSPHAT KOSGEI
      • declaration_date227-02-2024
      • placebo_presentNo
      • study_objectives<p>\n 1.To evaluate the immunogenicity profile of the altSonflex1-2-3 vaccine (Dose A, Dose B and Dose C) administered at 9 and 15 months using anti-LPS/OAg ELISA</p>\n<p>\n 2. To evaluate the seroresponse of the altSonflex1-2-3 vaccine (Dose A, Dose B and Dose C) administered at 9 and 15 months using anti-LPS/OAg ELISA</p>\n<p>\n 3.T o evaluate the safety and reactogenicity of the altSonflex1-2-3 vaccine (Dose A, Dose B and Dose C) administered at 9 and 15 months.</p>\n<p>\n 4 To evaluate the immunogenicity of co-administered MR-VAC administered at 9 and 15 months.</p>\n<p>\n 5. To evaluate the immunogenicity profile of the altSonflex1-2-3 vaccine (Dose A, Dose B and Dose C) administered at 9 and 15 months by SBA, in a subset of infants.</p>\n<p>\n 6. To evaluate the seroresponse of the altSonflex1-2-3 vaccine (Dose A, Dose B and Dose C) administered at 9 and 15 months by SBA, in a subset of infants.</p>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n Participants are eligible to be included in the study only if all of the following criteria apply:</p>\n<p>\n • Participants’ parent(s)/LAR(s), who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits).</p>\n<p>\n • Written or witnessed/thumb printed informed consent obtained from the parent(s)/LAR(s) of the participant prior to performance of any study specific procedure.</p>\n<p>\n • Healthy participants as established by medical history, clinical examination, and laboratory assessment.</p>\n<p>\n • Participants satisfying all screening requirements.</p>\n<p>\n • Participants seronegative for hepatitis B, and hepatitis C.</p>\n<p>\n • A male or female 9 months of age at the time of the first study intervention administration.</p>\n<p>\n • Normal nutritional (weight-for-length) Z score (-2 standard deviations or greater).</p>\n<p>\n • Previously completed routine childhood vaccinations to the best knowledge of the participant’s parent(s)/LAR(s).</p>\n<p>\n • Born at a gestation period of ≥37 weeks to the best knowledge of the participant’s parent(s)/LAR(s).</p>\n<p>\n • Participants negative for human immunodeficiency virus as confirmed by DNA polymerase chain reaction testing.</p>\n<p>\n • Participants negative for HLA-B27</p>\n
      • principal_exclusion_criteria<p>\n Medical Conditions</p>\n<p>\n •Known exposure to Shigella during lifetime of the participant as confirmed during interview with the participant’s parent(s)/LAR(s) or documented by participant’s records (e.g., history of microbiologically-confirmed Shigella infection).</p>\n<p>\n • Progressive, unstable, or uncontrolled clinical conditions. CONFIDENTIAL 219449 Protocol Final 19 Dec 2022 31</p>\n<p>\n • History (known or suspected) of any reaction or hypersensitivity likely to be exacerbated by any component of the study intervention.</p>\n<p>\n • Major congenital defects, as assessed by the investigator.</p>\n<p>\n • Recurrent history or uncontrolled neurological disorders or seizures.</p>\n<p>\n • Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required). • Hypersensitivity (known or suspected), including allergy, to medicinal products, vaccines, or medical equipment whose use is foreseen in this study.</p>\n<p>\n • Clinical conditions representing a contraindication to IM vaccination and blood draws.</p>\n<p>\n • Any behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the participant’s ability to participate in the study.</p>\n<p>\n • Acute disease and/or fever (defined as temperature ≥38.0°C) at the time of enrollment*. *The participant can still be enrolled into the study at a time when the acute disease and/or fever has resolved.</p>\n<p>\n • Any clinically significant* hematological and/or biochemical laboratory abnormality. *The investigator should use his/her clinical judgment to decide which abnormalities are clinically significant.</p>\n<p>\n • Confirmed positive COVID-19 test during the period starting 30 days before the first administration of study interventions (Day -30 to Day 1).</p>\n<p>\n • Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the participant due to participation in the study.</p>\n<p>\n • Acute or chronic clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by physical examination or laboratory screening tests.</p>\n
      • primary_end_points<p>\n 1. Anti-serotype-specific Shigella LPS/OAg* serum IgG GMCs/GMTs, as measured by ELISA, before each study intervention administration (Day 1 and Day 169), and 28 days after each study intervention administration (Day 29 and Day 197), for each study intervention group.</p>\n<p>\n 2. mber of infants with at least a 4-fold increase in anti-serotypespecific Shigella LPS/OAg* serum IgG, as measured by ELISA, at 28 days after each study intervention administration (Day 29 and Day 197), compared to baseline (Day 1), and compared to pre-administration (Day 1 and Day 169, respectively), for each study intervention group.</p>\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_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n The Kericho CRC is equipped with two emergency rooms with equipment and medications to provide immediate emergency care in the event of emergencies such as anaphylactic reactions and provisions (resuscitation equipment) are in place for immediate resuscitation on site. Additionally, the Kericho site has a standby, fully equipped ambulance for evacuation of participants for more specialized care when necessary. The study staff (clinicians/nurses) are trained on handling emergencies. For inpatient services, participants will be hospitalized at Unilever Tea Kenya (UTK) Central Hospital which is a private company facility owned by the UTK tea company. The site has been using UTK hospital as a satellite site for inpatient admissions of participants requiring inpatient services. The hospital is located about two kilometers from the CRC and has both outpatient and inpatient services.</p>\n
      • other_details_explanation<p>\n The clinical study will be performed in the same center (Kenya Medical Research Institute [“KEMRI”]/ United States Army Medical Research Directorate-Africa/Kenya [MRD-A/K]), where the altSonflex1-2-3 vaccine dose A, B and C have been previously administered in infants 9 months of age with a 3-dose vaccination schedule, in a FTiH Phase 1/2 study (NCT05073003). The Phase 1/2 clinical study included a Phase 1 (FTiH) part, conducted in healthy adults in Belgium; the Phase 2 part is ongoing in Kenya, using an age de-escalation approach, including adults, children and infants, with the primary objectives of identifying the preferred dose of the candidate vaccine among infants and evaluating the safety and reactogenicity of the candidate vaccine among adults, children and infants. The present study will only commence enrollment after all the planned safety reviews by the GSK iSRC and SRT in the Phase 1/2 trial have been completed as per protocol (i.e., after evaluation of data collected up to 7 days after the first study intervention administration in the dose-finding cohort of all infants who were vaccinated in the first 7 weeks of enrollment), and after enrollment has been completed.</p>\n
      • other_details_regulatory_notapproved<p>\n Walter Reed Army IRB</p>\n<p>\n Application submitted 24 Jan 2024.</p>\n
      • other_details_regulatory_approved<p>\n KEMRI SERU</p>\n<p>\n Approval attached dated 24 January 2024.</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n None</p>\n
      • estimated_duration2 years
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindYes
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupNo
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorTYPHIBEV, MR-VAC,
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKEMRI WRP CRC KERICHO
      • single_site_physical_addressOFF HOSPITAL ROAD
      • single_site_contact_personDR JOSPAHT KOSGEI
      • single_site_telephone+254 729 110 122
      • multiple_sites_member_stateNo
      • multiple_countriesNo
      • multiple_member_states
      • number_of_sites
      • multi_country_list
      • data_monitoring_committeeYes
      • total_enrolment_per_site200
      • total_participants_worldwide200
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • population_childrenNo
      • population_adolescentNo
      • population_above_18No
      • population_adultNo
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specify9-month old infants
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameFredrick
      • investigator1_middle_name
      • investigator1_family_nameSawe
      • investigator1_qualificationMBChB MMED
      • investigator1_professional_addressP O BOX 1357, KERICHO
      • investigator1_telephone+254 703 247 902
      • investigator1_emailFredrick.sawe@usamru-k.org
      • organisations_transferred_No
      • number_participants200
      • notification
      • approval_date31-05-2024
      • submitted1
      • deleted0
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      • date_submitted28-02-2024
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      • admin_stopped0
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      • approved2
      • approved_reasonReviewer comments have been addressed.
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      • quantity_destroyed(null)
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      • modified2025-04-22 17:26:57
      • created2024-02-27 08:45:53
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    • InvestigatorContact(array)
      • 0(array)
        • id1042
        • application_id1382
        • given_nameJosphat
        • middle_name
        • family_nameKosgei
        • qualificationMBChB, MSc, DLSHTM
        • professional_addressP O BOX 1357, KERICHO
        • telephone+254 729 110 122
        • emailJosphat.kosgei@usamru-k.org
        • created2024-02-27 09:25:48
        • modified2024-02-28 09:22:51
    • SiteDetail(array)
      • 0(array)
        • id1677
        • application_id1382
        • county_id(null)
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        • contact_details
        • contact_person
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        • misc(null)
        • created2024-02-27 09:25:48
        • modified2024-02-28 09:22:51
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id727
        • application_id1382
        • sponsorGlaxoSmithKline Biologicals SA
        • sponsor_typeIndustry
        • contact_person
        • addressRue De L\'Institut 89 1330 Rixensart Belgium
        • telephone_number+32 2 656 81 11
        • fax_number
        • cell_number+32 2 656 81 11
        • email_addresspietro.x.ferruzzi@gsk.com
        • created2024-02-27 09:25:48
        • modified2024-02-28 09:22:51
  • 2(array)
    • Application(array)
      • id4
      • user_id21
      • trial_status_id4
      • abstract_of_study<p style=\"margin-left:82.8pt;\">\n <u>DESIGN:</u>            This is a prospective, randomized, active-controlled clinical trial.</p>\n<p style=\"margin-left:82.8pt;\">\n  </p>\n<p style=\"margin-left:82.8pt;\">\n <u>Step 1:</u> Participants will be randomized 1:1:1 to oral etoposide (ET) plus antiretroviral therapy (ART), bleomycin and vincristine (BV) plus ART, or doxorubicin HCL liposome injection (Doxil^®, PLD) plus ART.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:82.8pt;\">\n <u>Step 2:</u> Participants who originally have a Kaposi’s sarcoma (KS) response (complete or partial [CR or PR]) to Step 1 chemotherapy, but then progress at a time <u>point</u> of at least 12 weeks or longer after the last dose of Step 1 chemotherapy, but prior to week 72, may be provided a second course of up to 6 cycles of the same chemotherapy utilized in Step 1. This option is available for study participants who have a confirmed initial KS response and subsequent Independent Endpoint Review Committee (IERC)-confirmed KS progression and who, in the opinion of the investigator and with concurrence of the protocol Clinical Management Committee (CMC) (see Section 7.1 for definition of IERC-confirmed KS progression), could potentially benefit from another course of the same chemotherapy. Participants who have received ET in Step 1 will initiate treatment in Step 2 at the dose last tolerated in Step 1.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:82.8pt;\">\n <u>Step 3</u>: Participants will be randomized (1:1) to one of the two chemotherapy arms not utilized in Step 1.  If IERC-confirmed KS progression or chemotherapy-related toxicity occurs in Step 1 or Step 2, participants will be offered alternative study treatment in Step 3. Participants must enter Step 3 within the 72 weeks following Step 1 randomization. Participants will move to Step 3 when (1) there is IERC-confirmed KS progression at any time during Step 1 <u>chemotherapy</u>; or (2) there is IERC-confirmed KS progression less than 12 weeks after the last chemotherapy dose in Step 1 in participants who have had complete or partial response; or (3) there is IERC-confirmed KS progression following Step 1 chemotherapy, without any prior response; or (4) there is IERC-confirmed KS progression in Step 2; or (5) there is dose-limiting toxicity after receiving less than 4 cycles of chemotherapy in Step 1 or Step 2, in the absence of a CR or PR. Participants otherwise eligible for Step 2 who, in the opinion of the investigator and the CMC, are unlikely to benefit from another course of the same chemotherapy received in Step 1 will also be eligible for randomization in Step 3.  If there is IERC-confirmed KS progression in Step 3, participants may enter Step 4 or be offered alternative care available locally outside of the study, whichever the investigator deems most appropriate. If an investigator offers locally-available alternative care, the participants will be followed according to their original Step 3 schedule.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:82.8pt;\">\n <u>Step 4</u>: Following CMC and IERC-confirmed KS progression on Step 3, or if there is dose-limiting toxicity after receiving less than 4 cycles of chemotherapy in Step 3, in the absence of a CR or PR, participants will be assigned to the remaining study-provided chemotherapy not given in Step 1, Step 2, or Step 3. Participants must enter Step 4 within the 72 weeks following Step 1 randomization.  If there is IERC-confirmed KS progression in Step 4, participants may be offered alternative care available locally, outside of the study. If an investigator offers locally-available alternative care, the participants will be followed according to their original Step 4 schedule.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:82.8pt;\">\n <u>DURATION:</u>       All participants will be followed for 5 years after randomization or assignment to the last step they enter. Therefore, participants could be followed for 5 to 7 years.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:82.8pt;\">\n <u>SAMPLE SIZE</u>:  706 participants ≥ 18 years of age</p>\n<p>\n  </p>\n<p style=\"margin-left:82.8pt;\">\n <u>POPULATION</u>: HIV-infected men and women with the following characteristics:</p>\n<p style=\"margin-left:54.0pt;\">\n  </p>\n<ul>\n <li>\n Biopsy diagnostic of KS</li>\n <li>\n Naïve to ART (as defined in Section 4.2.7), chemotherapy, and radiation therapy</li>\n <li>\n KS stage T1, (See section 4.1.3) </li>\n <li>\n Persons with chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, must have completed at least 14 consecutive days of appropriate anti-infective treatment prior to study entry and be clinically stable</li>\n</ul>\n<p style=\"margin-left:82.8pt;\">\n  </p>\n<p>\n <u>STRATIFICATION</u>:</p>\n<p>\n  </p>\n<ul>\n <li>\n CD4+ lymphocyte cell count < 100 or ≥ 100 cells/mm³</li>\n <li>\n By country</li>\n</ul>\n<p>\n <u>REGIMEN </u></p>\n<p>\n  </p>\n<p style=\"margin-left:118.8pt;\">\n Step 1:</p>\n<p style=\"margin-left:82.8pt;\">\n <u>Arm 1A</u>: Coformulated efavirenz, tenofovir, and emtricitabine (EFV/FTC/TDF) plus ET 50 mg twice a day (with escalation on subsequent cycles up to a maximum of 100 mg twice a day, depending on toxicity) for 7 consecutive days of every 3-week cycle.  Treatment with ET will continue for a maximum of 6 cycles at the highest dose achieved, or until toxicity requiring discontinuation of study chemotherapy, or until the site investigator and A5263/AMC 066 CMC have determined that alternative therapy is required, whichever occurs first.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:82.8pt;\">\n <u>Arm 1B</u>: Coformulated EFV/FTC/TDF plus bleomycin 15 units/m² IV (intravenous) plus vincristine 2mg IV every 3 weeks.  Treatment with BV may continue for a maximum of 6 cycles, or until toxicity requiring discontinuation of study chemotherapy, or until the site investigator and the A5263/AMC 066 CMC have determined that alternative therapy is required, whichever occurs first.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:82.8pt;\">\n <u>Arm 1C</u>: Coformulated EFV/FTC/TDF plus pegylated liposomal doxorubicin (PLD) 20 mg/m² IV every 3 weeks.  Treatment with PLD will continue for a maximum of 6 cycles, or until toxicity requiring discontinuation of study</p>\n<p style=\"margin-left:82.8pt;\">\n  </p>\n<p style=\"margin-left:82.8pt;\">\n chemotherapy, or until the site investigator and the A5263/AMC 066 CMC have determined that alternative therapy is required, whichever occurs first.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:118.8pt;\">\n Step 2: Coformulated EFV/FTC/TDF plus a second course of up to 6 cycles of the same chemotherapy utilized in Step 1</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:118.8pt;\">\n Step 3: Coformulated EFV/FTC/TDF plus a randomly assigned alternative study-provided chemotherapy regimen</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p style=\"margin-left:118.8pt;\">\n Step 4: Coformulated EFV/FTC/TDF plus the remaining study-provided chemotherapy regimen</p>\n
      • study_title<p>\n A5263/AMC 066 "A Randomized Comparison of Three Regimens of Chemotherapy with Compatible Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings"</p>\n
      • laymans_summary<p>\n AIDS-related Kaposi’s sarcoma (AIDS-KS) occurs in persons who are coinfected with HIV-1 and human herpesvirus 8 (HHV-8 or KSHV). In areas of the world where access to ART and chemotherapy is limited, and where rates of HIV and KSHV coinfection are higher, AIDS-KS is a more significant contributor to morbidity and mortality in HIV-1 infected persons.</p>\n<p>\n  </p>\n<p>\n Given that ART alone often improves or stabilizes AIDS-KS disease, it is possible that combining ART with chemotherapy might provide improved clinical responses.</p>\n<p>\n  </p>\n<p>\n A5263/AMC 066 is a prospective, randomized, active-controlled clinical trial. Randomization will be stratified by CD4+ lymphocyte cell count and country. The main objective is to compare the clinical efficacy of two regimens, oral Etoposide plus ART and Bleomycin and Vincristine (BV) plus ART, to pegylated liposomal doxorubicin (PLD) plus ART for initial treatment of advanced stage AIDS-KS</p>\n
      • short_titleTreatment of Advanced AIDS-KS in Resource-Limited Settings
      • protocol_noECCT/11/10/04
      • version_no2.0
      • date_of_protocol07-08-2012
      • study_drugbleomycin (B), vincristine (V), oral etoposide (ET), Paclitaxel
      • disease_conditionAIDS-KS (Kaposi’s sarcoma )
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_namebleomycin (B), vincristine (V), oral etoposide (ET), Paclitaxel
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressaksudoi@hotmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi0
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist0
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantAllan K Sudoi
      • declaration_date103-04-2013
      • declaration_principal_investigatorAbraham M Siika, MBChB, MMed, Msc
      • declaration_date203-04-2013
      • placebo_presentNo
      • study_objectives<h2>\n 1.1       Primary Objective</h2>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<p style=\"margin-left:37.45pt;\">\n To compare the clinical efficacy of two regimens, <strong>etoposide (</strong>ET) plus ART and <strong>bleomycin plus vincristine (</strong>BV<strong>)</strong> plus ART, to <strong>paclitaxel</strong> (PTX) plus ART for initial treatment of advanced stage <strong>AIDS-related Kaposi’s sarcoma</strong> <strong>(</strong>AIDS-KS<strong>)</strong>.</p>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<h2>\n 1.2       Secondary Objectives</h2>\n<p>\n  </p>\n<ol>\n <li value=\"NaN\">\n Compare <strong>Kaposi’s sarcoma (</strong>KS<strong>)</strong> tumor response in persons randomized to ET plus ART, BV plus ART, and PTX plus ART.</li>\n</ol>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<ol>\n <li value=\"NaN\">\n Compare measures of quality of life in persons randomized to ET plus ART, BV plus ART, and PTX plus ART.</li>\n</ol>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p>\n Compare the safety and toxicity in persons randomized to ET plus ART, BV plus ART, and PTX plus ART.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p>\n Compare suppression of plasma HIV-1 RNA and changes in CD4+ lymphocyte cell count in persons randomized to ET plus ART, BV plus ART, and PTX plus ART.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p>\n Compare adherence to ART in persons randomized to ET plus ART, BV plus ART, and PTX plus ART.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p>\n Compare the incidence of peripheral neuropathy (PN) and symptomatic peripheral neuropathy (SPN) in persons randomized to ET plus ART, BV plus ART, and PTX plus ART.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p>\n <strong>Evaluate</strong> clinical efficacy of the <strong>remaining regimen</strong> after failure of <strong>the</strong> initial regimen.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<p>\n Evaluate the relationship between response of KS to therapy and development of KS-associated immune reconstitution inflammatory syndrome (KS-IRIS) with:</p>\n<p style=\"margin-left:54.0pt;\">\n  </p>\n<p style=\"margin-left:115.2pt;\">\n 1    Baseline immunohistochemical markers of viral and cellular gene expression in KS tumors.</p>\n<p style=\"margin-left:98.4pt;\">\n  </p>\n<p style=\"margin-left:115.2pt;\">\n <strong>2</strong>    RNA levels for <strong>Kaposi’s sarcoma herpesvirus (</strong>KSHV<strong>)</strong> genes in tumor biopsies at baseline and during therapy.</p>\n<p style=\"margin-left:194.4pt;\">\n  </p>\n<p style=\"margin-left:115.2pt;\">\n .<strong>3</strong>    Suppression of KSHV viral load.</p>\n<p style=\"margin-left:194.4pt;\">\n  </p>\n<p style=\"margin-left:115.2pt;\">\n <strong>4</strong>    Cellular and humoral markers of immune function and immune activation.</p>\n<p style=\"margin-left:194.4pt;\">\n  </p>\n<p>\n Investigate the relationship between plasma and peripheral blood mononuclear cell (PBMC) KSHV viral load.</p>\n<p style=\"margin-left:194.4pt;\">\n  </p>\n<p>\n Encourage donation of excess biopsy materials to the AIDS and Cancer Specimen Resource.</p>\n<p style=\"margin-left:194.4pt;\">\n  </p>\n<p>\n To assess the risk of secondary leukemia and myelodysplasia after <strong>ET</strong>.</p>\n
      • principal_inclusion_criteria<p>\n <u>Inclusion Criteria Step 1</u></p>\n<ol>\n <li>\n HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.</li>\n <li>\n Biopsy diagnostic of KS at any time prior to study entry.</li>\n <li>\n Current KS stage T1 using ACTG criteria</li>\n</ol>\n<p style=\"margin-left:72.0pt;\">\n KS stage T1 is KS with any of the following:</p>\n<ul>\n <li>\n symptomatic tumor-associated edema</li>\n <li>\n tumor ulceration</li>\n <li>\n extensive oral KS (other than flat KS confined to the hard palate)</li>\n <li>\n gastrointestinal KS</li>\n <li>\n KS in any other non-nodal visceral organ (e.g., lung)</li>\n</ul>\n<ol>\n <li value=\"4\">\n A minimum of five indicator KS cutaneous marker lesions plus an additional two lesions greater or equal to 4x4 mm that are accessible for punch biopsy.</li>\n <li>\n CD4+ lymphocyte cell count obtained within 28 days prior to study entry at a DAIDS-approved laboratory.</li>\n <li>\n The following laboratory values obtained within 14 days prior to study entry:</li>\n</ol>\n<ul>\n <li>\n Absolute neutrophil count (ANC) ³ 1000 cells/mm³</li>\n <li>\n Hemoglobin ³ 9 g/dL</li>\n <li>\n Platelet count ³ 100,000/mm³</li>\n <li>\n Estimated creatinine clearance of ≥ 60 mL/min.</li>\n <li>\n AST (SGOT), ALT (SGPT), and alkaline phosphatase <5 ´ ULN</li>\n <li>\n Total bilirubin of < 1.5 X ULN</li>\n</ul>\n<ol>\n <li value=\"7\">\n Cardiac ejection fraction of greater than or equal to 50% obtained within 14 days prior to study entry.</li>\n <li>\n Female study volunteers of reproductive potential (defined as girls who have reached menarche, women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL performed within 24 hours before initiating the protocol-specified medications.� �</li>\n <li>\n All participants must agree <u>not</u> to participate in a conception process (active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).</li>\n <li>\n If participating in sexual activity that could lead to pregnancy, the study volunteer must agree that two reliable forms of contraceptives will be used simultaneously while receiving protocol-specified medications, and for 6 weeks after stopping the medications</li>\n <li>\n � Men and women age ³ 18 years.</li>\n <li>\n � Ability to swallow oral medications and adequate venous access.</li>\n <li>\n � Karnofsky performance status ≥ 60 within 28 days prior to entry.</li>\n <li>\n � Ability and willingness of participant or legal guardian/representative to provide informed consent.</li>\n</ol>\n<p>\n <u>Inclusion Criteria Step 2</u></p>\n<ol>\n <li>\n Complete or partial response to the chemotherapy regimen used in step 1.</li>\n <li>\n KS progression at a time point greater than 12 weeks after the last dose of Step 1 chemotherapy.</li>\n <li>\n Less than 72 weeks after Step 1 entry.</li>\n <li>\n The following laboratory values obtained within 14 days prior to Step 2 entry:</li>\n</ol>\n<ul>\n <li>\n ANC ≥1,000 cells/mm³</li>\n <li>\n Hemoglobin ≥9.0 g/dL</li>\n <li>\n Platelet count ≥100,000/mm³</li>\n <li>\n Estimated creatinine clearance of ≥ 60 mL/min.</li>\n <li>\n AST (SGOT), ALT (SGPT), and alkaline phosphatase < 5 ULN</li>\n <li>\n Total bilirubin of <u><</u> 1.5 X ULN</li>\n</ul>\n<ol>\n <li value=\"5\">\n For participants who received PLD in Step 1, cardiac ejection fraction of greater than 50% obtained within 14 days prior to Step 2 entry.</li>\n <li>\n For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to Step 2 entry.</li>\n <li>\n Karnofsky performance status ≥ 50 within 28 days prior to Step 2.</li>\n <li>\n All participants must agree not to participate in a conception process (active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).</li>\n</ol>\n<p>\n <u>Inclusion Criteria Step 3</u></p>\n<ol>\n <li>\n Inability to continue on Step 1 or Step 2 due to KS progression OR lack of a CR or PR after receiving less than 4 cycles of chemotherapy in Step 1 or Step 2 because of the development of dose-limiting toxicity.</li>\n <li>\n Less than 72 weeks after Step 1 entry.</li>\n <li>\n The following laboratory values obtained within 14 days prior to Step 3 entry:</li>\n</ol>\n<ul>\n <li>\n ANC ≥1,000 cells/mm³</li>\n <li>\n Hemoglobin ≥9.0 g/dL</li>\n <li>\n Platelet count ≥100,000/mm³</li>\n <li>\n Estimated creatinine clearance of ≥ 60 mL/min.</li>\n <li>\n AST (SGOT), ALT (SGPT), and alkaline phosphatase < 5 ULN</li>\n <li>\n Total bilirubin of <u><</u> 1.5 X ULN</li>\n</ul>\n<ol>\n <li value=\"4\">\n For participants who did NOT receive PLD in Step 1 or Step 2, cardiac ejection fraction of greater than 50% obtained within 14 days prior to Step 3 entry.</li>\n <li>\n For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to Step 3 entry.</li>\n <li>\n Karnofsky performance status ≥ 50 within 28 days prior to Step 3 entry.</li>\n <li>\n All participants must agree not to participate in a conception process (active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).</li>\n</ol>\n<p>\n <u>Inclusion Criteria Step 4</u></p>\n<ol>\n <li>\n Inability to continue on Step 3 due to KS progression OR lack of a CR or PR after receiving fewer than 4 cycles of chemotherapy in Step 3 because of the development of dose-limiting toxicity.</li>\n <li>\n Less than 72 weeks after Step 1 entry.</li>\n <li>\n The following laboratory values obtained within 14 days prior to Step 4 entry:� � � � � �</li>\n</ol>\n<ul>\n <li>\n ANC ≥1,000 cells/mm³.</li>\n <li>\n Hemoglobin ≥9.0 g/dL.</li>\n <li>\n Platelet count ≥100,000/mm³.</li>\n <li>\n Estimated creatinine clearance of ≥ 60 mL/min.</li>\n <li>\n AST (SGOT), ALT (SGPT), and alkaline phosphatase < 5 ULN.</li>\n <li>\n Total bilirubin of <u><</u> 1.5 X ULN.</li>\n</ul>\n<ol>\n <li value=\"4\">\n For patients who did NOT receive PLD in Step 1, Step 2 or Step 3, cardiac ejection fraction of greater than 50% obtained within 14 days prior to Step 4 entry.</li>\n <li>\n For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to Step 4 entry.</li>\n <li>\n Karnofsky performance status ≥ 50 within 28 days prior to Step 4 entry.</li>\n <li>\n All participants must agree not to participate in a conception process (active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).</li>\n</ol>\n
      • principal_exclusion_criteria<p>\n <u>Exclusion Criteria</u><u> Step 1</u></p>\n<ol>\n <li>\n Current chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, for which the participant has not completed at least 14 days of therapy prior to study entry and/or is not clinically stable.�</li>\n <li>\n Serious illness requiring systemic treatment and/or hospitalization within 14 days prior to entry.</li>\n <li>\n Current or history of known pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), emphysema, bronchiectasis, or diffuse or significant local radiographic interstitial infiltrates on chest x-ray (CXR) or computed axial tomography (CAT), that in the opinion of the investigator would exclude bleomycin use.</li>\n <li>\n Oxygen saturation less than 90% and/or exercise desaturation greater than 4% within 14 days prior to study enrollment.�</li>\n <li>\n Grade ≥3 peripheral neuropathy (PN) at entry.</li>\n <li>\n Breastfeeding.</li>\n <li>\n Receipt of ART for more than 28 days immediately prior to entry. ART is allowed within� the 28-day window prior to study entry.</li>\n <li>\n Prior or current systemic or locally administered chemotherapy.</li>\n <li>\n Prior or current radiation therapy.</li>\n <li>\n Prior or current immunotherapy, e.g., interferon alfa.</li>\n <li>\n Corticosteroid use at doses above those given as replacement therapy for adrenal insufficiency within the last 30 days prior to study entry. A tapering course of corticosteroids as acute therapy for <em>Pneumocystis carinii</em> pneumonia (PCP) or other conditions is an exception and is allowed.</li>\n <li>\n � Any immunomodulator, HIV vaccine, live attenuated vaccines, or other investigational therapy or investigational vaccine within 30 days prior to study entry.</li>\n <li>\n � Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.</li>\n <li>\n � Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.</li>\n <li>\n Current or anticipated receipt of any of the prohibited medications.</li>\n <li>\n In the opinion of the investigator, any psychological or social condition, or addictive disorder that would preclude compliance with the protocol.</li>\n <li>\n � NYHA (New York Heart Association) Functional Class II-IV heart failure.�</li>\n</ol>\n<p>\n <u>Exclusion Criteria Step 2</u></p>\n<ol>\n <li>\n Current chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, for which the participant has not completed at least 14 days of therapy prior to Step 2 entry and/or is not clinically stable.�</li>\n <li>\n Severe toxicity to the chemotherapy regimen used in Step 1 requiring discontinuation of study chemotherapy.</li>\n <li>\n Serious illness, other than progressive KS, requiring systemic treatment and/or hospitalization within 14 days prior to Step 2 entry.</li>\n <li>\n For patients who have not received bleomycin in Step 1:</li>\n</ol>\n<ul>\n <li>\n Development of pulmonary fibrosis, COPD, emphysema, bronchiectasis, and diffuse or significant local radiographic interstitial infiltrates on CXR or CT scan that in the opinion of the site investigator would exclude bleomycin use.</li>\n <li>\n Patients with an abnormal CXR or CT scan (which may indicate pulmonary KS) should undergo screening evaluations to rule out an infectious cause, per standard of care. If available, other diagnostic procedures such as bronchoscopy should be considered to confirm the presence or absence of pulmonary KS and/or an infectious agent. These procedures should be completed outside the study. These participants should be excluded if, in the opinion of the investigator, use of bleomycin in Step 2 would be detrimental.</li>\n <li>\n Oxygen saturation less than 90% or exercise desaturation greater than 4% within the last 30 days prior to Step 2 entry.�</li>\n</ul>\n<ol>\n <li value=\"5\">\n For patients who received vincristine in Step 1, Grade ≥3 PN at Step 2 entry.</li>\n <li>\n For participants who received PLD in Step 1, NYHA Functional Class II-IV heart failure.</li>\n <li>\n Breastfeeding.</li>\n <li>\n Other concurrent chemotherapy, immunotherapy, or radiotherapy.</li>\n <li>\n Systemic corticosteroid use at doses above those given as replacement therapy for adrenal insufficiency within 30 days of Step 2 entry.</li>\n</ol>\n<p>\n <u>Exclusion Criteria Step 3</u></p>\n<ol>\n <li>\n Current chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, for which the participant has not completed at least 14 days of therapy prior to Step 3 entry and/or is not clinically stable.�</li>\n <li>\n Serious illness, other than progressive KS, requiring systemic treatment and/or hospitalization within 14 days prior to Step 3 entry.</li>\n <li>\n For patients who did NOT receive bleomycin in Step 1 or Step 2:</li>\n</ol>\n<ul>\n <li>\n Development of pulmonary fibrosis, COPD, emphysema, bronchiectasis, and diffuse or significant local radiographic interstitial infiltrates on CXR or CT scan that in the opinion of the site investigator would exclude bleomycin use.</li>\n <li>\n Patients with an abnormal CXR or CT scan (which may indicate pulmonary KS) should undergo screening evaluations to rule out an infectious cause, per standard of care. If available, other diagnostic procedures such as bronchoscopy should be considered to confirm the presence or absence of pulmonary KS and/or an infectious agent. These procedures should be completed outside the study. These participants should be excluded if, in the opinion of the investigator, use of bleomycin in Step 3 would be detrimental.</li>\n <li>\n Oxygen saturation less than 90% or exercise desaturation greater than 4% within the last 30 days prior to Step 3 entry.�</li>\n</ul>\n<ol>\n <li value=\"4\">\n For participants who did NOT receive vincristine in Step 1 or Step 2, Grade ≥3 PN at Step 3 entry.</li>\n <li>\n For participants who did NOT receive PLD in Step 1 or Step 2, NYHA Functional Class II-IV heart failure.�</li>\n <li>\n � Breastfeeding.</li>\n <li>\n Other concurrent chemotherapy, immunotherapy, or radiotherapy.</li>\n <li>\n Systemic corticosteroid use at doses above those given as replacement therapy for adrenal insufficiency within 30 days of Step 3 entry.</li>\n</ol>\n<p>\n <u>Exclusion Criteria Step 4</u></p>\n<ol>\n <li>\n Current chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, for which the participant has not completed at least 14 days of therapy prior to Step 4 entry and/or is not clinically stable.�</li>\n <li>\n Serious illness, other than progressive KS, requiring systemic treatment and/or hospitalization within 14 days prior to Step 4 entry.</li>\n <li>\n For patients who did NOT receive bleomycin in Step 1, Step 2, or Step 3:</li>\n</ol>\n<ul>\n <li>\n Development of pulmonary fibrosis, COPD, emphysema, bronchiectasis, and diffuse or significant local radiographic interstitial infiltrates on CXR or CT scan that in the opinion of the site investigator would exclude bleomycin use.</li>\n <li>\n Patients with an abnormal CXR or CT scan (which may indicate pulmonary KS) should undergo screening evaluations to rule out an infectious cause, per standard of care. If available, other diagnostic procedures such as bronchoscopy should be considered to confirm the presence or absence of pulmonary KS and/or an infectious agent. These procedures should be completed outside the study. These participants should be excluded if, in the opinion of the investigator, use of bleomycin in Step 4 would be detrimental.</li>\n <li>\n Oxygen saturation less than 90% or exercise desaturation greater than 4% within the last 30 days prior to Step 4 entry.�</li>\n</ul>\n<ol>\n <li value=\"4\">\n For participants who did NOT receive vincristine in Step 1, Step 2, or Step 3: Grade ≥3 PN at Step 4 entry.</li>\n <li>\n For participants who did NOT receive PLD in Step 1, Step 2, or Step 3 NYHA Functional Class II-IV heart failure.�</li>\n <li>\n Breastfeeding.</li>\n <li>\n Other concurrent chemotherapy, immunotherapy, or radiotherapy.</li>\n <li>\n Systemic corticosteroid use at doses above those given as replacement therapy for adrenal insufficiency within 30 days of Step 4 entry.</li>\n</ol>\n
      • primary_end_points<p>\n Lack of clinical efficacy” defined as KS progression, death by week 48, entry into an additional step prior to week 48, or loss to follow-up.</p>\n
      • scope_diagnosis1
      • scope_prophylaxis1
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Abraham M. Siika MBChB, MMed, MS- Site Leader/ Principal Investigator</p>\n<p>\n Naftali Busakhala- MBChB, MMed- Investigator</p>\n<p>\n Charles Kwobah, MBChB- Medical Officer</p>\n<p>\n Mercy Karoney� MBChB- Medical Officer</p>\n<p>\n Simon Wachira Njuguna, B Pharm, MPSK - Pharmacist of Record</p>\n<p>\n Kipruto Kirwa, BSc, MPH, PhD- Quality Manager</p>\n<p>\n Priscilla Cheruiyot, BScN, MPH- Site Coordinator</p>\n<p>\n Martha Mokaya, BSc, MBA- Data Manager</p>\n<p>\n Wilson Lokitala Ekiru, BSc IT- Assistant Data Manager</p>\n<p>\n Agnes M. Nzioka, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Betty Meli, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Michael Tanui, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Julie Choge -� Recruitment Officer</p>\n<p>\n Dorothy Mwimali -� Recruitment Officer</p>\n<p>\n Cecilia Chebet, Dip Counselling - Recruitment Officer</p>\n<p>\n Beatrice Jakait, B Pharm- Back-up Pharmacist</p>\n<p>\n Zipporah Sambili, Dip Pharm- Back-up Pharmaceutical Technologist</p>\n<p>\n Chris Sande, KHRCN- Study Nurse</p>\n<p>\n �</p>\n
      • other_details_explanation<p>\n Eldoret Kenya is one of the international ACTG sites. When protocols are developed by the ACTG, sites express interests considering the patient population and relevance of the study. Our site expressed interest and one of the investigators Dr. Busakhala was involved in development of this protocol.</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n Moi Teaching and Referral Hospital/Moi University Institutional Research and Ethics Committee (IREC). Approved on 23 August 2011. Continuing review granted on August 22, 2012</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration All participants will be followed for 5 years after randomization or assignment to the last step they enter. Therefore, participants could be followed for 5 to 7 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_comparatorbleomycin and vincristine
      • 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_states8
      • number_of_sites2
      • multi_country_listBrazil, Peru, Malawi, Zimbabwe, Uganda, Kenya, South Africa, Botswana.
      • data_monitoring_committeeYes
      • total_enrolment_per_site100, Eldoret
      • total_participants_worldwide706
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameN/A
      • investigator1_middle_name
      • investigator1_family_nameN/A
      • investigator1_qualificationN/A
      • investigator1_professional_addressN/A
      • investigator1_telephoneN/A
      • investigator1_emailabrahamsiika@gmail.com
      • organisations_transferred_No
      • number_participants100 at Eldoret Site. Information on Kericho not immediately available to us
      • notification
      • approval_date07-08-2012
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted11-08-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2020-08-11 09:27:28
      • created2013-01-22 11:46:37
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id7
        • application_id4
        • given_nameAbraham
        • middle_nameMosigisi
        • family_nameSiika
        • qualificationMBChB, MMed, MSc
        • professional_addressP O Box, 4606-30100, Eldoret
        • telephone524721280785
        • emailambrahamsiika\"gmail.com
        • created2013-01-25 14:55:21
        • modified2020-08-11 09:27:28
    • SiteDetail(array)
      • 0(array)
        • id15
        • application_id4
        • county_id27
        • site_nameMoi University Clinical Research Centre
        • physical_addressAMPATH at MTRH, Nandi Road, Eldoret
        • contact_details+254 53 2060850
        • contact_personAllan Sudoi
        • site_capacity(null)
        • misc(null)
        • created2013-01-25 14:55:21
        • modified2020-08-11 09:27:28
        • County(array)
          • id27
          • county_nameUasin Gishu
          • created2012-06-15 10:25:15
          • modified2012-06-15 10:25:15
      • 1(array)
        • id16
        • application_id4
        • county_id35
        • site_nameKEMRI Walter Reed Project
        • physical_addressKericho District Hospital Grounds
        • contact_details0713603225
        • contact_personHellen Ngeno
        • site_capacity(null)
        • misc(null)
        • created2013-01-25 15:21:58
        • modified2020-08-11 09:27:28
        • County(array)
          • id35
          • county_nameKericho
          • created2012-06-15 10:26:16
          • modified2012-06-15 10:26:16
    • Sponsor(array)
      • 0(array)
        • id3
        • application_id4
        • sponsorNational Institutes of Health
        • sponsor_typeOthers
        • contact_person
        • address9000 Rockville Pike Bethesda, Maryland 20892
        • telephone_number301-496-4000
        • fax_number
        • cell_number301-496-4000
        • email_addressNIHinfo@od.nih.gov
        • created2013-01-25 14:55:21
        • modified2020-08-11 09:27:28
  • 3(array)
    • Application(array)
      • id181
      • user_id21
      • trial_status_id5
      • abstract_of_study<p>\n <u>DESIGN</u>                      A phase III, open-label, prospective, randomized study stratified by CD4+ lymphocyte cell count and antiretroviral therapy (ART) history.  This study will compare ART alone or with delayed chemotherapy to ART with immediate adjunctive chemotherapy for initial treatment of limited stage AIDS-related Kaposi’s sarcoma (AIDS-KS) in chemotherapy and radiation treatment naïve HIV-1 infected participants who are currently not receiving ART.</p>\n<p>\n  </p>\n<p>\n <u>DURATION</u>                Participants never recieving etoposide (VePesid^®, ET): 96 weeks</p>\n<p>\n Participants receiving ET at any point: 240 weeks (96 weeks + 144 weeks of follow-up for safety)</p>\n<p style=\"margin-left: 120px;\">\n  </p>\n<p>\n <u>SAMPLE SIZE </u>           468 participants (234 in each Arm of Step 1)</p>\n<p style=\"margin-left: 120px;\">\n  </p>\n<p style=\"margin-left: 120px;\">\n <u>POPULATION</u>            Males and females ³ 18 years of age with the following characteristics:</p>\n<ul>\n <li>\n <p>\n Documentation of HIV-1 infection</p>\n </li>\n <li>\n <p>\n Biopsy diagnostic of KS</p>\n </li>\n <li>\n <p>\n Current limited stage KS (T0 and some T1 stage KS; see section 4.1.3 for details)</p>\n </li>\n <li>\n <p>\n Systemic chemotherapy for KS and radiation treatment naïve</p>\n </li>\n <li>\n <p>\n Currently not receiving ART</p>\n </li>\n</ul>\n<p style=\"margin-left: 120px;\">\n  </p>\n<p>\n <u>STRATIFICATION</u>     Randomization will be stratified by screening peripheral blood CD4+ lymphocyte cell count (< 200 or  ³ 200 cells/mm³) and ART history (naïve or experienced). </p>\n<p style=\"margin-left: 40px;\">\n NOTE: Naïve is defined as no prior history of ART or <7 days cumulative therapy with any ART (except NVP or ZDV taken during pregnancy) at any time prior to study entry.  Experienced is defined as having had ART for ³ 7 cumulative days in the past (but must not have received ART within 6 months prior to study entry).</p>\n<p>\n  </p>\n<p>\n <u>REGIMEN</u>                  At study entry participants will be randomized 1:1 to one of the following arms in Step 1:</p>\n<p>\n <u>Step 1:</u>                         <u>Arm 1A:</u></p>\n<p style=\"margin-left: 120px;\">\n Co-formulated efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)</p>\n<p style=\"margin-left: 120px;\">\n                        </p>\n<p style=\"margin-left: 40px;\">\n <u>Arm 1B</u>:          </p>\n<p style=\"margin-left: 40px;\">\n Co-formulated EFV/FTC/TDF and ET</p>\n<p>\n  </p>\n<p style=\"margin-left: 40px;\">\n <u>Step 2:</u>                         <u>Arm 2A:</u></p>\n<p style=\"margin-left: 40px;\">\n At the discretion of the site investigator, after confirmation of disease progression by the IERC (Independent Endpoint Review Committee), participants who experience KS progression in Arm 1A will receive ET in addition to co-formulated EFV/FTC/TDF.</p>\n<p>\n  </p>\n<p style=\"margin-left: 40px;\">\n <u>Step 3:</u>                         Participants who received ET will remain on the study for 240 weeks (96 weeks + 144 weeks of follow-up for safety).</p>\n
      • study_title<p>\n A5264/AMC 067 "A Randomized Evaluation of Antiretroviral Therapy Alone or with Delayed Chemotherapy versus Antiretroviral Therapy with Immediate Adjunctive Chemotherapy for Treatment of Li1mited Stage AIDS-KS in Resource-Limited Settings (REACT-KS)"</p>\n
      • laymans_summary<p>\n AIDS-related Kaposi’s sarcoma (AIDS-KS) occurs in persons who are coinfected with HIV-1 and KSHV.  AIDS-KS remains a significant cause of morbidity and mortality in HIV-1 infected persons in areas of the world where access to ART and chemotherapy is limited. </p>\n<p>\n  </p>\n<p>\n Because AIDS-KS is a malignancy that results from HIV-1-related immunosuppression, optimal management of this disease may require immune reconstitution by treatment of HIV-1 infection with ART and treatment of KS disease.  KS disease stage is an important factor associated with prognosis of AIDS-KS.  Stage T0 disease (KS limited to the skin and lymph nodes with minimal oral disease) is associated with better clinical outcome compared to stage T1 disease (KS with tumor-associated edema or ulceration, extensive oral disease, and/or visceral disease). Advanced AIDS-KS is usually treated with combined ART and chemotherapy, but limited AIDS-KS often responds to ART alone.</p>\n<p>\n  </p>\n<p>\n A5264/AMC 067 is a phase III, open-label, prospective, randomized study stratified by CD4+ lymphocyte cell count and antiretroviral therapy (ART) history.  The study will compare the KS tumor outcomes of ART alone or with delayed Etoposide (ET) to ART with immediate ET, for initial treatment of limited stage AIDS-KS in chemotherapy and radiation treatment naïve HIV-1 infected participants who are currently not receiving ART</p>\n
      • short_titleRandomized Comparison of ART Alone versus ART with Immediate Chemotherapy
      • protocol_noECCT/10/11/06
      • version_no1.0
      • date_of_protocol04-08-2010
      • study_drugCo-formulated efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) and Etoposide (ET)
      • disease_conditionAdvanced AIDS-KS (Kaposi’s sarcoma )
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameAtripla, vepesid
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressaksudoi@hotmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist0
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantAllan K Sudoi
      • declaration_date123-07-2013
      • declaration_principal_investigatorAbraham M Siika, MBChB, MMed, Msc - Site Principal Investigator
      • declaration_date223-07-2013
      • placebo_presentNo
      • study_objectives<h2>\n Primary Objective</h2>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<p style=\"margin-left:36.0pt;\">\n To compare, in participants with limited stage KS, the week 48 KS tumor outcomes of low-dose concurrent administration of oral ET with ART to ART alone or ART with delayed ET with outcome at week 48 compared to entry categorized into one of three categories:</p>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<p style=\"margin-left:72.0pt;\">\n E1 (Failure) = KS progression at week 48 compared to baseline, initiation of a new chemotherapy agent other than ET by week 48, or no follow-up at  week 48 (including death and lost to follow-up by week 48 and missed visit at week 48);</p>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<p style=\"margin-left:72.0pt;\">\n E2 (Stable) = In follow-up at week 48, with neither KS progression nor response at week 48 and without initiation of a new chemotherapy other than ET by week 48,</p>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<p style=\"margin-left:72.0pt;\">\n E3 (Response) = In follow-up at week 48, with KS partial (PR) or complete response (CR) at week 48 compared to baseline and without initiation of a new chemotherapy agent other than ET by week 48.</p>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<h2>\n 1.3       Secondary Objectives</h2>\n<p style=\"margin-left:18.0pt;\">\n  </p>\n<p style=\"margin-left:72.0pt;\">\n 1.3.1    To evaluate the effects of randomized study treatment on the rate of KS clinical response. This will include comparison of the time to initial KS progression, time to initial KS response (PR and CR combined and separately), and KS progression and response rates at weeks 48 and 96.</p>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<ol>\n <li value=\"NaN\">\n To evaluate the safety and tolerability of randomized study treatment.  This will include comparison of adverse events, dose-limiting toxicities, treatment/dose changes related to management of toxicities, and KS-IRIS events.</li>\n</ol>\n<p>\n  </p>\n<ol>\n <li value=\"NaN\">\n To investigate the effects of randomized study treatment on quality of life.</li>\n</ol>\n<p>\n  </p>\n<ol>\n <li value=\"NaN\">\n To compare the effects of randomized study treatment on plasma HIV-1 RNA levels and peripheral blood CD4+ T-cell counts including both magnitudes and rates of change.</li>\n</ol>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<ol>\n <li value=\"NaN\">\n To evaluate the effects of concomitant ET on adherence to ART.</li>\n</ol>\n<p>\n  </p>\n<ol>\n <li value=\"NaN\">\n To investigate the response to delayed ET after KS progression on ART alone.</li>\n</ol>\n<p style=\"margin-left:72.0pt;\">\n  </p>\n<ol>\n <li value=\"NaN\">\n To determine baseline KS-associated herpesvirus (KSHV) viral load in saliva, plasma and peripheral blood mononuclear cells (PBMCs), compare the effects of randomized study treatment on KSHV viral load changes, and evaluate the relationship of KSHV viral load changes to KS clinical response.</li>\n</ol>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<ol>\n <li value=\"NaN\">\n To evaluate the relationship between response of KS to randomized treatment, development of KS-IRIS, and the following markers:</li>\n</ol>\n<p>\n  </p>\n<p style=\"margin-left:72.0pt;\">\n 1.3.8.1 Baseline immunohistochemical markers of viral and cellular gene expression in KS tumors</p>\n<p>\n  </p>\n<p style=\"margin-left:72.0pt;\">\n 1.3.8.2 RNA levels for genes in tumor biopsies at baseline and during therapy</p>\n<p>\n  </p>\n<p style=\"margin-left:72.0pt;\">\n 1.3.8.3 Cellular and humoral markers of immune function and immune activation.</p>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<ol>\n <li value=\"NaN\">\n To investigate the relationship between salivary, plasma, and PBMC KSHV viral load.</li>\n</ol>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<ol>\n <li value=\"NaN\">\n To encourage donation of excess biopsy materials to the AIDS and Cancer Specimen Resource (ACSR).</li>\n</ol>\n<p style=\"margin-left:36.0pt;\">\n  </p>\n<ol>\n <li value=\"NaN\">\n To assess the risk of secondary leukemia and myelodysplasia after etoposide use.</li>\n</ol>\n
      • principal_inclusion_criteria<table align=\"left\" cellpadding=\"0\" cellspacing=\"0\" hspace=\"0\" vspace=\"0\">\n <tbody>\n <tr>\n <td align=\"left\">\n <p>\n <u>Step 1 inclusion criteria</u></p>\n </td>\n </tr>\n </tbody>\n</table>\n<div style=\"clear:both;\">\n  </div>\n<ol>\n <li>\n HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.</li>\n <li>\n Biopsy diagnostic of KS at any time prior to study entry.</li>\n <li>\n Current limited stage KS using the ACTG criteria.</li>\n <li>\n A minimum of 5 cutaneous marker lesions</li>\n <li>\n The following laboratory values obtained within 14 days prior to study entry:</li>\n</ol>\n<ul>\n <li>\n Absolute neutrophil count (ANC) ³ 1,000 cells/mm³.</li>\n <li>\n Hemoglobin ³ 9.0 g/dL.</li>\n <li>\n Platelet count ³ 100,000/mm³.</li>\n <li>\n Calculated creatinine clearance of ≥ 60 mL/min</li>\n <li>\n <strong><em>AST (SGOT), ALT (SGPT), and alkaline phosphatase < 5 </em></strong><strong><em>´</em></strong><strong><em> ULN. </em></strong></li>\n <li>\n <strong><em>Total bilirubin of <u><</u> 1.5 X ULN.</em></strong></li>\n</ul>\n<ol>\n <li value=\"6\">\n Female participants of reproductive potential must have a negative serum or urine pregnancy test performed within 7 days prior to study entry.</li>\n <li>\n All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).</li>\n <li>\n Female participants who are participating in sexual activity that could lead to pregnancy must agree to use a combination of TWO of the following methods:</li>\n</ol>\n<ul>\n <li>\n Condoms (male or female) with or without a spermicidal agent.</li>\n <li>\n Diaphragm or cervical cap with spermicide</li>\n <li>\n IUD</li>\n <li>\n Hormonal-based contraception. This must be used while receiving ET, EFV, RIF, or other rifamycin, and for 6 weeks after stopping these drugs. </li>\n</ul>\n<ol>\n <li value=\"9\">\n Ability to swallow oral medications.</li>\n <li>\n  Men and women, age ³ 18 years<em>.</em></li>\n <li>\n  Karnofsky performance score ³ 60 within 30 days prior to entry.</li>\n <li>\n  Ability and willingness of participant or legal guardian/representative to provide informed consent.</li>\n <li>\n Peripheral blood CD4+ lymphocyte cell count obtained within 30 days prior to study entry at a DAIDS-approved laboratory.</li>\n <li>\n For treatment-experienced patients, the availability of an ART regimen that includes at least two ART drugs that in the opinion of the site investigator are expected to have activity based on historical genotypic testing (if available) and  treatment history.</li>\n <li>\n  For participants who are to receive ART other than EFV/TDF/FTC, the availability of those ART components.</li>\n</ol>\n<p>\n <u>Step 2: Inclusion Criteria</u></p>\n<ol>\n <li>\n KS progression as defined in Section 7.1 or KS progression after a complete or partial response as defined in sections 7.1.1-7.1.2, while on Step 1 Arm 1A, between weeks 8 and 80.</li>\n <li>\n Need for ET for treatment of KS progression, in the opinion of the site investigator, after confirmation of KS progression by the IERC.</li>\n <li>\n Willingness to receive ET for treatment of KS progression.</li>\n <li>\n Female participants of reproductive potential must have a negative serum or urine pregnancy test performed within 7 days prior to initiating ET.</li>\n <li>\n Karnofsky Performance Score ≥ 50.</li>\n <li>\n The following laboratory values obtained within 14 days prior to Step 2 entry:</li>\n</ol>\n<ul>\n <li>\n ANC ³ 1,000 cells/mm³.</li>\n <li>\n Hemoglobin ³ 9.0 g/dL.</li>\n <li>\n Platelet count ³ 100,000/mm³.</li>\n <li>\n Estimated creatinine clearance of ≥ 60 mL/min.</li>\n <li>\n <strong><em>AST (SGOT), ALT (SGPT), and alkaline phosphatase < 5 </em></strong><strong><em>´</em></strong><strong><em> ULN. </em></strong></li>\n <li>\n <strong><em>Total bilirubin of <u><</u> 1.5 X ULN.</em></strong></li>\n</ul>\n<ol>\n <li value=\"7\">\n Ability to swallow oral medications.</li>\n <li>\n All participants must agree not to participate in a conception process (e.g., active <strong><em>attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization).</em></strong></li>\n <li>\n Female participants who are participating in sexual activity that could lead to pregnancy must agree to use a combination of TWO of the following methods:</li>\n</ol>\n<ul>\n <li>\n Condoms (male or female) with or without a spermicidal agent.</li>\n <li>\n Diaphragm or cervical cap with spermicide</li>\n <li>\n IUD</li>\n <li>\n Hormonal-based contraception. This must be used while receiving ET, EFV, RIF, or other rifamycin, and for 6 weeks after stopping these drugs. </li>\n</ul>\n<p style=\"margin-left:72.0pt;\">\n For Etoposide, confirmation of lack of reproductive potential is required for all participants. Written documentation or oral communication from a clinician or clinician’s staff documented in source documents of one of the following:</p>\n<ul>\n <li>\n Physician report/letter </li>\n <li>\n Operative report or other source documentation in the patient record (a laboratory report of azoospermia is required to document successful vasectomy)</li>\n <li>\n Discharge summary</li>\n <li>\n Laboratory report of azoospermia</li>\n <li>\n FSH measurement elevated into the menopausal range as established by the reporting laboratory.</li>\n</ul>\n<p>\n <u>Step 3: Inclusion Criteria</u></p>\n<ol>\n <li>\n Received at least one dose of ET (Arm 1B or Arm 2A).</li>\n</ol>\n
      • principal_exclusion_criteria<table align=\"left\" cellpadding=\"0\" cellspacing=\"0\" hspace=\"0\" vspace=\"0\">\n <tbody>\n <tr>\n <td align=\"left\">\n <p>\n <u>Step 1 Exclusion criteria</u></p>\n </td>\n </tr>\n </tbody>\n</table>\n<div style=\"clear:both;\">\n  </div>\n<ol>\n <li>\n Any manifestation of KS which, in the opinion of the site investigator, requires immediate chemotherapy.        </li>\n <li>\n Receipt of ART within 6 months prior to study entry.</li>\n <li>\n Biopsy proven KS during previous ART. </li>\n <li>\n Breastfeeding.</li>\n <li>\n Allergy/sensitivity to any study drug or its formulations.</li>\n <li>\n Any prior systemic anti-neoplastic treatment for KS (including chemotherapy, biological therapy, immunotherapy or investigational therapy). </li>\n <li>\n Any prior local treatment of cutaneous marker lesions unless there was evidence of a clear-cut progression of the lesion.</li>\n <li>\n Receipt of any investigational therapy within 30 days prior to study entry.</li>\n <li>\n Current or anticipated receipt of any of the prohibited medications .</li>\n <li>\n In the opinion of the site investigator, any psychological or social condition, or addictive disorder that would preclude compliance with the protocol.</li>\n <li>\n Current chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, for which the participant has not completed at least 14 days of therapy prior to study entry and/or is not clinically stable. </li>\n</ol>\n<p>\n <u>Step 2: Exclusion Criteria</u></p>\n<p style=\"margin-left:36.0pt;\">\n 1. Current chronic, acute, or recurrent infections that are serious, in the opinion of the site investigator, for which the participant has not completed at least 14 days of therapy prior to initiating ET and/or is not clinically stable.</p>\n<p style=\"margin-left:36.0pt;\">\n 2. Current or anticipated receipt of any of the prohibited medications indicated in the PSWP.</p>\n<p style=\"margin-left:36.0pt;\">\n 3. Breastfeeding.</p>\n<p>\n <u>Step 3: Exclusion Criteria</u></p>\n<ol>\n <li>\n There are no exclusion criteria for Step 3.</li>\n</ol>\n
      • primary_end_points<p>\n A composite endpoint incorporating KS tumor response, KS progression, loss to follow-up, and initiation of new chemotherapy agent other than ET, as an ordinal, categorical outcome</p>\n
      • scope_diagnosis1
      • scope_prophylaxis1
      • scope_therapy1
      • scope_safety1
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Abraham M. Siika MBChB, MMed, MS- Site Leader/ Principal Investigator</p>\n<p>\n Naftali Busakhala- MBChB, MMed- Investigator</p>\n<p>\n Evangeline Wawira Njiru- MBChB,MMed- Investigator</p>\n<p>\n Charles Kwobah, MBChB- Medical Officer</p>\n<p>\n Mercy Karoney  MBChB- Medical Officer</p>\n<p>\n Simon Wachira Njuguna, B Pharm, MPSK - Pharmacist of Record</p>\n<p>\n Kipruto Kirwa, BSc, MPH, PhD- Quality Manager</p>\n<p>\n Priscilla Cheruiyot, BScN, MPH- Site Coordinator</p>\n<p>\n Martha Mokaya, BSc, MBA- Data Manager</p>\n<p>\n Wilson Lokitala Ekiru, BSc IT- Assistant Data Manager</p>\n<p>\n Agnes M. Nzioka, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Betty Meli, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Michael Tanui, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Julie Choge -  Recruitment Officer</p>\n<p>\n Dorothy Mwimali -  Recruitment Officer</p>\n<p>\n Cecilia Chebet, Dip Counselling - Recruitment Officer</p>\n<p>\n Beatrice Jakait, B Pharm- Back-up Pharmacist</p>\n<p>\n Zipporah Sambili, Dip Pharm- Back-up Pharmaceutical Technologist</p>\n<p>\n Chris Sande, KHRCN- Study Nurse</p>\n
      • other_details_explanation<p>\n Eldoret Kenya is one of the international ACTG sites. When protocols are developed by the ACTG, sites express interests considering the patient population and relevance of the study. Our site expressed interest and one of the investigators Dr. Busakhala was involved in development of this protocol.</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n Moi Teaching and Referral Hospital/Moi University Institutional Research and Ethics Committee (IREC).First  Approved on 20 July 2011, continuing Review granted on May 30, 2012 and May 30, 2013.</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_durationParticipants not on etoposide (VePesid®, ET): 96 weeks , Participants receiving ET at any point: 240 weeks (96 weeks + 144 weeks of follow-up for safety)
      • 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_comparatorCo-formulated EFV/FTC/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_states6
      • number_of_sites2
      • multi_country_listKenya, Peru, Brazil, Zimbabwe, South Africa and United States
      • data_monitoring_committeeYes
      • total_enrolment_per_site70 in MU-CRC, Eldoret Site
      • total_participants_worldwide468
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameN/A
      • investigator1_middle_name
      • investigator1_family_nameN/A
      • investigator1_qualificationN/A
      • investigator1_professional_addressN/A
      • investigator1_telephoneN/A
      • investigator1_emailamsiika@africaonline.co.ke
      • organisations_transferred_No
      • number_participantsUnknown
      • notification
      • approval_date04-08-2010
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted06-08-2020
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2020-08-06 10:39:49
      • created2013-07-23 12:04:56
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id117
        • application_id181
        • given_nameAbraham
        • middle_nameMosigisi
        • family_nameSiika
        • qualificationMBChB, MMed, MSc
        • professional_addressP O Box, 4606-30100, Eldoret
        • telephone0721280785
        • emailamsiika@africaonline.co.ke
        • created2013-07-23 12:17:25
        • modified2020-08-06 10:39:49
    • SiteDetail(array)
      • 0(array)
        • id146
        • application_id181
        • county_id35
        • site_nameWalter Reed Project Kericho
        • physical_addressKericho District Hospital Grounds
        • contact_details0713603255
        • contact_personHellen Ngeno
        • site_capacity(null)
        • misc(null)
        • created2013-07-23 12:40:24
        • modified2020-08-06 10:39:49
        • County(array)
          • id35
          • county_nameKericho
          • created2012-06-15 10:26:16
          • modified2012-06-15 10:26:16
      • 1(array)
        • id147
        • application_id181
        • county_id27
        • site_nameMoi University Clinical Research Centre
        • physical_addressAMPATH at MTRH, Nandi Road
        • contact_detailsP O Box 4606 Eldoret
        • contact_personAllan Sudoi
        • site_capacity(null)
        • misc(null)
        • created2013-07-23 13:06:15
        • modified2020-08-06 10:39:49
        • County(array)
          • id27
          • county_nameUasin Gishu
          • created2012-06-15 10:25:15
          • modified2012-06-15 10:25:15
    • Sponsor(array)
      • 0(array)
        • id93
        • application_id181
        • sponsorThe National Institute of Allergy and Infectious Diseases (NIAID),National Cancer Institute (NCI) and The National Institute of Dental and Craniofacial Research (NIDCR)
        • sponsor_typeOthers
        • contact_person
        • address6610 Rockledge Drive, MSC 6612 Bethesda, MD 20892-6612 (Zip Code for Courier: 20817)
        • telephone_number301-496-5717
        • fax_number301-402-3573
        • cell_number301-402-1663
        • email_addressocpostoffice@niaid.nih.gov
        • created2013-07-23 12:17:25
        • modified2020-08-06 10:39:49
  • 4(array)
    • Application(array)
      • id134
      • user_id21
      • trial_status_id5
      • abstract_of_study<p style=\"margin-left: 108pt;\">\n <u>DESIGN</u>                      A5273 is a phase III, dual-arm, open-label, randomized, non-inferiority study for participants who are on a failing non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing first-line regimen. The study will evaluate the difference in virologic failure rate between two treatment arms: lopinavir/ritonavir plus raltegravir (LPV/r + RAL) and LPV/r plus best available nucleos(t)ide reverse transcriptase inhibitors (NRTIs).The NRTIs to be used will be specified by the site prior to randomization.</p>\n<p style=\"margin-left: 108pt;\">\n NOTE: On-study virologic failure is defined as confirmed viral load >400 copies/mL at or after week 24.</p>\n<p>\n  </p>\n<p style=\"margin-left: 160px;\">\n <u>DURATION</u>                Each participant will be followed for 96 weeks after enrollment.</p>\n<p style=\"margin-left: 160px;\">\n <u>SAMPLE SIZE</u>            600 (300 per study arm)</p>\n<p>\n  </p>\n<p style=\"margin-left: 108pt;\">\n <u>POPULATION</u>            Human immunodeficiency virus (HIV)-1 infected adults (age ≥18 years) who have confirmed virologic failure on an NNRTI-containing first-line regimen.</p>\n<p style=\"margin-left: 108pt;\">\n <u>STRATIFICATION</u>     Participants will be stratified by screening HIV-1 RNA (≥100,000 versus <100,000 copies/mL), screening CD4+ cell count (≥100 versus <100 cells/mm³), and selection of ZDV in the NRTI regimen (yes/no). Randomization will be balanced by site.</p>\n<p style=\"margin-left: 108pt;\">\n  </p>\n<p style=\"margin-left: 108pt;\">\n <u>REGIMEN</u>: At entry, all participants will stop the failing NNRTI-based regimen and switch to one of the following arms, randomly assigned in a 1:1 ratio:</p>\n<p style=\"margin-left: 144pt;\">\n Arm A: LPV/r plus RAL</p>\n<p style=\"margin-left: 144pt;\">\n Arm B: LPV/r plus best available NRTIs</p>\n<p style=\"margin-left: 108pt;\">\n Best available NRTI combinations will be selected by the site investigator prior to randomization from a list of combinations approved by the study or in consultation with the A5273 Clinical Management Committee (CMC). The NRTIs provided by the study are emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), abacavir/lamivudine/zidovudine (ABC/3TC/ZDV), abacavir/lamivudine (ABC/3TC), lamivudine/zidovudine (3TC/ZDV), abacavir (ABC), lamivudine (3TC), and zidovudine (ZDV).</p>\n
      • study_title<p>\n A5273: Multicenter Study of Options for SEcond-Line Effective Combination Therapy (SELECT)</p>\n
      • laymans_summary(null)
      • short_titleSELECT (SEcond-Line Effective Combination Therapy)
      • protocol_noECCT/12/04/03
      • version_no1.0
      • date_of_protocol22-11-2010
      • study_drugLPV/r plus RAL
      • disease_conditionSecond line HIV treatment
      • 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_nameISENTRESS and Lopinavir/Ritonavir
      • product_type_medical_device_name
      • comparator(null)
      • comparator_name(null)
      • comparator_registered(null)
      • comparator_countries(null)
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressaksudoi@hotmail.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum0
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd(null)
      • applicant_prev_data(null)
      • applicant_stability_data(null)
      • applicant_analysis_cert(null)
      • applicant_pictorial_sample(null)
      • applicant_gcp_training(null)
      • applicant_dsmb_charter(null)
      • applicant_detailed_budget(null)
      • applicant_indemnity_pi(null)
      • applicant_practice_license(null)
      • applicant_registration_ctr(null)
      • applicant_pan_african(null)
      • applicant_hard_copies(null)
      • applicant_signed_checklist(null)
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantAllan K Sudoi
      • declaration_date122-05-2013
      • declaration_principal_investigatorAbraham M Siika, MBChB, MMed, Msc - Site Principal Investigator
      • declaration_date222-05-2013
      • placebo_presentNo
      • study_objectives(null)
      • principal_inclusion_criteria<p>\n Section 4.1 of the protocol</p>\n<h2>\n 4.1       Inclusion Criteria</h2>\n<p style=\"margin-left:72.0pt;\">\n 4.1.1    HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.</p>\n<p style=\"margin-left:72.0pt;\">\n NOTE: For sites located in countries other than the United States, the term “licensed” refers to a kit that has been certified or licensed by an oversight body within that country and validated internally.</p>\n<p style=\"margin-left:72.0pt;\">\n WHO and CDC (U.S. Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.2    Confirmation of first-line virologic failure</p>\n<p style=\"margin-left:72.0pt;\">\n Failure of the first-line regimen is defined as two consecutive measurements of plasma HIV-1 RNA ≥1,000 copies/mL obtained at least one week apart while on an initial NNRTI-based regimen. The first measurement of plasma HIV-1 RNA ≥1,000 copies/mL must be obtained after at least 24 weeks of a NNRTI-based regimen. The first value can be obtained from medical records up to 90 days prior to study entry regardless of the laboratory that performed the test. The second measurement must be obtained within 45 days prior to study entry and performed in any DAIDS-approved laboratory. For potential study candidates in whom failure of first NNRTI-based regimen is suspected based on clinical and/or immunological criteria only or in the event that there is no measurement available within the 90-day period, site investigators can obtain both HIV-1 RNA measurements as part of A5273 screening procedures (samples must be obtained at least 7 days apart).</p>\n<p style=\"margin-left:72.0pt;\">\n NOTE: If there were within-class drug substitutions in the initial regimen because of intolerance to one or more drugs, the participant is still considered to be on an initial regimen and is eligible for the protocol if he/she meets the other eligibility requirements.   </p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.3    Laboratory values obtained within 45 days prior to study entry</p>\n<ul>\n <li>\n Absolute neutrophil count (ANC) >500/mm³</li>\n <li>\n Hemoglobin >8.5 g/dL</li>\n <li>\n Platelet count >50,000/mm³</li>\n <li>\n AST, serum glutamic oxaloacetic transaminase (SGOT), ALT, serum glutamic pyruvic transaminase (SGPT), and alkaline phosphatase <u><</u>5 x ULN</li>\n <li>\n Total bilirubin <u><</u>2.5 x ULN</li>\n <li>\n Calculated creatinine clearance (CrCl) <u>></u>60 mL/min, as estimated by the Cockroft-Gault equation (see section 6.3.9 for CrCl instructions).</li>\n</ul>\n<p style=\"margin-left:72.0pt;\">\n NOTE: Investigators should refer to section 5.1.1 for additional guidance for those participants who are considering the use of a ZDV-containing regimen.</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.4    Females of reproductive potential (girls who have reached menarche, women who have not been post-menopausal for at least 24 consecutive months, (i.e., who have had menses within the preceding 24 months), or women who have not undergone surgical sterilization, hysterectomy or bilateral salpingectomy or bilateral oophorectomy or tubal ligation) must have a negative serum or urine pregnancy test within 48 hours prior to entry.</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.5    Participants must refrain from participating in a conception process (i.e., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) and, if participating in sexual activity that could lead to pregnancy, the participant/partner must use at least one type of contraceptive.  All female participants must continue to use contraceptives for 12 weeks after stopping study medications.</p>\n<p style=\"margin-left:72.0pt;\">\n Acceptable types of contraceptives:</p>\n<ul>\n <li>\n Condoms (male or female) with or without spermicidal agent</li>\n <li>\n Diaphragm or cervical cap with spermicide</li>\n <li>\n Intrauterine device (IUD)</li>\n <li>\n Birth control drugs given by pills, shots, or placed on or under the skin</li>\n <li>\n NuvaRing</li>\n</ul>\n<p style=\"margin-left:72.0pt;\">\n Participants who are not of reproductive potential (girls who have not reached menarche, women who have been post-menopausal for at least 24 consecutive months, women who have undergone hysterectomy or bilateral salpingectomy or bilateral oophorectomy or tubal ligation, or men who have documented azoospermia) are not required to use contraceptives.  However, use of barrier methods of contraception is strongly encouraged to reduce the risk of HIV transmission during sexual contact.</p>\n<p style=\"margin-left:72.0pt;\">\n Acceptable documentation of sterilization is written or oral documentation communicated by clinician or clinician’s staff of one of the following:</p>\n<ul>\n <li>\n Physician report/letter</li>\n <li>\n Operative report or other source documentation in the participant record</li>\n <li>\n Discharge summary</li>\n <li>\n Laboratory report of azoospermia</li>\n <li>\n Follicle stimulating hormone (FSH) measurement elevated into the</li>\n</ul>\n<p style=\"margin-left:90.0pt;\">\n menopausal range as established by the reporting laboratory</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.6    Karnofsky performance score ³70 within 45 days prior to entry.</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.7    Men and women age <u>></u>18 years.</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.8    Ability and willingness of participant or legal guardian/representative to provide informed consent.</p>\n<p style=\"margin-left:72.0pt;\">\n NOTE: Illiterate participants or participants with cognitive disabilities may be enrolled based on local regulatory policies, with the appropriate provisions for informed consent.</p>\n<p style=\"margin-left:72.0pt;\">\n 4.1.9    No intention to relocate away from current geographical area of residence for the duration of study participation.</p>\n
      • principal_exclusion_criteria<p>\n Section 4.2 of the protocol</p>\n<h2>\n 4.2       Exclusion Criteria</h2>\n<ol>\n <li value=\"NaN\">\n Use of any immunomodulator, HIV vaccine, or other investigational therapy within 45 days prior to study entry, with the exception of a tapering course of corticosteroids as acute therapy for pneumocystis jiroveci pneumonia (PCP) or acute asthma/chronic obstructive pulmonary disease flare and/or prednisone at a daily dose of <u><</u>10 mg (physiologic replacement dose).</li>\n <li value=\"NaN\">\n If the potential participant has had resistance testing, evidence of broad NRTI cross-resistance that, in the opinion of the investigator, would not allow selection of an effective NRTI combination if the participant were randomized to the LPV/r + best available NRTIs arm.</li>\n</ol>\n<p style=\"margin-left:72.0pt;\">\n NOTE: Resistance testing is not required for study participation.</p>\n<ol start=\"3\">\n <li>\n Prior exposure to a PI.</li>\n <li value=\"NaN\">\n Known history of congenital long QT syndrome, hypokalemia, or planned use of other drugs that prolong the QT interval.</li>\n <li value=\"NaN\">\n Pregnancy or breast-feeding.</li>\n <li value=\"NaN\">\n Known history of chronic HBV infection or current HBV infection defined by the presence of hepatitis B surface antigen in serum or plasma.</li>\n <li value=\"NaN\">\n Active tuberculosis (TB) requiring treatment with rifampicin.</li>\n <li value=\"NaN\">\n Previously diagnosed malignancies other than basal cell carcinoma and cutaneous Kaposi sarcoma.</li>\n</ol>\n<p style=\"margin-left:72.0pt;\">\n NOTE: Women with precancerous cervical lesions are not excluded from this protocol. If the lesions progress and the participant becomes too ill to participate, clinicians may choose to terminate the woman’s participation in the study.</p>\n<ol start=\"9\">\n <li>\n Requirement for taking any medications that are prohibited with the study drugs (see section 5.4).</li>\n <li value=\"NaN\">\n Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.</li>\n <li value=\"NaN\">\n Active drug or alcohol use or dependence or other condition that, in the opinion of the site investigator, would interfere with adherence to study requirements.</li>\n <li value=\"NaN\">\n Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.</li>\n</ol>\n
      • primary_end_points<p>\n Section 9.2.1 of protocol</p>\n<p>\n 9.2.1   Primary Endpoint</p>\n<p style=\"margin-left:72.0pt;\">\n The primary endpoint is time to virologic failure. Virologic failure is defined as confirmed viral load >400 copies/mL at or after week 24. </p>\n<p style=\"margin-left:72.0pt;\">\n Notes:</p>\n<ol>\n <li>\n Time to virologic failure will be defined as the time from randomization to the first of two consecutive HIV-1 RNA samples defining virologic failure.</li>\n <li>\n Confirmation will be determined based on any two consecutive evaluations meeting the virologic failure criterion regardless of the time between them.</li>\n <li>\n Participants discontinuing the study (for any reason, including death and end of study) will be handled as follows:\n <ol style=\"list-style-type:lower-alpha;\">\n <li>\n Participants with a final HIV-1 RNA evaluation at week 4 that is >400 copies/mL and <0.5 log₁₀lower than baseline will be considered a virologic failure at week 4.</li>\n <li>\n Participants with a final HIV-1 RNA evaluation at week 12 that is >400 copies/mL and <1 log₁₀ lower than baseline will be considered a virologic failure at week 12.</li>\n <li>\n Participants with an unconfirmed virologic failure (HIV-1 RNA >400 copies/mL) at or after week 24 will be considered as virologic failure as the study visit week of the unconfirmed value.</li>\n <li>\n All remaining participants will have their time to virologic failure censored at the study week of the last measured plasma HIV-1 RNA sample.</li>\n </ol>\n </li>\n</ol>\n
      • scope_diagnosis1
      • scope_prophylaxis1
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Abraham M. Siika MBChB, MMed, MS- Site Leader/ Principal Investigator</p>\n<p>\n Faraj Some- MBChB, MSc- Investigator</p>\n<p>\n Charles Kwobah, MBChB- Medical Officer</p>\n<p>\n Mercy Karoney MBChB- Medical Officer</p>\n<p>\n Simon Wachira Njuguna, B Pharm, MPSK - Pharmacist of Record</p>\n<p>\n Kipruto Kirwa, BSc, MPH, PhD- Quality Manager</p>\n<p>\n Priscilla Cheruiyot, BScN, MPH- Site Coordinator</p>\n<p>\n Martha Mokaya, BSc, MBA- Data Manager</p>\n<p>\n Wilson Lokitala Ekiru, BSc IT- Assistant Data Manager</p>\n<p>\n Agnes M. Nzioka, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Betty Meli, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Michael Tanui, Dip Clin Med- Research Clinical Officer</p>\n<p>\n Julie Choge - Recruitment Officer</p>\n<p>\n Amina Msuo Shali- Recruitment Officer</p>\n<p>\n Dorothy Mwimali - Recruitment Officer</p>\n<p>\n Cecilia Chebet, Dip Counselling - Recruitment Officer</p>\n<p>\n Beatrice Jakait, B Pharm- Back-up Pharmacist</p>\n<p>\n Zipporah Sambili, Dip Pharm- Back-up Pharmaceutical Technologist</p>\n<p>\n Chris Sande, KHRCN- Study Nurse</p>\n
      • other_details_explanation<p style=\"margin-left:36.0pt;\">\n A5273 is intended to provide information that is applicable to the vast majority of RLS where resistance testing is not used routinely for selection of second-line regimens and PIs not needing refrigeration are preferred.</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n Moi Teaching and Referral Hospital/Moi University Institutional Research and Ethics Committee (IREC). Continuing Approval granted on March Approved on March 27,2013for Eldoret site only.</p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_durationEach participant will be followed for 96 weeks after enrollment.
      • 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_comparatorLPV/r plus RAL
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaMoi University Clinical Research Centre
      • single_site_physical_address(null)
      • single_site_contact_person(null)
      • single_site_telephone(null)
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_statesTen (10)
      • number_of_sites
      • multi_country_listKenya, India, Peru, South Africa, Thailand, Malawi, Haiti, Brazil, Tanzania, Zimbabwe
      • data_monitoring_committeeYes
      • total_enrolment_per_site100 at Eldoret Site
      • total_participants_worldwide600
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
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      • subjects_others_specify
      • investigator1_given_nameN/A
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      • investigator1_qualificationN/A
      • investigator1_professional_addressN/A
      • investigator1_telephoneN/A
      • investigator1_emailamsiika@africaonline.co.ke
      • organisations_transferred_No
      • number_participantsUnknown
      • notification
      • approval_date22-11-2010
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted22-05-2013
      • is_child0
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      • initial_date_submitted(null)
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      • final_date(null)
      • modified2018-12-07 10:57:19
      • created2013-05-22 09:33:46
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id83
        • application_id134
        • given_nameAbraham
        • middle_nameMosigisi
        • family_nameSiika
        • qualificationMBChB, MMed, MSc
        • professional_addressP O Box, 4606-30100, Eldoret
        • telephone0721280785
        • emailamsiika@africaonline.co.ke
        • created2013-05-22 09:41:11
        • modified2013-05-22 15:57:16
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      • 0(array)
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        • application_id134
        • county_id27
        • site_name
        • physical_address
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        • site_capacity(null)
        • misc(null)
        • created2013-05-22 09:41:11
        • modified2013-05-22 15:57:16
        • County(array)
          • id27
          • county_nameUasin Gishu
          • created2012-06-15 10:25:15
          • modified2012-06-15 10:25:15
    • Sponsor(array)
      • 0(array)
        • id64
        • application_id134
        • sponsorThe National Institute of Allergy and Infectious Diseases
        • sponsor_type(null)
        • contact_personAnn Collier, MD
        • addressUniversity of Washington Harborview Medical Center, Box 359929 325 9th Avenue Seattle, WA 98104
        • telephone_number(206) 744-3293
        • fax_number(206) 744-3483
        • cell_number(206) 744-3293
        • email_addressacollier@u.washington.edu
        • created2013-05-22 09:41:11
        • modified2013-05-22 15:57:16
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