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      • abstract_of_study<div>\n <p align=\"center\" style=\"margin-left: 196.1pt;\">\n <strong>SCHEMA IMPAACT P1093</strong></p>\n <p>\n  </p>\n <p align=\"center\" style=\"margin-left: 9.1pt;\">\n <strong>P</strong><strong>hase I/II Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in</strong></p>\n <p align=\"center\" style=\"margin-left: 120.2pt;\">\n <strong>H</strong><strong>IV-1 Infected Infants, Children and Adolescents</strong></p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>DE</strong><strong>SIGN:                                </strong>Phase I/II, multi-center, open-label, non-comparative intensive PK and safety study</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>SAMPLE SIZE:                      </strong>Approximately 160 HIV-1 infected infants, children and adolescents to provide a minimum of 120 evaluable* subjects:</p>\n <p style=\"margin-left: 185.05pt;\">\n Stage I – a minimum of 10 subjects, per cohort</p>\n <p style=\"margin-left: 185.05pt;\">\n Stage II – a minimum of 60 evaluable subjects across all cohorts</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n *Evaluable is defined as having been treated exclusively on the dose determined to be optimal for a given age cohort and having either completed 24 (or 48) weeks of exposure to the study drug or having been classified as a safety failure, due to a study drug related adverse event occurring during the first 24 (or 48) weeks of treatment.</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>POPULATION:                      </strong>HIV infected infants, children and adolescents aged ≥ 4 weeks to < 18 years of age.</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>STRATIFICATION:              </strong>All subjects enrolled into the study will be stratified at screening into one of nine age specific cohorts as follows:</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>C</strong><strong>ohort I:         </strong>Adolescents ≥ 12 to <18 years of age</p>\n <p align=\"center\" style=\"margin-left: 219.2pt;\">\n (Film-coated Tablets)</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>C</strong><strong>ohort IIA:    </strong>Children ≥ 6 to <12 years of age</p>\n <p align=\"center\" style=\"margin-left: 219.2pt;\">\n (Film-coated Tablets)</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>C</strong><strong>ohort IIB:     </strong>Children ≥ 6 to <12 years of age</p>\n <p style=\"margin-left: 221.05pt;\">\n (Granules for suspension)</p>\n <p style=\"margin-left: 221.05pt;\">\n Note: Dispersible tablets may also be evaluated in this cohort if requested by regulatory authorities.</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>C</strong><strong>ohorts III:    </strong>Children ≥ 2 to < 6 years of age</p>\n <p style=\"margin-left: 221.05pt;\">\n (Granules for suspension)</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>C</strong><strong>ohort III-DT</strong>: Children ≥ 2 to < 6 years of age</p>\n <p align=\"center\" style=\"margin-left: 219.2pt;\">\n (Dispersible Tablets)</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>C</strong><strong>ohort IV</strong>:      Children ≥ 6 months to < 2 years of age</p>\n <p style=\"margin-left: 221.05pt;\">\n (Granules for suspension)</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>C</strong><strong>ohort IV-DT: </strong>Children ≥ 6 months to < 2 years of age</p>\n <p align=\"center\" style=\"margin-left: 219.2pt;\">\n (Dispersible Tablets)</p>\n</div>\n<p>\n  </p>\n<div>\n <p style=\"margin-left: 149.05pt;\">\n <strong>C</strong><strong>ohort V</strong>:        Infants <u>></u> 4 weeks to < 6 months of age</p>\n <p style=\"margin-left: 221.05pt;\">\n (Granules for suspension)</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>C</strong><strong>ohort V-DT: </strong>Infants <u>></u> 4 weeks to < 6 months</p>\n <p align=\"center\" style=\"margin-left: 219.2pt;\">\n (Dispersible Tablets)</p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>REG</strong><strong>IMEN:                            </strong>Three different dolutegravir (DTG) formulations will be evaluated as follows: film-coated tablets; a granule formulation for suspension; and dispersible tablets. The final dose for each formulation and each age cohort will be selected based on real-time PK evaluations and safety to achieve exposure similar to that observed in adults treated with 50 mg QD.</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n See Sections 5.0-5.4 for details on DTG drug regimens, formulations, drug supply and handling.</p>\n <p>\n  </p>\n <p style=\"margin-left: 5pt;\">\n <strong>TREAT</strong><strong>MENT DURATION:  </strong>Stages I and II: 48 Weeks</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n Long Term Safety Follow-up: All subjects who successfully complete 48 weeks of DTG treatment will continue to receive DTG for a minimum of three years as part of long term safety follow-up. (See Section 6.3 and Appendix IE for details).</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n <strong>H</strong><strong>Y</strong><strong>POTHESIS:                      </strong>DTG will be generally well tolerated and demonstrate an acceptable safety profile, adequate PK and antiviral activity when used concurrently with an optimized background therapy (OBT) in HIV-1 infected infants, children and adolescents.</p>\n <p>\n  </p>\n <p style=\"margin-left: 5pt;\">\n <strong>O</strong><strong>B</strong><strong>JECTIVES:</strong></p>\n <p>\n  </p>\n <p style=\"margin-left: 5pt;\">\n <u>PRIMARY OBJECTIVES</u></p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 1.   To select a dose for each formulation of DTG for chronic dosing in infants, children and adolescents that achieves similar exposure to the DTG 50 mg once daily dose in adults.</p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 2.   To determine the safety and tolerability of DTG in HIV-1 infected infants, children and adolescents at 24 and 48 weeks.</p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 3.   To evaluate the steady-state pharmacokinetics of DTG in combination with other antiretrovirals (OBT) in treatment-experienced and/or treatment-naïve HIV-1 infected infants, children and adolescents and to determine the dose of DTG that achieves a targeted AUC24 (primary PK endpoint) and C24h (secondary PK endpoint) in this population.</p>\n <p>\n  </p>\n <p style=\"margin-left: 5pt;\">\n <u>SECONDARY OBJECTIVES</u></p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 1.   To evaluate the antiviral activity of DTG in combination with an OBT by measuring virologic response in infants, children and adolescents at 24 and 48 weeks.</p>\n <p>\n  </p>\n <p style=\"margin-left: 23pt;\">\n 2.   To evaluate the effect on immunologic response from baseline to 24 and 48 weeks.</p>\n</div>\n<p>\n  </p>\n<p style=\"margin-left: 23pt;\">\n 3.   To assess changes in HIV-1 genotype and phenotype to DTG and other components of the OBT</p>\n<p style=\"margin-left: 41pt;\">\n in subjects experiencing virologic failure.</p>\n<p>\n  </p>\n<p style=\"margin-left: 23pt;\">\n 4.   To determine DTG exposure, its variability and clinical covariates that impact DTG disposition</p>\n<p style=\"margin-left: 41pt;\">\n (e.g. age, weight) using intensive and sparse sampling and population pharmacokinetic analysis.</p>\n<p>\n  </p>\n<p style=\"margin-left: 41pt;\">\n 5.   To determine the extended long term (≥48 weeks) safety and tolerability of DTG in HIV-1 infected infants, children and adolescents.</p>\n<p>\n  </p>\n<p style=\"margin-left: 23pt;\">\n 6.   To explore the relationship between DTG exposure and the antiviral activity.</p>\n
      • study_title<p align=\"center\" style=\"margin-left: 4.55pt;\">\n <strong>P</strong><strong>h</strong><strong>ase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 Infected Infants, Children and Adolescents</strong><strong>P</strong><strong>h</strong><strong>ase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 Infected Infants, Children and Adolescents</strong></p>\n
      • laymans_summary<p>\n This is a study enrolling infants, children and adolescents aged >4weeks to <18 years to asses the safety tolerability and antiviral activity of DTG. Participants are followed up for a total duration of 4 years.</p>\n
      • short_titleIMPAACT P1093
      • protocol_noECCT/16/11/02
      • version_noVersion 4.0
      • date_of_protocol13-04-2016
      • study_drugDolutegravir (DTG)
      • disease_conditionHIV
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameTivicay
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressjoel.chebon@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_countries0
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd0
      • applicant_prev_data0
      • applicant_stability_data0
      • applicant_analysis_cert0
      • applicant_pictorial_sample0
      • applicant_gcp_training0
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi0
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african0
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantJoel Chebon
      • declaration_date119-09-2016
      • declaration_principal_investigatorLucy C. Koech
      • declaration_date219-09-2016
      • placebo_presentNo
      • study_objectives<div>\n <p style=\"margin-left: 5pt;\">\n <u>PRIMARY OBJECTIVES</u></p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 1.   To select a dose for each formulation of DTG for chronic dosing in infants, children and adolescents that achieves similar exposure to the DTG 50 mg once daily dose in adults.</p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 2.   To determine the safety and tolerability of DTG in HIV-1 infected infants, children and adolescents at 24 and 48 weeks.</p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 3.   To evaluate the steady-state pharmacokinetics of DTG in combination with other antiretrovirals (OBT) in treatment-experienced and/or treatment-naïve HIV-1 infected infants, children and adolescents and to determine the dose of DTG that achieves a targeted AUC24 (primary PK endpoint) and C24h (secondary PK endpoint) in this population.</p>\n <p>\n  </p>\n <p style=\"margin-left: 5pt;\">\n <u>SECONDARY OBJECTIVES</u></p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 1.   To evaluate the antiviral activity of DTG in combination with an OBT by measuring virologic response in infants, children and adolescents at 24 and 48 weeks.</p>\n <p>\n  </p>\n <p style=\"margin-left: 23pt;\">\n 2.   To evaluate the effect on immunologic response from baseline to 24 and 48 weeks.</p>\n</div>\n<p>\n  </p>\n<p style=\"margin-left: 23pt;\">\n 3.   To assess changes in HIV-1 genotype and phenotype to DTG and other components of the OBT</p>\n<p style=\"margin-left: 41pt;\">\n in subjects experiencing virologic failure.</p>\n<p>\n  </p>\n<p style=\"margin-left: 23pt;\">\n 4.   To determine DTG exposure, its variability and clinical covariates that impact DTG disposition</p>\n<p style=\"margin-left: 41pt;\">\n (e.g. age, weight) using intensive and sparse sampling and population pharmacokinetic analysis.</p>\n<p>\n  </p>\n<p style=\"margin-left: 41pt;\">\n 5.   To determine the extended long term (≥48 weeks) safety and tolerability of DTG in HIV-1 infected infants, children and adolescents.</p>\n<p>\n  </p>\n<p style=\"margin-left: 23pt;\">\n 6.   To explore the relationship between DTG exposure and the antiviral activity.</p>\n
      • principal_inclusion_criteria<div>\n <p style=\"margin-left: 5pt;\">\n <strong>4.1       Inclusion Criteria</strong></p>\n <p>\n  </p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 4.1.1    Age: ≥ 4 weeks to <strong><</strong>18 years at study entry</p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 4.1.2    Confirmed HIV-1 infection</p>\n <p>\n  </p>\n <p style=\"margin-left: 95pt;\">\n ·    Documentation of HIV-1 infection defined as positive results from <u>two</u> samples collected at <u>different</u> time points. All samples tested must be whole blood, serum or plasma. All test methods should be FDA-approved if available. If FDA-approved methods are not available, test methods should be verified according to GCLP and approved by the IMPAACT central laboratory.</p>\n <p style=\"margin-left: 113pt;\">\n o  Sample #1 may be tested by non-study public or PEPFAR programs.</p>\n <p style=\"margin-left: 131pt;\">\n However, both the result and the assay date must be recorded in the subject’s</p>\n <p style=\"margin-left: 131pt;\">\n chart. Source documentation (patient’s medical record/chart, in-country</p>\n <p style=\"margin-left: 131pt;\">\n Ministry of Health registers, laboratory results, etc.) must be available if requested.</p>\n <p style=\"margin-left: 131pt;\">\n o  Sample #2 must be performed in a CAP/CLIA-approved laboratory (for US sites) or in a laboratory that operate according to GCLP guidelines and participates’ in appropriate external quality assurance program (for non-US sites).</p>\n</div>\n<p>\n  </p>\n<div>\n <p>\n  </p>\n <p style=\"margin-left: 74pt;\">\n <u>4.1.2.1 Acceptable tests when subjects are ≤ 18 months of age</u></p>\n <p>\n  </p>\n <p style=\"margin-left: 74pt;\">\n Sample #1 and Sample #2 may be tested using any of the following:</p>\n <p>\n  </p>\n <p style=\"margin-left: 74pt;\">\n ·    One HIV DNA PCR</p>\n <p style=\"margin-left: 74pt;\">\n ·    One quantitative HIV RNA  PCR (above the limit of detection of the assay)</p>\n <p style=\"margin-left: 74pt;\">\n ·    One qualitative HIV RNA PCR</p>\n <p style=\"margin-left: 74pt;\">\n ·    One total HIV nucleic acid</p>\n <p>\n  </p>\n <p style=\"margin-left: 77pt;\">\n Note: Subjects ≤ 18 months of age can be enrolled on the basis of one positive test result (from Sample #1) if the results from Sample #2 are pending. The HIV RNA test required at screening per the Schedule of Evaluations may serve as Sample #2 and may be</p>\n <p style=\"margin-left: 77pt;\">\n pending at the time of enrollment. However, any subject in whom infection is not confirmed by the results of Sample #2 should discontinue study drug, per Section 6.6 and be followed per Appendix IF.</p>\n <p>\n  </p>\n <p style=\"margin-left: 77pt;\">\n <u>4.1.2.2 Acceptable tests when subjects are > 18 months of age</u></p>\n <p>\n  </p>\n <p style=\"margin-left: 77pt;\">\n Sample #1 may be tested using any of the following:</p>\n <p>\n  </p>\n <p style=\"margin-left: 95pt;\">\n ·    Two rapid antibody tests from different manufacturers or based on different principles and epitopes</p>\n <p style=\"margin-left: 77pt;\">\n ·    One EIA OR Western Blot OR immunofluorescence OR chemiluminescence</p>\n <p style=\"margin-left: 77pt;\">\n ·    One HIV DNA PCR</p>\n <p style=\"margin-left: 77pt;\">\n ·     One quantitative HIV RNA PCR (above the limit of detection of the assay)</p>\n <p style=\"margin-left: 77pt;\">\n ·    One qualitative HIV RNA PCR</p>\n <p style=\"margin-left: 77pt;\">\n ·    One HIV culture (prior to August 2009)</p>\n <p style=\"margin-left: 77pt;\">\n ·    One total HIV nucleic acid</p>\n <p>\n  </p>\n <p style=\"margin-left: 77pt;\">\n Sample #2 may be tested using any of the following:</p>\n <p>\n  </p>\n <p style=\"margin-left: 95pt;\">\n ·    Rapid antibody test. If this option is used in combination with the two tests for Sample #1, at least one of the three rapid antibody tests for Sample #1 must be FDA approved and the third rapid test must be from a third manufacturer or based on a third principle or epitope.</p>\n <p style=\"margin-left: 77pt;\">\n ·    One EIA  OR  Western Blot OR immunofluorescence OR chemiluminescence</p>\n <p style=\"margin-left: 77pt;\">\n ·    One HIV DNA PCR</p>\n <p style=\"margin-left: 77pt;\">\n ·    One quantitative HIV RNA PCR (above the limit of detection of the assay)</p>\n <p style=\"margin-left: 77pt;\">\n ·    One qualitative HIV RNA PCR</p>\n <p style=\"margin-left: 77pt;\">\n ·    One HIV culture (prior to August 2009)</p>\n <p style=\"margin-left: 77pt;\">\n ·    One total HIV nucleic acid</p>\n <p>\n  </p>\n <p>\n  </p>\n <p>\n  </p>\n <p style=\"margin-left: 41pt;\">\n 4.1.3     Subjects must belong to one of the ARV exposure groups below:</p>\n <p>\n  </p>\n <p style=\"margin-left: 77pt;\">\n 4.1.3.1  ARV-treatment experienced (not including receipt of ARVs as prophylaxis or</p>\n <p align=\"center\" style=\"margin-left: 111.2pt;\">\n PMTCT)</p>\n <p>\n  </p>\n <p style=\"margin-left: 113pt;\">\n Previously took ARVs as treatment, but not currently taking ARVs :</p>\n</div>\n<p>\n  </p>\n<div>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n ·    Must have been off treatment ≥ 4 weeks</p>\n <p>\n  </p>\n <p style=\"margin-left: 151.35pt;\">\n OR</p>\n <p>\n  </p>\n <p align=\"center\" style=\"margin-left: 111.2pt;\">\n -    Currently taking ARVs for treatment but failing:</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n ·    Must be on an unchanged, failing therapeutic regimen within the 4 to</p>\n <p style=\"margin-left: 167.05pt;\">\n 12 weeks prior to screening (≤1 log drop in HIV-1 RNA within the 4 to 12 weeks prior to screening).</p>\n <p>\n  </p>\n <p style=\"margin-left: 149.05pt;\">\n NOTE: Dose adjustments for growth or formula substitutions (i.e. switching from single agent to fixed dose combination) are permitted during this 4 to 12 week period. Substitutions of one ARV within the same class for toxicity or tolerability management, or discontinuation of ARVs are also allowed within the 4 to 12 weeks period.</p>\n <p>\n  </p>\n <p align=\"center\" style=\"margin-left: 165.2pt;\">\n OR</p>\n <p>\n  </p>\n <p style=\"margin-left: 131pt;\">\n -    For subjects < 2 years of age, initiated ARVs for treatment < 4 weeks prior to screening.</p>\n <p>\n  </p>\n <p style=\"margin-left: 77pt;\">\n 4.1.3.2  ARV treatment naive (no exposure to ARVs for treatment; could have received</p>\n <p style=\"margin-left: 113pt;\">\n ARVs for prophylaxis or PMTCT)</p>\n <p style=\"margin-left: 149.05pt;\">\n ·    Age < 2 years</p>\n <p>\n  </p>\n <p style=\"margin-left: 89pt;\">\n 4.1.4        If an infant has received NVP as prophylaxis to prevent mother to child transmission (PMTCT), he or she must have <strong>not </strong>received NVP for at least 14 days prior to enrollment into Stage I or II.</p>\n <p>\n  </p>\n <p align=\"center\" style=\"margin-left: 39.2pt;\">\n 4.1.5    HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening</p>\n <p>\n  </p>\n <p style=\"margin-left: 77pt;\">\n NOTE: For subjects enrolling into cohorts IV, IV-DT, V, and V-DT, the HIV RNA test performed at screening may be pending at the time of enrollment. If the screening HIV RNA is ≤ 1000 c/mL, the subject should discontinue study drug, per Section 6.6 and be followed per Appendix IF.</p>\n <p>\n  </p>\n <p style=\"margin-left: 77pt;\">\n 4.1.6     Demonstrated ability or willingness to swallow assigned study medications. NOTE: Film coated tablets MAY NOT be crushed or dissolved. Dispersible tablets MAY NOT be cut and must be used in five milligram intervals.</p>\n <p>\n  </p>\n <p align=\"center\" style=\"margin-left: 39.2pt;\">\n 4.1.7    Parent or legal guardian able and willing to provide signed informed consent.</p>\n <p>\n  </p>\n <p style=\"margin-left: 77pt;\">\n 4.1.8    Female subjects who are of child bearing potential and who are engaging in sexual activity that could lead to pregnancy, must use two adequate birth control methods while on study and for two weeks after stopping study drug. Hormonal birth control alone (e.g., pills, shots, or slow release inserts placed under/on the skin) would not be considered adequate. An effective, medically accepted barrier method of contraception (e.g., female/male condoms, diaphragm or cervical cap with a cream or gel that kills sperm (excluding nonoxydyl-9), intrauterine device [IUD], others) also must be used during the</p>\n</div>\n<p>\n  </p>\n<p style=\"margin-left: 77pt;\">\n study. Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV-1 transmission.</p>\n<p>\n  </p>\n<p style=\"margin-left: 72.6pt;\">\n 4.1.9   Males engaging in sexual activity that could lead to HIV-1 transmission must use a condom.</p>\n<p>\n  </p>\n<p style=\"margin-left: 41pt;\">\n 4.1.10 Optimized background therapy (OBT):</p>\n<p>\n  </p>\n<p style=\"margin-left: 90.6pt;\">\n ·    Subjects aged ≥2 years of age (Cohorts I, II, III, and III-DT) must have available at least one fully active drug for the OBT to enroll. Historical genotypes obtained within 1 year of screening will be considered by the Protocol Team for determination of fully active drugs if screening genotype testing is inconclusive.</p>\n<p style=\"margin-left: 90.6pt;\">\n ·    Subjects < 2 years of age (Cohorts IV, IV-DT, V, and V-DT) can enroll if genotype testing has been obtained with results pending.</p>\n<p>\n  </p>\n<p style=\"margin-left: 90.6pt;\">\n Note: Subjects enrolled with genotype results pending but found to have no active drugs per genotype performed at screening should discontinue study drug, per Section</p>\n<p style=\"margin-left: 90.6pt;\">\n 6.6 and be followed per Appendix IF. However, such subjects who have a > 1 log drop in HIV RNA by 4 weeks can continue study drug with approval by the Protocol Team.</p>\n
      • principal_exclusion_criteria<div>\n <p style=\"margin-left: 5pt;\">\n <strong>4.2       Exclusion Criteria</strong></p>\n <p>\n  </p>\n <p>\n  </p>\n <p style=\"margin-left: 36.6pt;\">\n 4.2.1    Presence of any active AIDS defining opportunistic infection</p>\n <p>\n  </p>\n <p style=\"margin-left: 36.6pt;\">\n 4.2.2    At enrollment, subject < 3.0 kg</p>\n <p>\n  </p>\n <p style=\"margin-left: 72.6pt;\">\n 4.2.3    Known ≥ Grade 3 of any of the following laboratory toxicities within 30 days prior to study entry: neutrophil count, hemoglobin, platelets, AST, ALT, lipase, serum creatinine and total bilirubin. A single repeat within the 30 days is allowed for eligibility determination. NOTE: ≥ Grade 3 total bilirubin is allowable, if the subject is on ATV.</p>\n <p>\n  </p>\n <p style=\"margin-left: 72.6pt;\">\n 4.2.4    ANY known Grade 4 laboratory toxicities within 30 days prior to study entry. NOTE: Grade 4 total bilirubin is allowable, if the subject is on ATV.</p>\n <p>\n  </p>\n <p style=\"margin-left: 36.6pt;\">\n 4.2.5    The following liver toxicities within 30 days prior to study entry: ALT > 3x ULN <u>AND</u></p>\n <p style=\"margin-left: 72.6pt;\">\n direct bilirubin is > 2x ULN</p>\n <p>\n  </p>\n <p style=\"margin-left: 72.6pt;\">\n 4.2.6    Any prior history of malignancy, with the exception of localized malignancies such as squamous cell or basal cell carcinoma of the skin</p>\n <p>\n  </p>\n <p style=\"margin-left: 36.6pt;\">\n 4.2.7    Clinical or symptomatic evidence of pancreatitis, as determined by the clinician</p>\n <p>\n  </p>\n <p style=\"margin-left: 72.6pt;\">\n 4.2.8    Use of any disallowed medications at time of screening (see Section 4.3.2 for a complete list of disallowed medications)</p>\n <p>\n  </p>\n <p style=\"margin-left: 36.6pt;\">\n 4.2.9    Known history of exposure to integrase inhibitor treatment by the subject or subject’s</p>\n <p style=\"margin-left: 72.6pt;\">\n mother prior to delivery/cessation of breast feeding</p>\n <p>\n  </p>\n <p style=\"margin-left: 36.6pt;\">\n 4.2.10   Known resistance to an integrase inhibitor</p>\n</div>\n<p>\n  </p>\n<p style=\"margin-left: 36.6pt;\">\n 4.2.11   Women who are pregnant or breastfeeding.</p>\n<p>\n  </p>\n<p style=\"margin-left: 72.6pt;\">\n 4.2.12   Subject is currently participating in or has participated in a study with a compound or device that is not commercially available within 30 days of signing informed consent, unless permission from both Protocol Teams is granted</p>\n<p>\n  </p>\n<p style=\"margin-left: 72.6pt;\">\n 4.2.13   Subject is unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study to a non-IMPAACT study site</p>\n<p>\n  </p>\n<p style=\"margin-left: 72.6pt;\">\n 4.2.14   Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator’s opinion, would compromise the outcome of this study</p>\n<p>\n  </p>\n<p style=\"margin-left: 72.6pt;\">\n 4.2.15   Subject has used, or anticipates using, chronic systemic immunosuppressive agents or systemic interferon (e.g. for treatment of HCV infection) within 30 days prior to beginning DTG study treatment. Systemic corticosteroids (e.g. prednisone or equivalent up to 2 mg/kg/day) for replacement therapy or short courses (≤30 days) are permitted. (See disallowed medications Section 4.3.2)</p>\n<p>\n  </p>\n<p style=\"margin-left: 72.6pt;\">\n 4.2.16   Any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol.</p>\n<p>\n  </p>\n<p style=\"margin-left: 72.6pt;\">\n 4.2.17   Active TB disease and/or requirement for treatment that includes rifampin at the time of the screening visit. However, subjects who need rifampin treatment while on DTG will be allowed to continue in P1093 provided the DTG dose is adjusted according to Section</p>\n<p style=\"margin-left: 72.6pt;\">\n 6.1.8.</p>\n
      • primary_end_points<p style=\"margin-left: 41pt;\">\n 8.2.1    Primary Endpoints:</p>\n<p>\n  </p>\n<p style=\"margin-left: 77pt;\">\n 8.2.1.1  Toxicity through Week 24</p>\n<p style=\"margin-left: 113pt;\">\n ·    All adverse events or lab toxicities of Grade 3 or higher severity</p>\n<p style=\"margin-left: 131pt;\">\n ·    Adverse events or lab toxicities of Grade 3 or higher severity judged to be at least possibly attributable to the study medication</p>\n<p style=\"margin-left: 113pt;\">\n ·    Termination from treatment due to a drug-related adverse event</p>\n<p style=\"margin-left: 113pt;\">\n ·    Death</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic1
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology1
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<p>\n See the SSA APPEDIX 1 WHICH STATES THE KEMRI /WRP CRC ROLES OF STUDY PERSONNEL</p>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n N/A</p>\n
      • other_details_regulatory_approved<p>\n Walter Reed Army Institute of Research IRB approved through letter dated: Aug 10 2016</p>\n<p>\n KEMRI SERU approved through letter dated: Aug 18 2016</p>\n
      • other_details_regulatory_rejected
      • other_details_regulatory_halted
      • estimated_duration After been on study for 48 weeks, all participants shall enter long term followup phase for 3 years.
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaKENYA MEDICAL RESEARCH INSTITUTE/WALTER REED PROJECT HIV PROGRAME
      • single_site_physical_addressHospital Road P.O Box 1357 - 20200 Kericho
      • single_site_contact_personLucy Koech
      • single_site_telephone254522030686
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states5
      • number_of_sites
      • multi_country_listKenya, USA, Haiti, Thailand, South Africa
      • data_monitoring_committeeYes
      • total_enrolment_per_site20
      • total_participants_worldwide100
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerYes
      • 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_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentYes
      • subjects_specifychildren
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameWinnie
      • investigator1_middle_name
      • investigator1_family_nameKeter
      • investigator1_qualificationclinical officer
      • investigator1_professional_address1357
      • investigator1_telephone0522030686
      • investigator1_emailwinnie.keter@usamru-k.org
      • organisations_transferred_Yes
      • number_participants20
      • notification
      • approval_date28-03-2017
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted02-03-2020
      • 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)
      • modified2024-04-11 10:36:27
      • created2016-09-15 15:01:46
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id358
        • application_id556
        • given_nameLucy
        • middle_name
        • family_nameKoech
        • qualificationMBCHB
        • professional_address1357
        • telephone0522030686
        • emaillucy.koech@usamru-k.org
        • created2016-09-16 12:06:16
        • modified2020-03-02 14:32:58
    • SiteDetail(array)
      • 0(array)
        • id433
        • application_id556
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2016-09-16 12:06:16
        • modified2020-03-02 14:32:58
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id286
        • application_id556
        • sponsorNational Institute of Allergy and Infectious Diseases
        • sponsor_typeOthers
        • contact_personEllen Townley
        • addressMaternal Adolescent Pediatric Branch HJF DAIDS, DAIDS/NIAD/NIH 5601 Fischers Lane Room 8B37
        • telephone_number2402924784
        • fax_number2406273465
        • cell_number2402924784
        • email_addressellen.townley@nih.gov
        • created2016-09-16 12:06:16
        • modified2020-03-02 14:32:58
  • 1(array)
    • Application(array)
      • id92
      • user_id613
      • trial_status_id7
      • abstract_of_study<p>\n Areas of high HIV prevalence and intense malaria transmission significantly overlap especially sub-Saharan Africa where a majority of HIV-infected individuals also live in malaria-endemic regions.  Sub-Saharan Africa remains the region most heavily affected by HIV, accounting for 67% of all people living with HIV and 75% of AIDS deaths in 2007.  Each year 350–500 million cases of malaria occur worldwide, and over one million people die, most of them young children, in sub-Saharan Africa.                                           </p>\n<p>\n Recent studies have indicated that the interaction between HIV and malaria infection is bi-directional and synergistic. HIV-infected persons are at increased risk for clinical malaria and potential malaria treatment failure. In addition to an apparent increased vulnerability to malaria parasitemia in HIV-infected adults living in malaria endemic regions, malaria may also enhance HIV replication.  Evidence suggests that HIV/malaria coinfection is associated with increased HIV viral load and may therefore impact negatively upon HIV disease progression and/or increase the risk of HIV transmission.  In Kenya, the burden of both HIV and malaria remains significant.  However, while clinic programs and research studies are ongoing targeting HIV and malaria separately, very little if any research is ongoing focusing upon the HIV/malaria co-infection.</p>\n<p>\n Methods used to prevent the spread of malaria disease endemic areas include prophylactic drugs, mosquito eradication, and the prevention of mosquito bites. Attention to non-traditional malaria therapies that may have antimalarial effects is ongoing given the magnitude of malaria related morbidity and mortality.  Identifying drugs, such as PIs used in the treatment of HIV/AIDS (which are becoming more available in sub-Saharan Africa), with antimalarial activity will provide additional tools in comprehensive malaria control and prevention programs.</p>\n<p>\n This study will test the superiority of LPV/r-based ART compared with nNRTI-based ART clearance of <em>Pf</em> SCP.  The primary endpoint is PCR defined clearance of <em>Pf</em> parasitemia on three consecutive occasions within a 24-hour period. HIV-infected participants ≥18 years with CD4+ counts >200 and <u><</u>350 cells/mm³ who will be starting ART and have <em>Pf</em> SCP will be enrolled and randomized to receive either LPV/r or nNRTI-based ART for 15 days. After the 15 day <em>Pf</em> SCP clearance evaluation, all participants will receive nNRTI-based ART plus TMP/SMX prophylaxis to take for 15 days.</p>\n<p>\n The Kericho site will recruit about 20-30 participants, in part dependent upon timing of protocol activation compared to the other 5 sites in this international, multi-center study.  Recruitment will be focused at the Kericho District Hospital HIV clinic.  Nearby health and HIV Testing and Counseling (HTC) facilities under the KEMRI/WRP PEPFAR program will also be utilized.  Participants will be followed for 30 days. The site accrual rate is estimated to be 2-3 participants per month; hence estimated duration of accrual is about 12 months.</p>\n<p>\n  </p>\n<p>\n If PIs are shown to have marked benefit in clearance of subclinical malaria, such information would be informative to both clinical researchers (i.e. KEMRI) in considering future HIV/malaria infection research as well as policy stakeholders (i.e. Ministry of Health) in considering optimal treatment and prevention initiatives.</p>\n
      • study_title<p align=\"center\">\n  </p>\n<p style=\"text-align: justify;\">\n <strong>An Open-Label, Proof of Concept, Randomized Trial Comparing a LPV/r-Based to an nNRTI-Based Antiretroviral Therapy Regimen for Clearance of </strong></p>\n<p style=\"text-align: justify;\">\n <strong><em>Plasmodium falciparum</em></strong><strong> Subclinical Parasitemia in HIV-infected Adults with CD4+ Counts >200 and <u><</u>350 cells/mm³</strong> .</p>\n
      • laymans_summary<p>\n The areas that has highest problems of HIV infection, also experiences the biggest burden of malaria. Sub-Saharan Africa remains the region most heavily affected by HIV.  Each year 350–500 million cases of malaria occur worldwide, and over one million people die, most of them young children, in sub-Saharan Africa. Methods used to prevent the spread of malaria disease endemic areas include prophylactic drugs, mosquito eradication, and the prevention of mosquito bites. Attention to non-traditional malaria therapies that may have antimalarial effects is ongoing given the magnitude of malaria related morbidity and mortality.  Identifying drugs, such as those used in the treatment of HIV/AIDS (which are becoming more available in sub-Saharan Africa), with antimalarial activity will provide additional tools in comprehensive malaria control and prevention programs</p>\n
      • short_titleHIV-Malaria Study_A5297
      • protocol_noECCT/13/04/03
      • version_noVersion 1.0
      • date_of_protocol29-02-2012
      • study_drugefavirenz (EFV), nevirapine (NVP), emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), lopinavir/ritonavir (LPV/r), and trimethoprim/sulfamethoxazole (TMP/SMX) DS.
      • disease_conditionHIV and Malaria
      • 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_nameefavirenz (EFV), nevirapine (NVP), emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), lopinavir/ritonavir (LPV/r), and trimethoprim/sulfamethoxazole (TMP/SMX) DS.
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressjosphat.kosgei@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_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_checklist1
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantKEMRI Walter Reed Project. P.O. Box 1357-20200 Kericho
      • declaration_date108-04-2013
      • declaration_principal_investigatorDr Josphat Kiprop Kosgei, Principal Investigator.
      • declaration_date208-04-2013
      • placebo_presentNo
      • study_objectives<div>\n Primary Objective</div>\n<div>\n To compare the proportions of Pf SCP clearance between LPV/r-based and</div>\n<div>\n nNRTI based ART in participants after 15 days of therapy (Step 1).</div>\n<div>\n 1.4 Secondary Objectives</div>\n<div>\n 1.4.1 To compare time to Pf SCP clearance in participants with Pf SCP who have</div>\n<div>\n received 15 days of LPV/r-based and nNRTI-based ART.</div>\n<div>\n 1.4.2 To compare Pf parasite densities in participants with Pf SCP who have received</div>\n<div>\n 15 days of LPV/r-based and nNRTI-based ART.</div>\n<div>\n 1.4.3 To estimate changes in Pf parasite densities from day 1 to day 30 in four cohorts:</div>\n<div>\n (1) randomized to nNRTI-based ART with continued Pf SCP at day 15, (2)</div>\n<div>\n randomized to nNRTI-based ART with clearance of Pf SCP at day 15, (3)</div>\n
      • principal_inclusion_criteria<p style=\"margin-left: 1in;\">\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.</p>\n<p style=\"margin-left: 1in;\">\n  </p>\n<p style=\"margin-left: 1in;\">\n Note: The term “licensed” refers to a US FDA-approved kit, which is required for all US sites and recommended for non-US ones. For non-US sites that are unable to obtain an FDA-approved kit, a kit that has been certified or licensed by an oversight body within that country and validated internally is acceptable.</p>\n<p style=\"margin-left: 1.5in;\">\n  </p>\n<p style=\"margin-left: 1in;\">\n WHO (World Health Organization) and CDC (Center 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 (eg, indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.</p>\n<p style=\"margin-left: 1in;\">\n  </p>\n<p style=\"margin-left: 1in;\">\n CD4+ count > 200 and <u><</u> 350 cells/mm³ obtained within 30 days prior to study entry at a DAIDS-approved laboratory.</p>\n<p>\n  </p>\n<p style=\"margin-left: 1in;\">\n <em>Pf</em> SCP confirmed in a laboratory approved to conduct parasitemia microscopy.</p>\n<p style=\"margin-left: 1in;\">\n  </p>\n<p style=\"margin-left: 1in;\">\n Note: <em>Pf</em> SCP will be defined as meeting all three of the following criteria within 72 hours prior to study entry:</p>\n<p style=\"margin-left: 1in;\">\n  </p>\n<p style=\"margin-left: 1.6in;\">\n Microscopy confirmed parasitemia (see section 6.3.6 and the A5297 Manual of Procedures [MOPS])</p>\n<p style=\"margin-left: 1.6in;\">\n  </p>\n<p style=\"margin-left: 1.6in;\">\n An oral temperature <u><</u> 37.5^°C temperature</p>\n
      • principal_exclusion_criteria<p>\n Previous history or current use of ART. </p>\n<p>\n  </p>\n<p>\n Single dose NVP or dual therapies used for PMTCT within 2 years prior to entry.</p>\n<p>\n  </p>\n<p style=\"margin-left: 1in;\">\n Use of any medication with antimalarial activity, including TMP/SMX (see list of prohibited medications in the A5297 MOPS), within 14 days prior to study entry. </p>\n<p>\n  </p>\n<p style=\"margin-left: 1in;\">\n Confirmed or clinically suspected OIs (including but not limited to tuberculosis, clinical malaria, <em>PCP</em>), or other pulmonary or gastrointestinal infections for which potential participants did not complete treatment more than 30 days prior to enrollment or have signs and symptoms during screening.</p>\n
      • primary_end_points<p>\n The primary endpoint is PCR defined clearance of <em>Pf</em> parasitemia defined as < 10 parasites/µL on three consecutive occasions within a 24-hour period.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others1
      • scope_others_specifyProof of Concept
      • trial_human_pharmacology1
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<h1>\n 1SITE INVESTIGATORS AND CONTACT INFORMATION</h1>\n<p>\n  </p>\n<p>\n <strong>A) Site Principal Investigator</strong></p>\n<p>\n Dr Josphat K Kosgei, MBChB</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O Box 1357 – 20200</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686 / +254 52 30388</p>\n<p>\n Mobile: +254 729 110122</p>\n<p>\n Fax: +254 52 30662 / +254 52 30546</p>\n<p>\n Email: josphat.kosgei@usamru-k.org</p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n <strong>B) Associate Investigators</strong></p>\n<p>\n Dr Fredrick K Kirui, MBBS, MPH, MMed</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O. Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686/+254 52 30388</p>\n<p>\n Mobile: +254 727 531 373</p>\n<p>\n Fax: +254 52 30662/+254 52 30546.</p>\n<p>\n Email: <a href=\"mailto:jkosgei@wrp-kch.org\">fredrick.kirui@usamru-k.org</a></p>\n<p>\n  </p>\n<p>\n Dr Deborah C Langat, MBChB</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O. Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686/+254 52 30388</p>\n<p>\n Mobile: +254 714 059596</p>\n<p>\n Fax: +254 52 30662/+254 52 30546.</p>\n<p>\n Email: <a href=\"mailto:jkosgei@wrp-kch.org\">deborah.langat@usamru-k.org</a></p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n Dr Kathleen C. Rono, MBChB, MPH & TM</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O. Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686/+254 52 30388</p>\n<p>\n Mobile: +254 716 555535</p>\n<p>\n Fax: +254 52 30662/+254 52 30546.</p>\n<p>\n Email: <a href=\"mailto:jkosgei@wrp-kch.org\">krono@wrp-kch.org</a></p>\n<p>\n  </p>\n<p>\n Dr Lucy Koech, MBChB,</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O Box 1357 – 20200</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686 / +254 52 30388</p>\n<p>\n Mobile: +254 719 193275</p>\n<p>\n Fax: +254 52 30662 / +254 52 30546</p>\n<p>\n Email: <a href=\"mailto:fsawe@wrp-kch.org\">lucy.</a>koech@usamru-k.org</p>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n Dr Fredrick K. Sawe, MBChB, MMED</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O Box 1357 – 20200</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686 / +254 52 30388</p>\n<p>\n Mobile: +254 724 255623</p>\n<p>\n Fax: +254 52 30662 / +254 52 30546</p>\n<p>\n Email: <a href=\"mailto:fsawe@wrp-kch.org\">fsawe@wrp-kch.org, fsawe@hivresearch.org</a></p>\n<p>\n  </p>\n<p>\n Dr Douglas N. Shaffer, MD, MHS</p>\n<p>\n United States Army Medical Research Unit-Kenya</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O. Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686/+254 52 30388</p>\n<p>\n Mobile: +254 716 555535</p>\n<p>\n Fax: +254 52 30662/+254 52 30546</p>\n<p>\n  </p>\n<p>\n <strong>C) Pharmacist</strong></p>\n<p>\n Dr. Noah K. Tarus, B Pharm, MSc</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686 / +254 30388</p>\n<p>\n Mobile: +254 713 603222</p>\n<p>\n Fax: +254 52 30662 / +254 52 30546</p>\n<p>\n Email: <a href=\"mailto:ntarus@wrp-kch.org\">noah.tarus@usamru-k.org</a></p>\n<p>\n  </p>\n<p>\n <strong>D) Laboratory Director</strong></p>\n<p>\n Dr Kibet Shikuku, MBChB, MMed</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O. Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686/+254 52 30388</p>\n<p>\n Mobile: +254 716 555537</p>\n<p>\n Fax: +254 52 30662/+254 52 30546.</p>\n<p>\n Email: <a href=\"mailto:jkosgei@wrp-kch.org\">kibet.shikuku@usamru-k.org</a></p>\n<p>\n <strong>E) Data Manager</strong></p>\n<p>\n Ignatius Kiptoo</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O. Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686/+254 52 30388</p>\n<p>\n Mobile: +254 727 531375</p>\n<p>\n Fax: +254 52 30662/+254 52 30546.</p>\n<p>\n Email: <a href=\"mailto:jkosgei@wrp-kch.org\">ignatius.kiptoo@usamru-k.org</a></p>\n<p>\n  </p>\n<p>\n <strong>F) Study Coordinator</strong></p>\n<p>\n Hellen Ngeno, BSN</p>\n<p>\n P.O Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686 / +254 52 30388</p>\n<p>\n Mobile: +254 713 603225</p>\n<p>\n Fax: +254 52 30662 / +254 52 30546</p>\n<p>\n Email: <a href=\"mailto:hngeno@wrp-kch.org\">hngeno@wrp-kch.org</a></p>\n<p>\n  </p>\n<p>\n <strong>G) Local DoD Research  Monitor</strong></p>\n<p>\n <u>Primary DoD Research Monitor</u></p>\n<p>\n  </p>\n<p>\n Dr. Appolonia Aoko, MBChB</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686 / +254 52 30388</p>\n<p>\n Mobile: +254 715 551234</p>\n<p>\n Fax: +254 52 30662 / +254 52 30546</p>\n<p>\n Email: <a href=\"mailto:aaoko@wrp-kch.org\">aaoko@wrp-kch.org</a></p>\n<p>\n  </p>\n<p>\n Alternate DoD Research Monitor</p>\n<p>\n  </p>\n<p>\n Dr. Jonah Maswai, MBChB, MPH</p>\n<p>\n Kenya Medical Research Institute/Walter Reed Project</p>\n<p>\n HIV Program</p>\n<p>\n P.O Box 1357 – 20200,</p>\n<p>\n Hospital Road, Kericho, Kenya</p>\n<p>\n Tel: +254 52 30686 / +254 52 30388</p>\n<p>\n Mobile: +254 716 430271</p>\n
      • other_details_explanation<p>\n Kenya has a high prevalence of both HIV and Malaria, which is a requirement of the study.</p>\n
      • other_details_regulatory_notapproved<p>\n None.</p>\n
      • other_details_regulatory_approved<p>\n Kenya Medical Research Institute (KEMRI) Ethical Research Committee. Approval date 26 March 2013. This is for Kericho site only.</p>\n
      • other_details_regulatory_rejected<p>\n None.</p>\n
      • other_details_regulatory_halted<p>\n Not Applicable.</p>\n
      • estimated_durationOne year
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindNo
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorNNRTI arm
      • 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_states4
      • number_of_sites2
      • multi_country_listKenya, Botswana, Malawi, India
      • data_monitoring_committeeYes
      • total_enrolment_per_site20-30
      • total_participants_worldwide52
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyNo
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameDavid
      • investigator1_middle_nameC.
      • investigator1_family_nameWekulo
      • investigator1_qualificationBScN
      • investigator1_professional_addressKEMRI WRP P.O. Box 1357-20200 Kericho
      • investigator1_telephone254729110146
      • investigator1_emaildavid.wekulo@usamru-k.org
      • organisations_transferred_Yes
      • number_participants20-30
      • notification
      • approval_date26-03-2013
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted17-03-2020
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<div>\n A5297 is a phase I/II, open-label, proof of concept, two-step, two-arm, controlled randomized clinical trial (RCT) to</div>\n<div>\n test the superiority of lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) to nonnucleoside reverse</div>\n<div>\n transcriptase (nNRTI)-based ART for clearance of Plasmodium falciparum (Pf) subclinical parasitemia (SCP).</div>\n<div>\n Participants were followed for 30 days in order to evaluate parasitemia clearance, Pf parasitemia, gametocytemia,</div>\n<div>\n and plasmepsin sequencing. Participants will have blood collected twice at entry, day 3, 6, 9, 12, 20, and 25 and</div>\n<div>\n three times for day 15 and day 30.</div>\n<div>\n Fifty-two participants (26 per arm) enrolled between January 10, 2014 and May 20, 2016 with 46 (88%) from two</div>\n<div>\n sites in Kenya. Fifty-one participants completed the primary outcome (Step 1) visit, and 49 completed the protocol</div>\n<div>\n as specified. The study population was mostly male (67%) with a median age of 31 (Q1, Q3=24, 39) years. The</div>\n<div>\n median baseline CD4 count was 324 cells/mm3 (259, 404) and median baseline log10 (HIV-1 RNA) was 5.18</div>\n<div>\n copies/mL (4.60, 5.71). The median baseline parasite density was 2.66 log10 parasites/μL (1.92, 3.35) (Table 1).</div>\n<div>\n For the primary outcome, there was no statistically significant difference in clearance between the LPV/r-based</div>\n<div>\n (n=6, 23%) and nNRTI-based (7, 27%) ART arms (Table 2). Sensitivity analyses were conducted around missing data:</div>\n<div>\n one where missing data were assumed to have cleared and one where missing data were excluded. Sensitivity</div>\n<div>\n analyses were also conducted using less stringent definitions of clearance: one where participants were considered</div>\n<div>\n cleared if any 2 of 3 samples had <10 estimated parasites/μL at day 15 by qRT-PCR and one where participants</div>\n<div>\n were considered cleared if any 1 of 3 samples had < 10 parasites/μL at day 15 by qRT-PCR. In all sensitivity</div>\n<div>\n analyses, the difference in clearance between the treatment arms remained non-significant.</div>\n<div>\n Secondary objective analyses included time-to–Pf parasite clearance, between-arm parasite densities over time,</div>\n<div>\n and safety outcomes. No statistically significant differences in time-to-Pf 9 parasite clearance were observed</div>\n<div>\n between arms (P=0.80, Figure 2). Mean Pf parasite densities through the 30-day study window were examined</div>\n<div>\n (Figure 3). While overall, a trend was observed in decreasing Pf parasite densities in both arms throughout the</div>\n<div>\n study, there was no difference between the two treatment arms during days 1-15 (LPV/r Arm median = -0.61 [Q1,</div>\n<div>\n Q3 = -1.78,0.00] and nNRTI Arm -0.46 [-1.31,0.41]) or days 15-30 (LPV/r Arm -1.04 [-2.39,-0.67] and nNRTI Arm -</div>\n<div>\n 1.40 [-2.51,-0.52]). Overall, Pf parasite density decreased between entry and day 30 (-2.36 [-3.46,-0.94]); at the</div>\n<div>\n same time median CD4 counts increased (101 cells/mm3) and median log10 HIV RNA decreased (-2.48 copies/mL)</div>\n<div>\n with no significant between arm differences.</div>\n<div>\n During the study period, there were few adverse events with no hospitalizations. Three cases of uncomplicated,</div>\n<div>\n Grade 2 clinical malaria (LPV/r Arm n=2, nNRTI Arm n=1) occurred during Step 1, and all received SOC</div>\n<div>\n artemether/lumefantrine. One participant in both treatment arms experienced Grade 2 anemia (n=2).</div>\n<div>\n The Study’s results did not find a statistically significant difference in parasite clearance rates nor in time-toparasite</div>\n<div>\n clearance between PI and nNRTI treatment arms. To the Study’s knowledge, the proof-of-concept RCT of</div>\n<div>\n HIV-infected adults beginning first-line ART with Pf SCP is the first direct comparison between a PI (LPV/r) and</div>\n<div>\n nNRTI.</div>\n
      • implication_results<div>\n Yes, from the Primary Manuscript:</div>\n<div>\n  The Study’s results did not find a statistically significant difference in parasite clearance rates</div>\n<div>\n nor in time-to-parasite clearance between PI and nNRTI treatment arms. To the Study’s knowledge, the</div>\n<div>\n proof-of-concept RCT of HIV-infected adults beginning first-line ART with Pf SCP is the first direct</div>\n<div>\n comparison between a PI (LPV/r) and nNRTI.</div>\n<div>\n  The Study provides a unique cohort testing the clinical impact of PIs in a setting without and with</div>\n<div>\n TMP/SMX. While participants had CD4 counts >200 given requirements for TMP/SMX in people with lower</div>\n<div>\n CD4 counts, the Study observed no complicated malaria, PCP, or diarrheal disease.</div>\n<div>\n  Three cases of uncomplicated malaria (parasitemia and fever) during the first 15 days in the absence of</div>\n<div>\n TMP/SMX. This likely reflects fluctuations in SCP in the absence of TMP/SMX and occasional fever</div>\n<div>\n threshold densities being passed.</div>\n<div>\n  This Study also provides unique opportunity for further investigation into parasite and gametocyte life</div>\n<div>\n cycles and kinetics.</div>\n
      • quantity_importedFind attached product accountability documents
      • quantity_dispensedFind attached product accountability documents
      • quantity_destroyedFind attached product accountability documents
      • quantity_exportedFind attached product accountability documents
      • balance_siteFind attached product accountability documents
      • final_date0000-00-00
      • modified2024-06-25 12:46:16
      • created2013-04-04 14:58:19
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id60
        • application_id92
        • given_nameJosphat
        • middle_nameK.
        • family_nameKosgei
        • qualificationMBChB
        • professional_addressKEMRI WRP P.O. Box 1357-20200 Kericho
        • telephone254729110122
        • emailjosphat.kosgei@usamru-k.org
        • created2013-04-04 15:03:34
        • modified2020-03-17 12:04:08
    • SiteDetail(array)
      • 0(array)
        • id80
        • application_id92
        • county_id35
        • site_nameKemri Walter Reed Project-Kericho
        • physical_addressHospital road
        • contact_detailsP.O. Box 1357-20200
        • contact_personJosphat Kosgei
        • site_capacity(null)
        • misc(null)
        • created2013-04-04 15:03:34
        • modified2020-03-17 12:04:08
        • County(array)
          • id35
          • county_nameKericho
          • created2012-06-15 10:26:16
          • modified2012-06-15 10:26:16
      • 1(array)
        • id83
        • application_id92
        • county_id27
        • site_nameMoi University Clinical Research Centre
        • physical_addressMoi Teaching Referral Hospital Building, Nandi Road, Eldoret, Kenya
        • contact_detailsP.O. Box 4604 - 30100 Kenya Tel:254-53 2060850
        • contact_personRonald Kibet
        • site_capacity(null)
        • misc(null)
        • created2013-04-04 17:36:47
        • modified2020-03-17 12:04:08
        • County(array)
          • id27
          • county_nameUasin Gishu
          • created2012-06-15 10:25:15
          • modified2012-06-15 10:25:15
    • Sponsor(array)
      • 0(array)
        • id46
        • application_id92
        • sponsorThe National Institute of Allergy and Infectious Diseases
        • sponsor_typeOthers
        • contact_personBeverly Alston-Smith, MD
        • address6700 B Rockledge Drive, Room 5109 Bethesda, MD 20892-7605
        • telephone_number301-435-3773
        • fax_number301-480-4582
        • cell_number301-435-3773
        • email_addressbalston@niaid.nih.gov
        • created2013-04-04 15:03:34
        • modified2020-03-17 12:04:08
  • 2(array)
    • Application(array)
      • id1127
      • user_id263
      • trial_status_id5
      • abstract_of_study<p>\n Sickle cell disease (SCD) is a related group of common and rare hemoglobin (Hb) genotypes in which all affected individuals are either homozygotes for the sickle Hb (HbS) mutation of the β-globin subunit or compound heterozygotes for HbS and another globin gene mutation. A hallmark symptom of SCD is a painful Vaso-occlusive crisis (VOC). An interplay of the various pathologic processes in SCD perpetuates and feeds forward an inflammatory priming that, in the presence of a precipitating event, can lead to a VOC. VOCs are responsible for a wide variety of clinical complications of SCD, including pain syndromes, acute chest syndrome (ACS), stroke, priapism, leg ulcers, spontaneous abortion, renal insufficiency, and multiorgan failure leading to death. Frequency of VOCs, along with Absolute Neutrophil count (ACS), is the most common predictor of death in patients with SCD. Thus, early identification, treatment, and prevention of VOCs could significantly impact the natural course of the disease. Interventions for treatment and prevention of longer-term complications are urgently needed.</p>\n<p>\n  </p>\n<p>\n About 240,000 children in Africa, are born each year with Sickle Cell Disease (SCD), while here in Kenya, it is estimated that 6,000 children are born with the disease. Sadly, between 50 to 80 per cent of these children die before their fifth birthday. The recurrent pain and complications caused by the disease, can interfere with many aspects of the patient’s life, including education, employment and psychosocial development.</p>\n
      • study_title<p align=\"center\">\n <strong>A Phase 2a Randomized, Double-Blind, Placebo-Controlled Study to Characterize the Pharmacokinetics and Pharmacodynamics of Rifaximin Novel Formulations in Patients with Sickle Cell Disease</strong></p>\n
      • laymans_summary<p>\n The objective of this study is to understand/characterize the pharmacokinetic/PK (how our bodies affect the drug) and the Pharmacodynamics/PD (meaning how the drug affects our bodies) of a drug called Rifaximin, which is used in treatment of patients with sickle cell disease.</p>\n<p>\n Of the current treatment options available for sickle cell disease, only bone marrow transplant is a permanent cure, but few patients qualify for this treatment. Patients on the other treatment options e.g., hydroxyurea and L glutamine may still experience acute clogging of blood vessels called Vaso Occlusive crisis (VOC) There is a need to find more treatment options for sickle cell disease that prevents the VOC.</p>\n
      • short_titleSickle Cell Disease
      • protocol_noECCT/22/03/06
      • version_noVersion 2.0_16 Aug 2021
      • date_of_protocol16-08-2021
      • study_drugrifaximin ER and DER
      • 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_namexifaxan
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressamina.salim@iqvia.com
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample1
      • applicant_gcp_training1
      • applicant_dsmb_charter1
      • applicant_detailed_budget1
      • applicant_indemnity_pi1
      • applicant_practice_license1
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist1
      • statistical_analysis_plan1
      • applicant_contractual_agreement1
      • declaration_applicantMichelle Botha
      • declaration_date120-03-2022
      • declaration_principal_investigatorDr L Tina
      • declaration_date220-03-2022
      • placebo_presentYes
      • study_objectives<p>\n The objectives of this study are: To characterize the pharmacokinetics/pharmacodynamics (PK/PD) of rifaximin ER and DER in subjects with sickle cell disease (SCD) and to assess the safety and tolerability of rifaximin (Extended Release) ER and Delayed Extended Release (DER).</p>\n
      • principal_inclusion_criteria<p>\n Participants are eligible for the study only if all the following criteria are met:</p>\n<ol>\n <li>\n Subject must have the ability and willingness to sign a written informed consent form.</li>\n <li>\n Subject is between the ages of 18 to 70 years old (inclusive) at the time of consent.</li>\n <li>\n Subject has SCD of any genotype (HbSS, HbSC, HbS β-thalassemia). If the subject’s genotype has not been previously documented, genotyping will be performed during Screening using high-performance liquid chromatography (HPLC)/electrophoresis.</li>\n <li value=\"4\">\n Subject must have experienced at least 2 VOCs within the 12 months prior to Screening. A VOC is defined as: </li>\n</ol>\n<p>\n                             a. The occurrence of appropriate symptoms consistent with a painful crisis, acute chest syndrome (ACS), or priapism, and</p>\n<p style=\"margin-left: 72pt;\">\n b. Requires a visit to a medical facility and/or healthcare professional, and</p>\n<p style=\"margin-left: 72pt;\">\n c. Receipt of either a parenteral or oral opioid or NSAID analgesia.</p>\n<ol>\n <li value=\"5\">\n If subject is receiving hydroxyurea (HU)/hydroxycarbamide (HC), subject must have been receiving the treatment for at least 6 months prior to Screening and must agree to maintain the same dose and schedule for the duration of the study.</li>\n <li value=\"6\">\n Subjects must have laboratory values at Screening within the following ranges:\n <ul>\n <li>\n Absolute Neutrophil Count ≥1.0 x 109/L</li>\n <li>\n Platelets ≥ 75 x 109/L</li>\n <li>\n Hemoglobin (Hgb) ≥ 6.0 g/dL</li>\n <li>\n Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m2 using the CKD-EPI formula</li>\n <li>\n Direct (conjugated) bilirubin ≤ 2.0 x ULN</li>\n <li>\n Alanine transaminase (ALT) ≤ 3.0 x ULN</li>\n <li>\n International Normalized Ratio (INR) ≤ 2.0</li>\n </ul>\n </li>\n <li value=\"7\">\n Eastern Cooperate Oncology Group (ECOG) performance status ≤ 2.</li>\n <li value=\"8\">\n Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must have a negative serum pregnancy test at Screening and agree to use standard prevention methods for the duration of the study.</li>\n</ol>\n
      • principal_exclusion_criteria<p>\n Participants are not eligible for inclusion for the trial if any of the following criteria are met:</p>\n<ol>\n <li>\n Subject is receiving concomitant treatment with voxelotor, crizanlizumab, or L-glutamine.</li>\n <li>\n Subject has any history of stem cell transplant is planning to begin or has received in the past 30 days.</li>\n <li value=\"3\">\n Subject experiences an acute VOC, requiring a visit to a medical facility and/or healthcare professional, ending within 7 days prior to Day 1 dosing.</li>\n <li value=\"4\">\n Subject has received any blood products within 30 days of Day 1 dosing.</li>\n <li value=\"5\">\n Subject has uncontrolled liver disease or renal impairment, ulcerative colitis, Crohn’s disease, or other chronic GI disorder.</li>\n <li value=\"6\">\n Subject has received active treatment in another investigational trial within 30 days or 5 half-lives of the last dose of the investigational agent, whichever is greater, prior to Screening.</li>\n <li value=\"7\">\n Subject has received penicillin prophylaxis or antibiotics for treatment of infection within 30 days or 5 half-lives of the treatment, whichever is greater, prior to Screening.</li>\n <li value=\"8\">\n Subject has a significant medical condition that required hospitalization (other than for a VOC) within 2 months prior to Screening.</li>\n <li value=\"9\">\n Subject is planning on undergoing an exchange transfusion during the duration of the study or has completed one within 4 weeks prior to Day 1 dosing.</li>\n <li value=\"10\">\n Subject has a hypersensitivity to rifaximin, rifampin, rifamycin antimicrobial agents, or any components of rifaximin ER and DER.</li>\n <li value=\"11\">\n Subject has used therapeutic anticoagulation (prophylactic doses are permitted) or antiplatelet therapy (other than aspirin or NSAIDs) within 10 days prior to Day 1 dosing.</li>\n <li value=\"12\">\n Subject is pregnant or a nursing woman.</li>\n <li value=\"13\">\n Subject has a history of illicit drug use or abuse, either documented or in the opinion of the Investigator.</li>\n <li value=\"14\">\n Subject is using any medication that is known to inhibit or induce CYP3A4, P-gp, or OATP1B1/B3 (See Appendix 3) within 30 days or 5 half-lives, whichever is longer, prior to Day 1 dosing, or in the opinion of the Investigator, may affect the evaluation of the study product or place the subject at undue risk.</li>\n <li value=\"15\">\n Subject has had any prior gastrointestinal surgery which has altered the anatomy of the esophagus, stomach, or small/large intestine (with the exception of appendectomy, cholecystectomy, and fundoplication).</li>\n <li value=\"16\">\n Subject has had a colonoscopy or sigmoidoscopy within 30 days prior to Day 1 or plans to undergo such a procedure during the duration of the study.</li>\n <li value=\"17\">\n Subject has used bowel prep, laxative, or enema within 30 days prior to Day 1.</li>\n <li value=\"18\">\n Subject has a bleeding disorder including, but not limited to, acquired or congenital platelet function defects, disseminated intravascular coagulation (DIC), bleeding factor deficiencies, hemophilia, idiopathic thrombocytopenia purpura (ITP), or von Willebrand’s disease.</li>\n <li value=\"19\">\n Subject is planning to undergo a major surgical procedure during the duration of the study.</li>\n <li value=\"20\">\n Subject has a positive test for human immunodeficiency virus (HIV)1 or HIV2.</li>\n <li value=\"21\">\n Subject has an active Hepatitis B infection (HBsAg positive). Prior infection that is not active (i.e., HBsAg negative, HBcAb positive, and HBsAb positive) is permitted.</li>\n <li value=\"22\">\n Subject has a positive test for Hepatitis C (HCV RNA). Prior infection with spontaneous resolution or sustained resolution for ≥ 24 weeks after cessation of antivirals is permitted.</li>\n <li value=\"23\">\n Subject has an active COVID-19 infection or complication(s) related to COVID-19 infection that are unresolved or, in the opinion of the Investigator, may affect evaluation of the study drug or place the subject at undue risk.</li>\n <li value=\"24\">\n Subjects has received a vaccine (including COVID-19 vaccine) within 2 weeks prior to Screening. If subject has received their first of two COVID-19 vaccination doses, as applicable, they must wait for at least 2 weeks after receiving the second dose, and be symptom-free, prior to beginning Screening. Subject must not be planning for COVID-19 or other vaccinations while on study.</li>\n <li value=\"25\">\n Subject has a malignant disease. Exceptions include malignancies that were treated curatively and have not recurred within 2 years prior to study treatment, completely resected basal cell and squamous cell skin cancers, and any completely resected carcinoma in situ.</li>\n <li value=\"26\">\n Subjects has prolonged QT interval as assessed by ECG history within the past 3 months. For subjects with no historical ECG information, subject has a resting QTcF ≥ 460 msec for males and ≥ 470 msec for females at Screening.</li>\n <li value=\"27\">\n Subject has any unstable cardiac condition that, in the opinion of the Investigator, may worsen during the study or interfere with successful evaluation of the study treatment.</li>\n <li value=\"28\">\n Subject has a serious mental or physical illness which, in the opinion of the Investigator, would compromise participation in the study.</li>\n <li value=\"29\">\n Subject has any condition which, in the opinion of the Investigator, is likely to interfere with the successful collection of the measurements required for the study.</li>\n</ol>\n
      • primary_end_points<p>\n Full rifaximin and 25-desacetyl rifaximin plasma PK profiles following administration on Days 1 and 29 and C_max and C_trough on Days 8, 15, and 29 will be evaluated at specified timepoints according to the schedule of activities.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy0
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n 1. Victoria Biomedical Research Institute (VIBRI) (PI:  LO Tina):</p>\n<p>\n VIBRI is a non-profit providing pharmaceutical, academic research and non-profit organization with a network of clinical sites and expertise focusing on accelerating transformative therapeutics, vaccines, and devices research for major gloabl health diseases in Kenya.  VIBRI is located at the Kisumu County Referral Hospital in Kisumu County, western Kenya.  VIBRI was established to conduct biomedical research including clinical trials, bioequivalence studies, basic science research studies, epidemiology and population health studies, implementation science studies, build a strong doundation in data science, conduct training and capacity building on clinical research in Kenya.  VIBRI has experienced and accomplished clinical research scientists who have designed and conducted GCP compliance phase 1b to phase IV paediatric and adult clinical trials.  </p>\n<p>\n 2. CREATES (PI:  Dr Bernhards Ogutu):</p>\n<p>\n The KUTRH is designed for clinical trials with a bed space of 600 and ICU beds of 25.  It is a referral healthcare facility experienced in clinical trials. The PI is support by a large team of experienced Sub Investigators and SSCs.  Along with experienced pharmacists to manage the IP.  The site has ample well-equipped clinical laboratories, radiological services and ample clinical observation areas as well as spacious research operations office.</p>\n<p>\n 3. International Cancer Institute (PI:  Prof. FC Asirwa):</p>\n<p align=\"left\" style=\"margin-left:.45pt;\">\n The study will be conducted at the International Cancer Institute (ICI) in Eldoret, Kenya. Recruitment will occur at the research and care clinic located along Nandi Road. ICI research and care clinic is staffed by qualified research personnel including 1 Medical Oncologist, 1 Clinical Oncologist, 4 medical officers, 1 Pharmacist, 1 pharmaceutical Technologist, 1 clinical officer, 4 nurses,1 consultant pathologist, 2 laboratory technologists, 1 patient navigator and 1 administrator. ICI has a research and molecular diagnostics laboratory, for sample testing and storage. The site has a registration area, consultation rooms, examination rooms, chemotherapy administration area, records and data storage, pharmacy and laboratory. International Cancer Institute currently runs a clinic where patients with SCD from Uasin Gishu County and different parts of the Country are managed. The site participates in several other Randomized controlled trials with key focus on Haemato-oncology trials.</p>\n<p>\n 4. KEMRI/USAMRD-K Kombewa Clinical Research Center (PI: Janet Oyieko)</p>\n<div>\n The KEMRI/WRP Kombewa Clinical Research Center (KCRC) is designed for large clinical</div>\n<div>\n trials and has a full clinical laboratory including microbiology capability.</div>\n<div>\n KCRC is part of The Walter Reed Project (WRP), which is a 40-year collaboration between the</div>\n<div>\n Kenya Medical Research Institute, (KEMRI) and the Walter Reed Army Institute of Research</div>\n<div>\n (WRAIR). The US Army Medical Research Unit in Kenya (USAMRU-K) is a WRAIR</div>\n<div>\n attachment stationed in Kenya with headquarters in Nairobi and field stations in Kericho and</div>\n<div>\n Kisumu. WRP-Kisumu conducts a wide spectrum of field and laboratory work including</div>\n<div>\n numerous clinical research trials.</div>\n
      • other_details_explanation<p>\n Study is being conducted in America</p>\n
      • other_details_regulatory_notapproved<p>\n Applications are planned for Egypt and Lebanon</p>\n
      • other_details_regulatory_approved<p>\n US FDA provided approval to proceed on 11 June 2021</p>\n
      • other_details_regulatory_rejected<p>\n Not applicable</p>\n
      • other_details_regulatory_halted<p>\n Not applicable</p>\n
      • estimated_duration6 months
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorPlacebo
      • design_controlled_other_medicinalNo
      • design_controlled_placeboYes
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateNo
      • location_of_area
      • single_site_physical_address
      • single_site_contact_person
      • single_site_telephone
      • multiple_sites_member_stateYes
      • multiple_countriesYes
      • multiple_member_states2
      • number_of_sites4
      • multi_country_listNorth America\nMiddle east
      • data_monitoring_committeeNo
      • total_enrolment_per_site3-10
      • total_participants_worldwide60
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_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_nameLucas
      • investigator1_middle_nameOtieno
      • investigator1_family_nameTina
      • investigator1_qualificationMBChB, MSc, DLSHTM
      • investigator1_professional_addressVictoria Biomedical Research Institute
      • investigator1_telephone+254720596654
      • investigator1_emaillucas.tina0818@gamil.com
      • organisations_transferred_Yes
      • number_participants20
      • notification
      • approval_date15-09-2022
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted09-05-2022
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe reviewer comments have been addressed
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2024-06-11 12:33:58
      • created2022-03-09 10:16:30
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id799
        • application_id1127
        • given_nameJanet
        • middle_name
        • family_nameOyieko
        • qualificationMBChB, MMED, PhD
        • professional_addressKombewa Clinical Research Centre
        • telephone+254721996988
        • emailjanet.oyieko@gmail.com
        • created2022-03-09 11:01:56
        • modified2022-05-09 16:38:41
      • 1(array)
        • id800
        • application_id1127
        • given_nameFredrick
        • middle_nameChite
        • family_nameAsirwa
        • qualificationProf, M.D.
        • professional_addressInternational Cancer Institute (ICI).
        • telephone+254 718 473 446
        • emaildirector@intercancer.com
        • created2022-03-11 10:09:31
        • modified2022-05-09 16:38:41
      • 2(array)
        • id801
        • application_id1127
        • given_nameBernhards
        • middle_name
        • family_nameOgutu
        • qualificationMBChB, MSc
        • professional_addressCREATES - Strathmore University Medical Centre
        • telephone+254733812613
        • emailogutu6@gmail.com
        • created2022-03-11 10:09:31
        • modified2022-05-09 16:38:41
    • SiteDetail(array)
      • 0(array)
        • id1253
        • application_id1127
        • county_id42
        • site_nameKombewa Clinical Research Centre
        • physical_addressOff Kisumu-Bondo Road, opposite Kombewa county Hospital
        • contact_details+254721996988
        • contact_personDr. Janet Oyieko
        • site_capacity(null)
        • misc(null)
        • created2022-03-09 11:01:56
        • modified2022-05-09 16:38:41
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 1(array)
        • id1254
        • application_id1127
        • county_id42
        • site_nameVictoria Biomedical Research institute
        • physical_addressP.O BOX 7180-40100 KISUMU
        • contact_details+254720597654
        • contact_personDr. Lucas Otieno tina
        • site_capacity(null)
        • misc(null)
        • created2022-03-11 09:22:47
        • modified2022-05-09 16:38:41
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 2(array)
        • id1255
        • application_id1127
        • county_id27
        • site_nameInternational Cancer Centre
        • physical_addressNandi road, P.O BOX 8088, Eldoret
        • contact_details+254700522149
        • contact_personDr. Fredrick Asirwa
        • site_capacity(null)
        • misc(null)
        • created2022-03-11 09:22:47
        • modified2022-05-09 16:38:41
        • County(array)
          • id27
          • county_nameUasin Gishu
          • created2012-06-15 10:25:15
          • modified2012-06-15 10:25:15
      • 3(array)
        • id1256
        • application_id1127
        • county_id47
        • site_nameCREATES - Strathmore University Medical Centre
        • physical_addressP.O BOX 59857 - 00200 Madaraka Estate, Nairobi
        • contact_details+254733812613
        • contact_personDr. Bernhards Ogutu
        • site_capacity(null)
        • misc(null)
        • created2022-03-11 09:22:47
        • modified2022-05-09 16:38:41
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
    • Sponsor(array)
      • 0(array)
        • id583
        • application_id1127
        • sponsorSalix Pharmaceuticals, Inc., a division of Bausch Health US, LLC.
        • sponsor_typeIndustry
        • contact_person
        • addressBausch Health US, LLC Bridgewater, NJ 08807 USA
        • telephone_number1-800-321-4576
        • fax_number
        • cell_number 908-927-1400
        • email_addressSean.Humphrey@bauschhealth.com
        • created2022-03-09 11:01:56
        • modified2022-05-09 16:38:41
  • 3(array)
    • Application(array)
      • id148
      • user_id613
      • trial_status_id5
      • abstract_of_study<p>\n <br />\n Cryptococcal meningitis [CM] is the commonest complication of the central nervous system [CNS] accounting for many AIDS associated deaths in Kenya and other parts of the developing world .The preferred regimen of CM treatment is the two week induction with intravenous amphotericin B infusions followed by a course oral fluconazole. The administration of ampho-B in resource poor setting poses a challenge due to its requisite safety monitoring and prohibitive cost and therefore the use fluconazole as a single oral agent is quite desirable.<br />\n This study is randomized, open label clinical trial being carried out in over 10 sites worldwide by the AIDS Clinical Trials Group (ACTG).The overall aim of the study is to establish a Maximum Tolerable Dose [MTD] of fluconazole which can be safely and effectively used as a single oral agent in the management of AIDS associated cryptococcal meningitis.<br />\n The study will be conducted in two stages ; Stage 1, Dose Escalation, up to three induction doses of fluconazole will be tested in sequentially enrolled cohorts. At this stage, safety will be evaluated i.e the maximum tolerable dose of fluconazole will be determined.<br />\n Stage 2, Dose Validation, induction doses of fluconazole that were found to be safe in Stage 1 will be tested against Amphotericin B for efficacy in simultaneously enrolled cohorts. This comparison aims to identify the lower dose of fluconazole with the highest efficacy. This will also serve as a pilot for a larger phase III efficacy trial and obtain additional AE reports in a larger study population.<br />\n The Kericho Site will recruit between 20-30 HIV-1 infected males and females 18 years and above presenting with their first episode of cryptococcal meningitis who have not received ART within 30 days prior to study entry.<br />\n Recruitment will primarily be done through the Kericho District Hospital HIV clinic. All enrolled participants will be followed up for 24 weeks. Due to the nature of the study (pauses between doses in Stage 1 and to confirm efficacy prior to initiating Stage 2), it is difficult to estimate the duration of accrual on this study. However it is anticipated that accrual may be completed approximately 1 year after all eligible sites are able to begin enrolling.</p>\n
      • study_title<p align=\"center\">\n <strong>A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis</strong></p>\n<p align=\"center\">\n  </p>\n<p align=\"center\">\n <strong>A Multicenter Trial of the AIDS Clinical Trials Group (ACTG)</strong></p>\n
      • laymans_summary<p>\n Cryptococcal Meningitis is a common infection in people with AIDS. The purpose of this study is to help find out if a new treatment for Cryptococcal Meningitis using high doses of oral fluconazole is a safe and effective alternative to the existing treatment using Intra-Venous amphotericin B. This study is being done to see if taking fluconazole alone at a dose of 1200 mg per day, 1600 mg per day, or 2000 mg per day is tolerable, safe, and effective for the treatment of Cryptococcal Meningitis for up to 10 weeks. Fluconazole is a drug that is taken by mouth that is approved throughout the world and in Kenya by the Pharmacy and Poisons Board in doses up to 400 mg per day for the treatment of Cryptococcal Meningitis. Currently, fluconazole is given alone mainly for people with mild cases of Cryptococcal Meningitis. Doses higher than 400 mg per day have not been approved by the U.S. Food and Drug Administration. The study will also collect information about treating Cryptococcal Meningitis with amphotericin B (alone or with another drug, either flucytosine or fluconazole). Amphotericin B is a drug that must be given to you through a vein in your arm. The study was planned in two stages whereby stage 1 was Dose escalation and stage 2 dose validation.</p>\n<p>\n The Kericho Site will recruit between 20-30 HIV-1 infected males and females 18 years and above presenting with their first episode of cryptococcal meningitis in those who are on antiretroviral therapy or in those who have not initiated ART. Kericho site recruited 13 participants in stage 1 and will recruit up to 15 participants in stage 2</p>\n
      • short_titleA5225/ HiFLAC
      • protocol_noECCT/10/09/05
      • version_no2.0
      • date_of_protocol11-05-2012
      • study_drugFluconazole
      • disease_conditionAIDS-Associated Cryptococcal Meningitis
      • 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_nameFluconazole
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameIV Amphotericin B
      • comparator_registeredYes
      • comparator_countriesKenya
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addresssamwel.chirchir@usamru-k.org
      • applicant_covering_letter1
      • applicant_protocol1
      • applicant_patient_information1
      • applicant_investigators_brochure1
      • applicant_investigators_cv1
      • applicant_signed_declaration1
      • applicant_financial_declaration1
      • applicant_gmp_certificate1
      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter0
      • applicant_statement1
      • applicant_participating_countries0
      • applicant_addendum1
      • applicant_fees1
      • applicant_complete_form(null)
      • applicant_impd1
      • applicant_prev_data1
      • applicant_stability_data1
      • applicant_analysis_cert1
      • applicant_pictorial_sample0
      • applicant_gcp_training0
      • applicant_dsmb_charter0
      • applicant_detailed_budget1
      • applicant_indemnity_pi0
      • applicant_practice_license0
      • applicant_registration_ctr(null)
      • applicant_pan_african1
      • applicant_hard_copies(null)
      • applicant_signed_checklist0
      • statistical_analysis_plan(null)
      • applicant_contractual_agreement(null)
      • declaration_applicantSamwel K Chirchir -Study coordinator. KEMRI/WRP Kericho Box 1357 Kericho.
      • declaration_date114-06-2013
      • declaration_principal_investigatorDr Deborah Langat-PI.KEMRI/WRP kericho Box 1357 Kericho.
      • declaration_date214-06-2013
      • placebo_presentNo
      • study_objectives<div>\n Primary Objectives</div>\n<div>\n 1 To assess the MTD of fluconazole by comparing the safety and tolerability of induction regimens of 1200, 1600, and 2000 mg/day.</div>\n<div>\n 2 To determine whether the safety and efficacy of high induction-dose fluconazole therapy support development of a phase II/III trial, and, if so, to select the most appropriate fluconazole dose regimen (based on safety and efficacy data from this study) to be evaluated in that trial.</div>\n<div>\n  </div>\n<div>\n Secondary Objectives</div>\n<div>\n 1 To compare the clinical and fungicidal effects of different induction regimens of fluconazole during induction at weeks 2, 4, 6, 8, and 10.</div>\n<div>\n 2 To assess functional status (prior to onset of current CM illness, at study entry, at week 10, and at premature treatment or study discontinuation) and to assess neurological status [at entry, weeks 2, 10, 24, and at progression of symptoms and premature treatment or study discontinuation].</div>\n<div>\n 3 To assess the time to death in each cohort and the combined rates of DLT (Dose limiting toxicities) and death.</div>\n<div>\n 4 To describe the effect of baseline clinical, neurological, and mycological characteristics on clinical and mycological success at week 10 and on time to CSF sterility.</div>\n<div>\n 5 To assess the length of hospitalization between study entry and hospital discharge and for any subsequent readmission for the treatment of CM.</div>\n<div>\n 6 To assess the incidence of progression of symptoms and its components among all participants receiving ART during the study.</div>\n<div>\n 7 To estimate the tolerability, toxicity, and efficacy of an ampho B-based regimen in the setting of non-U.S. sites for the purposes of planning additional studies.</div>\n<div>\n 8 To assess the relationship of antifungal drug susceptibility of cryptococcal isolates to fluconazole and microbiological and clinical outcomes.</div>\n<div>\n 9 To assess the pharmacology [pharmacokinetics (PK), pharmacodynamics (PD)], and toxicity of high-dose fluconazole and, if samples are available, relationships with concomitant RIF and/or efavirenz (EFV) (see section 10.1 for specific pharmacology objectives].</div>\n<div>\n  </div>\n<div>\n Exploratory Objectives</div>\n<div>\n 1 To assess the relationship of antifungal drug susceptibility of cryptococcal isolates to fluconazole and microbiological and clinical outcomes.</div>\n<div>\n 2 To assess the pharmacology [pharmacokinetics (PK), pharmacodynamics (PD)], and toxicity of high-dose fluconazole and, if samples are available, relationships with concomitant RIF and/or efavirenz (EFV) (see section 10.1 for specific pharmacology objectives].</div>\n<div>\n 3 To evaluate a lateral flow cryptococcal antigen (LFCrAg) detection assay using urine, serum, plasma, and CSF samples from participants with confirmed CM.</div>\n
      • principal_inclusion_criteria<p>\n Inclusion Criteria-Step 1<br />\n 10.3.1.1 Cryptococcal meningitis documented either by a positive CSF cryptococcal culture, a positive CSF India ink preparation, or a positive CSF cryptococcal antigen latex agglutination test within 7 days prior to entry.<br />\n For the Kericho Site, a positive CSF India ink preparation or a positive CSF cryptococcal antigen latex agglutination test performed at the KEMRI/CRC laboratory will be used for eligibility.<br />\n 10.3.1.2 CSF collection for quantitative cryptococcal culture within 72 hours prior to study entry or planned to be performed at study entry.<br />\n 10.3.1.3 HIV-1 infection documentation; For the Kericho Site, HIV-1 infection will be confirmed at screening based upon 2 serial rapid HIV tests that will be done at the KEMRI/WRP CRC Kericho according to MOH guidelines. Volunteers entering the study will have HIV infection re-confirmed by 2 serial ELISA and Western Blot tests consistent with the KEMRI/WRP laboratory algorithm.<br />\n NOTE: HIV infection must be re-confirmed by day 10 of the study, using the standard and approved Kericho laboratory algorithm of 2 serial ELISA followed by a Western Blot. Enrollment procedures and administration of study drugs will only begin after the HIV screening results (2 serial rapid tests) are obtained.<br />\n 10.3.1.4 Men and women age ≥ 18 years.<br />\n 10.3.1.5 Ability to take oral medications.<br />\n NOTE: Administration of fluconazole tablets via nasogastric tube is permitted.<br />\n 10.3.1.6 For patients with a co-morbid complication of HIV, including opportunistic infections, receipt of stable treatment for the co-morbid complication and clinically stable, as judged by the site investigator.<br />\n NOTE: Stable treatment is defined as treatment that has been taken for at least 2 weeks without change in dose or formulation of any of its components.<br />\n 10.3.1.7 For female participants of reproductive potential (defined as girls who have reached menarche or 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 have not undergone surgical sterilization [e.g., hysterectomy, or bilateral oophorectomy or salpingotomy]) a negative serum or urine pregnancy test result must be obtained within 2 days prior to study entry.<br />\n 10.3.1.8 All participants must agree not to participate in the conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization).<br />\n If participating in sexual activity that could lead to pregnancy, all participants must use two forms of contraception (listed below) while on study treatment and for 6 weeks after fluconazole (at any dose greater than a single 150 mg dose) has been discontinued.<br />\n Two of the following contraceptives MUST be used appropriately:<br />\n • Condoms (male or female) with or without a spermicidal agent<br />\n • Diaphragm or cervical cap with spermicide<br />\n • IUD (intrauterine device)<br />\n • Injectable DepoProvera<br />\n • Tubal Ligation<br />\n NOTE: Use of oral hormone-based contraceptives is prohibited while a participant is taking a daily dose of fluconazole that is greater than 200 mg.<br />\n 10.3.1.9 Participants who are not of reproductive potential (defined as women who have been post-menopausal for at least 24 consecutive months, or women who have undergone surgical sterilization [e.g., hysterectomy, or bilateral oophorectomy or salpingotomy]), or men who have documented azoospermia), are eligible without the requirement to use contraception.<br />\n NOTE: Lack of reproductive potential requires written documentation or oral communication from a clinician or clinician’s staff documented in source documents.<br />\n 10.3.1.10 Willingness and ability to adhere to dose schedules and mandatory procedures<br />\n 10.3.1.11 Measured or calculated creatinine clearance of ≥50 mL/min within 3 days prior to study entry obtained at the KEMRI/CRC laboratory.<br />\n The Cockcroft-Gault method will be used to calculate creatinine clearance:<br />\n For men: [(140 - age in years) x (body weight in kg)] ÷ (serum creatinine in mg/dL x 72).<br />\n For women: use the same calculation as for men, then multiply the result by 0.85.<br />\n 10.3.1.12 The following laboratory values within 3 days prior to study entry obtained at the KEMRI/WRP laboratory:<br />\n • aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 5 X the upper limit of normal (ULN)<br />\n • total bilirubin ≤ 2.5 X ULN<br />\n • absolute neutrophil count (ANC) ≥ 750/mm3<br />\n • platelet count ≥ 50,000/mm3<br />\n • hemoglobin ≥ 7.0 g/dL<br />\n 10.3.1.13 Ability and willingness of the participant or next of kin to give informed consent.<br />\n 10.3.1.14 Availability at the site of at least 2 weeks of its standard of care ampho B-based regimen.</p>\n
      • principal_exclusion_criteria<p>\n Exclusion Criteria - Step 1<br />\n 10.3.2.1 Expected survival of ≤ 2 weeks, in the opinion of the site investigator.<br />\n 10.3.2.2 For patients with a co-morbid complication of HIV, anticipated difficulty, in the opinion of the site investigator, in judging response to study treatment as a result of the co-morbid complication or the drugs used to treat it.<br />\n 10.3.2.3 Breast-feeding.<br />\n 10.3.2.4 A prior episode of CM, either as indicated by patient or as noted in patient medical records.<br />\n 10.3.2.5 Use of any of the following drugs, within the time periods described:<br />\n • any ARV within 30 days prior to study entry<br />\n • rifampin within 2 weeks prior to study entry<br />\n • warfarin within 3 days prior to study entry<br />\n • terfenadine or cisapride within 24 hours prior to study entry<br />\n • other drugs known to interact with fluconazole, the co-administration of which may lead to life-threatening side effects, within 10 days prior to study entry as per the current A5225/HiFLAC MOPs.<br />\n • drugs that may decrease the effect of fluconazole, or whose co-administration may increase their own toxicity or decrease their own efficacy, within 24 hours prior to study entry as per the current A5225/HiFLAC MOPs.<br />\n • phenytoin, carbamazepine, cyclosporin A, tacrolimus, sirolimus, astemizole, or long-acting barbiturates within 7 days prior to study entry<br />\n • more than 72 cumulative hours of systemic treatment with any antifungal for any reason within 14 days prior to study entry.<br />\n 10.3.2.6 Suspected or active tuberculosis (TB), even if untreated, for participants screening at the time that a 1200 mg daily fluconazole induction cohort is enrolling. A chest x-ray may be used to confirm suspected tuberculosis, but is not required.<br />\n 10.3.2.7 Known allergy, sensitivity to, or intolerance of fluconazole or other imidazole or triazole compounds, or to ampho B or other components of the standard of care ampho-B based regimen.<br />\n 10.3.2.8 History of clinically significant cardiac disease, in opinion of site investigator, including symptoms of ischemia, coronary artery disease, congestive heart failure, or arrhythmia.<br />\n 10.3.2.9 ECG (electrocardiogram) with QTc interval greater than 450 msec within 7 days prior to study entry.<br />\n 10.3.2.10 History of CNS disorder (excluding mood disorders) or concurrent CNS disorder(s) that, in the opinion of the investigator, would interfere with assessment of efficacy (e.g., ability to perform CSF sampling) such as lymphoma, neurocysticercosis, or toxoplasmosis.<br />\n 10.3.2.11 Receipt of investigational drug therapy within 30 days prior to study entry without prior approval of the A5225/HiFLAC core team.<br />\n 10.3.2.12 Receipt of any of the following for treatment of the current episode of CM:<br />\n • more than 2400 mg of fluconazole cumulative<br />\n • more than 1.5 mg/kg of ampho B cumulative<br />\n • more than 750 mg/kg of flucytosine cumulative<br />\n • more than 72 cumulative hours of any systemic antifungal therapy<br />\n 10.3.2.13 Active drug or alcohol use, dependence, or other conditions that in the opinion of the site investigator would jeopardize the safety of a participant in the study or would render the person unable to comply with the study plan.</p>\n
      • primary_end_points<p>\n The primary efficacy outcome measure is the change in quantitative CSF culture for cryptococcus. During screening or at entry, CSF samples for culture will be collected from all participants. At week 2, CSF samples will again be collected from all participants and will be cultured. Additional CSF samples will be collected and cultured at weeks 4, 6, 8, and 10, until a negative culture following 2 weeks of incubation is obtained. Treatment failure for any participant is defined as a week 10 CSF culture (which is read by or at week 12) that is positive for <em>C. neoformans</em>.</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology1
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other1
      • trial_other_specifyHigh dose finding study
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Please refer to the attached SSA section 1 page 3-5</p>\n
      • other_details_explanation<p>\n N/A</p>\n
      • other_details_regulatory_notapproved<p>\n None</p>\n
      • other_details_regulatory_approved<p>\n 1.KEMRI ERC</p>\n<p>\n 2.WRAIR IRB</p>\n<p>\n  </p>\n
      • other_details_regulatory_rejected<p>\n N/A</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration3Years
      • 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_comparatorAmphotericin B Deoxychola
      • 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_stateNo
      • multiple_countriesYes
      • multiple_member_states6
      • number_of_sites
      • multi_country_listKenya, South Africa, Uganda, Thailand, Zimbabwe, United States
      • data_monitoring_committeeYes
      • total_enrolment_per_site9
      • total_participants_worldwide96
      • 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_patientsNo
      • subjects_vulnerable_populationsNo
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionNo
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameSamwel
      • investigator1_middle_name
      • investigator1_family_nameChirchir
      • investigator1_qualificationBSc Nursing
      • investigator1_professional_addressKenya Medical Research Institute/Walter Reed Project,P.O. BOX 1357,Hospital Road, Kericho, Kenya, 20200
      • investigator1_telephone052 20 36100
      • investigator1_emailsamwel.chirchir@usamru-k.org
      • organisations_transferred_Yes
      • number_participants32
      • notification<p>\n N/A</p>\n
      • approval_date08-02-2013
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted19-05-2020
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reason
      • final_report<table border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"702\">\n <tbody>\n <tr>\n <td style=\"width:702px;height:18px;\">\n <p>\n <strong>Study Status at Close-out:</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:85px;\">\n <p>\n [X] Study was completed</p>\n <p>\n [] Study was started but closed prior to completion</p>\n <p>\n [] Study was not started</p>\n <p>\n [] Study is being transferred to another institution</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:24px;\">\n <p>\n <strong>Summary of research objectives:</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:24px;\">\n <p>\n This was a two-stage, randomized, open-label phase I/II dose escalation and validation study of the safety, tolerability, and therapeutic effect of an induction-consolidation strategy of high-dose fluconazole alone for the treatment of cryptococcal meningitis (CM) in HIV-infected participants in comparison to amphotericin B deoxycholate alone or in combination with 5-fluorocytosine or fluconazole, according to local standard of care.</p>\n <p>\n  </p>\n <p>\n A total of 22 participants were screened and 16 enrolled at Kericho; Of the 16 participants enrolled, 6 died, 2 were withdrawn from the study because of negative cryptococcal cultures, 8 participants completed study visits and currently no participant is on follow up. Accrual to the study was closed on 19 August 2016. A total of 168 participants were enrolled in all the international sites for this study.</p>\n <p style=\"margin-left:.25in;\">\n <strong>Primary Objective</strong></p>\n <ol>\n <li>\n To assess the MTD of fluconazole by comparing the safety and tolerability of induction regimens of 1200, 1600, and 2000 mg/day.</li>\n <li>\n To determine whether the safety and efficacy of high induction-dose fluconazole therapy support development of a phase II/III trial, and, if so, to select the most appropriate fluconazole dose regimen (based on safety and efficacy data from this study) to be evaluated in that trial.</li>\n </ol>\n <p style=\"margin-left:.5in;\">\n <strong>Secondary Objectives</strong></p>\n <ol>\n <li>\n To compare the clinical and fungicidal effects of different induction regimens of fluconazole during induction at weeks 2, 4, 6, 8, and 10. </li>\n <li>\n To assess functional status (prior to onset of current CM illness, at study entry, at week 10, and at premature treatment or study discontinuation) and to assess neurological status [at entry, weeks 2, 10, 24, and at progression of symptoms and premature treatment or study discontinuation]. </li>\n <li>\n To assess the time to death in each cohort and the combined rates of DLT (Dose limiting toxicities) and death.</li>\n <li>\n To describe the effect of baseline clinical, neurological, and mycological characteristics on clinical and mycological success at week 10 and on time to CSF sterility.</li>\n <li>\n To assess the length of hospitalization between study entry and hospital discharge and for any subsequent readmission for the treatment of CM.</li>\n <li>\n To assess the incidence of progression of symptoms and its components among all participants receiving ART during the study. </li>\n <li>\n To estimate the tolerability, toxicity, and efficacy of an ampho B-based regimen in the setting of non-U.S. sites for the purposes of planning additional studies.</li>\n </ol>\n <p style=\"margin-left:.25in;\">\n <strong>Exploratory Objectives</strong></p>\n <ol>\n <li>\n To assess the relationship of antifungal drug susceptibility of cryptococcal isolates to fluconazole and microbiological and clinical outcomes.</li>\n <li>\n To assess the pharmacology [pharmacokinetics (PK), pharmacodynamics (PD)], and toxicity of high-dose fluconazole and, if samples are available, relationships with concomitant RIF and/or efavirenz (EFV) (see section 10.1 for specific pharmacology objectives].</li>\n <li>\n To evaluate a lateral flow cryptococcal antigen (LFCrAg) detection assay using urine, serum, plasma, and CSF samples from participants with confirmed CM.</li>\n </ol>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:46px;\">\n <p>\n <strong>F. Summary of Study Results: </strong>Please summarize the results of this research project, even if only for the study cohort enrolled locally.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:35px;\">\n <p>\n  In stage 1 of the study, HIV-infected participants with CM were assigned to receive one of the 3 induction doses of fluconazole alone: 1200, 1600, or 2000 mg/day or IV amphotericin B. These regimens were tested sequentially in stage 1 so that safety could be assessed at each level before the decision was made to expose new participants to the next higher dose. The 1200 mg fluconazole arm showed evidence of inferior efficacy compared to the amphotericin control arm. Fluconazole was tolerated up to 2000 mg/day. There were no clear differences in safety or efficacy of either the 1600 mg or 2000 mg fluconazole arms compared to the amphotericin control arm.</p>\n <p>\n  </p>\n <p>\n In stage 2 of the study, the induction doses of fluconazole that were found to be safe in Stage 1 (1600 mg/day and 2000 mg/day) and IV amphotericin were tested in simultaneously enrolled cohorts. Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day fluconazole for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than Amphotericin B. The WHO recommended 1200mg fluconazole was associated with a high mortality. While not statistically significant, mortality was numerically lower in the amphotericin B compared to 1600mg and 2000mg fluconazole.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:41px;\">\n <p>\n <strong>G. List Outputs arising from study e.g. Manuscripts, Thesis, Research Reports, Technical Briefs, Policy Briefs, Abstracts, Patents, Book Chapter etc. (attach copies of the outputs(s). </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:48px;\">\n <ol style=\"list-style-type:lower-alpha;\">\n <li>\n A5225 Manuscript: Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)-report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group</li>\n </ol>\n <p>\n  </p>\n <ol style=\"list-style-type:lower-alpha;\">\n <li value=\"2\">\n A5225 Oral Abstract presented at the CROI Conference on March 4-7, 2018 at Boston Massachusetts, - Higher High Dose Fluconazole for the Treatment of Cryptococcal Meningitis.</li>\n </ol>\n <p>\n  </p>\n <ol style=\"list-style-type:lower-alpha;\">\n <li value=\"3\">\n Poster presented at the 9th International Conference on Cryptococcus and Cryptococcosis (9th ICCC) in 2014. High-dose fluconazole for the treatment of Cryptococcal meningitis in HIV-infected individuals.</li>\n </ol>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:14px;\">\n <ol style=\"list-style-type:upper-alpha;\">\n <li value=\"8\">\n <strong>Confirm destruction of each study participant’s identifiers and provide an assurance/evidence that the destruction has occurred (send copies of the blacked-out books). </strong></li>\n </ol>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:31px;\">\n <p>\n Study documents have been transferred to a safe, secured, long-term archive room that is only accessible to regulatory personnel. All other research staff do not have access to this archive room. Access to study documents is controlled and restricted and the site is responsible for ensuring that any access is accurately recorded and any documents accessed/removed and returned are recorded. Destruction approval will be obtained from the sponsor and the IRBs will be notified when this is done.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>I. Detail the plan for future use of data from the study (if applicable) </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:33px;\">\n <ul style=\"list-style-type:circle;\">\n <li>\n There are currently no plans for future analysis of individual participant data by study site personnel. Analysis of aggregated data and publication for secondary objectives will continue.</li>\n </ul>\n <p style=\"margin-left:.5in;\">\n  </p>\n <ul style=\"list-style-type:circle;\">\n <li>\n Any plans for future (non-aggregated) analyses will be reviewed and approved by KEMRI SERU prior to the work being completed.</li>\n </ul>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>J. Confirm destruction of surplus investigational agents and provide an assurance/evidence that the destruction has occurred (if applicable) </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:25px;\">\n <table border=\"1\" cellpadding=\"0\" cellspacing=\"0\">\n <tbody>\n <tr>\n <td style=\"width:646px;height:18px;\">\n <p>\n Find attached destruction documents.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:646px;height:4px;\">\n <p>\n  </p>\n </td>\n </tr>\n </tbody>\n </table>\n <p>\n  </p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>K. Detail the plan for the destruction, storage, or future use of biological specimens obtained as part of this study (include number of samples being destroyed or stored) </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:42px;\">\n <p style=\"margin-left:.25pt;\">\n All work for this study is complete and the samples that were not for safety testing were all shipped out with the approval of KEMRI ERC for analysis. Future use of individually coded data will have to be approved by the IRB. Participants were informed through the informed consent forms that they signed, that the stored samples may be shipped out of the country and used for future ACTG -approved HIV related research, which will help understand Cryptococcal Meningitis/HIV better. The participants were also made aware that any use of the samples and stored data whether locally or out of the country will have to be approved by Kenya Medical Research Institute Ethical Review Committee.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>L. Were the study results communicated to the local community? If yes provide details where and when- if not kindly explain why not.</strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:27px;\">\n <p>\n The study results have been communicated to the local community through continuous medical education and meeting with the community Advisory Board as well as meetings organized in the community.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;\">\n <p>\n <strong>M. Is there a policy implication or best practice that should be forwarded to the MOH or any relevant authority?  </strong></p>\n </td>\n </tr>\n <tr>\n <td style=\"width:702px;height:47px;\">\n <p>\n Yes, from the Publication:</p>\n <ul style=\"list-style-type:circle;\">\n <li>\n The WHO recommends high dose 1200 mg fluconazole (FLU) if amphotericin B (AmB) is not available or not feasible to use in persons with AIDS associated cryptococcal meningitis (CM) in resource limited settings. The safety and efficacy of high dose (1200-2000mg/d) oral FLU for the initial treatment of AIDS-associated CM in an AmB-controlled 2-stage dose escalation study is recommended.</li>\n </ul>\n <p>\n  </p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • implication_results<p>\n Yes, from the Publication:</p>\n<ul style=\"list-style-type:circle;\">\n <li>\n The WHO recommends high dose 1200 mg fluconazole (FLU) if amphotericin B (AmB) is not available or not feasible to use in persons with AIDS associated cryptococcal meningitis (CM) in resource limited settings. The safety and efficacy of high dose (1200-2000mg/d) oral FLU for the initial treatment of AIDS-associated CM in an AmB-controlled 2-stage dose escalation study is recommended.</li>\n</ul>\n
      • quantity_imported38
      • quantity_dispensed38
      • quantity_destroyed0
      • quantity_exported0
      • balance_site0
      • final_date0000-00-00
      • modified2023-04-13 12:52:59
      • created2013-06-05 11:09:19
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id91
        • application_id148
        • given_nameDeborah
        • middle_nameChepngeno
        • family_namelangat
        • qualificationMBChB, MSc
        • professional_addressKenya Medical Research Institute/Walter Reed Project,P.O. BOX 1357,Hospital Road, Kericho, Kenya, 20200
        • telephone052 20 36100
        • emaildeborah.langat@usamru-k.org
        • created2013-06-05 11:12:27
        • modified2020-05-19 15:02:31
    • SiteDetail(array)
      • 0(array)
        • id113
        • application_id148
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2013-06-05 11:12:27
        • modified2020-05-19 15:02:31
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id72
        • application_id148
        • sponsorThe National Institute of Allergy and Infectious Diseases
        • sponsor_typeResearch Institution
        • contact_person
        • addressHIV Research Branch TRP, DAIDS, NIAID, NIH 6700B Rockledge Drive Bethesda, MD 20892
        • telephone_number+1-301- 451-2761
        • fax_number
        • cell_number+1-301- 451-2761
        • email_addressactg.user.support@fstrf.org
        • created2013-06-05 11:12:27
        • modified2020-05-19 15:02:31
  • 4(array)
    • Application(array)
      • id820
      • user_id43
      • trial_status_id7
      • abstract_of_study<table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:624px;\" width=\"0\">\n <tbody>\n <tr>\n <td style=\"width:199px;\">\n <p>\n <strong>Phase of Study:</strong></p>\n </td>\n <td style=\"width:444px;\">\n <p>\n Phase II</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:199px;\">\n <p>\n <strong>Participating Institutions:</strong></p>\n </td>\n <td style=\"width:444px;\">\n <p>\n This protocol will be open to all AMC international member sites in sub-Saharan Africa. Participating institutions will also be required to complete Celgene’s pregnancy prevention counseling training before activating this trial.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:199px;\">\n <p>\n <strong>Accrual Target:</strong></p>\n </td>\n <td style=\"width:444px;\">\n <p>\n 30 participants</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:199px;\">\n <p>\n <strong>Population:</strong></p>\n </td>\n <td style=\"width:444px;\">\n <p>\n Participants with KS and HIV infection.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:199px;\">\n <p>\n <strong>Regimen:</strong></p>\n </td>\n <td style=\"width:444px;\">\n <p>\n Each cycle of treatment includes administration of 21 doses of pomalidomide during a 4-week period, administered on Days 1-21 of a 28-day cycle.</p>\n <p>\n Eligible participants will begin pomalidomide therapy at Dose Level 1, 4 mg/day on Days 1-21 of each 28-day cycle.</p>\n <p>\n Dose level -1, 3 mg/day on Days 1-21 of each 28-day cycle, is provided for participants entered on Dose Level 1 who require dose reduction.</p>\n <p>\n Safety and the need for dose reduction will be continuously monitored by the protocol team.</p>\n <p>\n Antitumor effects will be assessed immediately prior to the start of each 28-day treatment cycle in all participants and every 12 weeks after completion of pomalidomide therapy in participants showing complete or partial response.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:199px;\">\n <p>\n <strong>Duration:</strong></p>\n </td>\n <td style=\"width:444px;\">\n <p>\n The maximum duration of treatment is 12, 4-week cycles.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:199px;\">\n <p>\n <strong>Primary Objective:</strong></p>\n </td>\n <td style=\"width:444px;\">\n <p>\n To determine if pomalidomide monotherapy induces a minimal level of antitumor efficacy to justify its further development for HIV-associated KS in sub-Saharan Africa and is safe and tolerable.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:199px;\">\n <p>\n <strong>Secondary Objectives:</strong></p>\n </td>\n <td style=\"width:444px;\">\n <p>\n To evaluate the effects of pomalidomide monotherapy on standard measures of HIV control, i.e., CD4 counts and HIV viral loads, in this participant population.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:199px;\">\n <p>\n <strong>Exploratory Objectives:</strong></p>\n </td>\n <td style=\"width:444px;\">\n <ol>\n <li>\n To assess the effect of pomalidomide treatment on serum cytokine levels.</li>\n <li>\n To evaluate if changes in serum cytokine levels correlate with clinical response.</li>\n </ol>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • study_title<p align=\"center\">\n <strong>A Phase II Multicenter Study of Pomalidomide Monotherapy in HIV-Positive Individuals with Kaposi Sarcoma (KS) in Sub-Saharan Africa (SSA)</strong></p>\n
      • laymans_summary<p>\n This is a Phase II Multicenter Study of Pomalidomide Monotherapy in HIV-Positive Individuals with Kaposi Sarcoma (KS) in Sub-Saharan Africa (SSA). The study objective is to determine if pomalidomide monotherapy induces an antitumor efficacy and whether it is safe and tolerable, in order to justify its further development for treatment of HIV-associated KS in sub-Saharan Africa.</p>\n
      • short_titleAMC-100
      • protocol_noECCT/19/10/02
      • version_no5
      • date_of_protocol07-05-2019
      • study_drugPomalidomide
      • disease_conditionKaposis Sarcoma
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
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      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_namePomalidomide
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressamckenya@yahoo.com
      • applicant_covering_letter1
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      • declaration_applicantDR. EVANGELINE NJIRU
      • declaration_date123-08-2019
      • declaration_principal_investigatorDR. NAFTALI BUSAKHALA
      • declaration_date223-08-2019
      • placebo_presentNo
      • study_objectives<p>\n Primary Objective</p>\n<p>\n To determine if pomalidomide monotherapy induces a minimal level of antitumor efficacy to justify its further development for HIV-associated KS in sub-Saharan Africa and is safe and tolerable.</p>\n<p>\n Secondary Objective</p>\n<ol>\n <li>\n To evaluate the effects of pomalidomide monotherapy on CD4 counts and HIV viral loads in this participant population.</li>\n <li>\n To assess the effect of pomalidomide treatment on serum cytokine levels.</li>\n <li>\n To evaluate if changes in serum cytokine levels correlate with clinical response.</li>\n</ol>\n
      • principal_inclusion_criteria<h2>\n Eligibility Criteria</h2>\n<ol>\n <li>\n Participants must have measurable cutaneous KS that has been pathologically confirmed by an AMC-approved pathologist.</li>\n <li>\n Participants may not show evidence for ongoing improvement in KS lesions in the 4 weeks prior to enrollment.</li>\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 Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of Pomalidomide in participants <18 years of age, children are excluded from this study.</li>\n <li>\n Eastern Cooperative Oncology Group (ECOG) performance status <u><</u> 2 (Karnofsky Performance Status (KPS) <u>></u> 50.</li>\n <li>\n Life expectancy ≥ 12 weeks.</li>\n <li>\n Participants must have organ and marrow function within the following parameters, unsupported by hematopoietic growth factors within 7 days prior to enrollment:</li>\n</ol>\n<ul>\n <li>\n Hemoglobin ≥ 8 g/dL</li>\n <li>\n Absolute neutrophil count (ANC): ≥ 1,000 cells/mm³ (1.0 x 10⁹/L)</li>\n <li>\n Platelets: ≥ 75,000 cells/mm³ (75.0 x 10⁹/L)</li>\n <li>\n Total bilirubin: £ 1.5 times the upper limit of normal (ULN), unless the participant is receiving an antiretroviral drug known to be associated with increased bilirubin, in which case the direct fraction should be £ 2 times the ULN.</li>\n <li>\n Serum AST (SGOT) / ALT (SGPT): £ 2.5 x ULN</li>\n <li>\n Estimated or measured creatinine clearance ≥ 60 mL/minute (1.00 mL/s) (serum creatinine £ 2.0 mg/dL / 176.8 mmol/L)</li>\n</ul>\n<p>\n         8. Currently receiving local standard of care ART for ≥ 12 weeks, with HIV viral load ≤ 400 copies/mL within the preceding 12 weeks prior to enrollment.</p>\n<p>\n             Participants are required to be on antiretroviral regimens that are in accordance with the current International AIDS Society guidelines concurrently with    chemotherapy. Excepting agents containing zidovudine, which is prohibited, the specific agents are at the discretion of the Investigator and the use of investigational ART agents currently available on an expanded access basis is allowed.</p>\n<p>\n        9.  A FCBP is a female who has achieved menarche at some point, is < 60 years of age, and who meets one of the following criteria:</p>\n<p>\n             i) has not undergone a hysterectomy or bilateral oophorectomy, or</p>\n<p>\n             ii) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months     (i.e.,         has had menses at any time in the preceding 24 consecutive months), or</p>\n<p>\n             iii) does not have a serum or plasma FSH >40 mIU/mL and a history of amenorrhea x ≥ 1 year</p>\n<p>\n FCBP must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 14 days prior to enrollment and again within 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or, if complete abstinence cannot be assured, they must begin TWO acceptable methods of birth control, including one of the following highly effective, long-acting methods, DepoProvera, an intrauterine device (IUD), an implant*, or bilateral tubal ligation, if it can be verified that the procedure was performed, and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide. FCBP must also agree to ongoing pregnancy testing.</p>\n<p style=\"margin-left:81.0pt;\">\n <strong>* NOTE:</strong> Implants containing levonorgestrel and etonogestrel are prohibited in women receiving efavirenz, as drug interactions will render the implants ineffective.</p>\n<p>\n Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy.</p>\n<p>\n All participants must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Serum or urine pregnancy testing will be repeated in FCBP, and must be negative, within 24 hours of starting each new cycle of pomalidomide.</p>\n<p>\n 10. Able to take aspirin (≥ 75 mg) daily as prophylactic anticoagulation.</p>\n<p>\n 11.  Ability to understand and the willingness to sign a written informed consent document.</p>\n<p>\n  </p>\n
      • principal_exclusion_criteria<h2>\n Exclusion Criteria</h2>\n<p>\n 1.         Participants who are receiving any other investigational agents (except as permitted by the study).</p>\n<p>\n 2.         Any prior use of thalidomide, lenalidomide, or pomalidomide.</p>\n<p>\n 3.         History of allergic reactions attributed to compounds of similar chemical or biologic composition to pomalidomide.</p>\n<p>\n 4.         Participants who have visceral disease requiring cytotoxic chemotherapy (i.e., pulmonary KS, symptomatic gastrointestinal KS). KS-related lymphedema is permitted.</p>\n<p>\n 5.         Use of agents containing zidovudine (including Combivir^® and Trizivir^®) are prohibited. In order to be eligible, participants taking zidovudine must change to a different regimen at least 7 days prior to therapy initiation. Changes to ART therapy during the study may be made if medically necessary (toxicity, failure of regimen, etc.).</p>\n<p>\n Use of medications or substances that are strong inhibitors of CYP1A2, which include amiodarone, cimetidine, fluoroquinolones (e.g., ciprofloxacin, enoxacin), fluvoxamine, and ticlopidine is prohibited.</p>\n<p>\n Co-administration of efavirenz, an inhibitor of CYP1A2, with strong inhibitors of CYP3A4 and P-glycoprotein (P-gp) is prohibited. Use of erythropoietin is prohibited.</p>\n<p>\n Co-administration of corticosteroids greater than doses required for treatment of adrenal insufficiency is prohibited.</p>\n<p>\n Because the lists of these agents are constantly changing, it is important to regularly consult frequently updated medical references.</p>\n<p>\n 6.         Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection for which the participant has not completed at least 14 days of therapy prior to study enrollment and/or is not clinically stable; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements.</p>\n<p style=\"margin-left:1.0in;\">\n 7.         Pregnant women are excluded from this study because pomalidomide is a thalidomide analogue with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pomalidomide, breastfeeding should be discontinued if the mother is treated with pomalidomide.</p>\n<p>\n 8.         Specific KS therapy, including cytotoxic chemotherapy but not including ART, within the past 4 weeks.</p>\n<p>\n 9.         Use of other anticancer treatments or agents within the past 4 weeks.</p>\n<p>\n 10.       History of malignant tumors other than KS, unless:</p>\n<ul>\n <li>\n In complete remission for ≥ 1 year, or</li>\n <li>\n Completely resected basal cell carcinoma, or</li>\n <li>\n In situ squamous cell carcinoma of the cervix or anus.</li>\n</ul>\n<p>\n 11.       Grade ≥ 3 peripheral neuropathy.</p>\n<p>\n 12.       History of myocardial infarction (MI), cerebrovascular accident, or venous or arterial thromboembolism, unless line-related thrombosis without embolus occurring greater than 1 year prior to study entry.</p>\n<p>\n 13.       Known procoagulant disorder including prothrombin gene mutation 20210, antithrombin III deficiency, protein C deficiency, protein S deficiency and antiphospholipid syndrome but not including heterozygosity for the Factor V Leiden mutation or the presence of a lupus anticoagulant in the absence of other criteria for the antiphospholipid syndrome.</p>\n<p>\n 14.       Any condition, including the presence of current laboratory abnormalities or other factor that, in the opinion of the investigator, places the participant at unacceptable risk if they were to participate in the study or confounds the ability to interpret data from the study.</p>\n<p>\n  </p>\n
      • primary_end_points<ul>\n <li>\n Overall response rate</li>\n <li>\n Complete response rate</li>\n <li>\n Proportion of participants who experience toxicities of grade 3 or higher</li>\n</ul>\n
      • scope_diagnosis1
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
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      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory0
      • trial_therapeutic_use0
      • design_controlledNo
      • site_capacity(null)
      • staff_numbers<p style=\"margin-left:5.2pt;\">\n <u>S</u><u>taff</u></p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Naftali Busakhala MBChB, MMed, Principal Investigator</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Evangeline W. Njiru- MBChB, MMed- Investigator</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Gabriel Kigen, B Pharm, Pharmacist of Record</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Job Kisuya, PhD - Site Coordinator</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Seth Kirui, Bsc - Data Manager</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Joyce Musimbi, Bsc - Research Assistant</p>\n<p style=\"margin-left:5.2pt;\">\n  </p>\n<p style=\"margin-left:5.2pt;\">\n David Oduori - Recruitment Officer</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Simon Wachira, B Pharm- Back-up Pharmacist</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n Fred Kiplagat, Dip Pharm- Back-up Pharmaceutical Technologist</p>\n<p>\n  </p>\n<p style=\"margin-left:5.2pt;\">\n <u>S</u><u>ite/Emergency Facilities:</u></p>\n<p>\n  </p>\n<p style=\"margin-left:23.2pt;\">\n ·    AMPATH Program– Has 24 care sites and 34 satellite clinics in North Rift and Western</p>\n<p style=\"margin-left:41.2pt;\">\n Kenya</p>\n<p style=\"margin-left:23.2pt;\">\n ·    AMPATH Oncology Clinic-Has 1 care site and 4 satellite clinics in North Rift and</p>\n<p style=\"margin-left:41.2pt;\">\n Western</p>\n<p style=\"margin-left:23.2pt;\">\n ·    AMPATH Reference Laboratory and MTRH histopathology Laboratory</p>\n<p style=\"margin-left:23.2pt;\">\n ·    Moi Teaching and Referral Hospital (MTRH)- Second largest referral Hospital in Kenya.</p>\n<p>\n  </p>\n
      • other_details_explanation<p>\n Eldoret, Kenya is one of the Africa AMC sites. When protocols are developed by the AMC, sites express interests considering the patient population and relevance of the study. Our site expressed interest and was chosen as a participating site.</p>\n
      • other_details_regulatory_notapproved<p>\n None</p>\n
      • other_details_regulatory_approved<p>\n AUTHORITY: MOI UNIVERSITY INSTITUTIONAL RESEARCH AND ETHICS COMMITTEE</p>\n<p>\n DATE OF APPROVAL : 2019</p>\n
      • other_details_regulatory_rejected<p>\n None</p>\n
      • other_details_regulatory_halted<p>\n None</p>\n
      • estimated_duration60 months
      • design_controlled_randomised
      • design_controlled_open
      • design_controlled_single_blind
      • design_controlled_double_blind
      • design_controlled_parallel_group
      • design_controlled_cross_over
      • design_controlled_other
      • design_controlled_specify
      • design_controlled_comparator
      • design_controlled_other_medicinal
      • design_controlled_placebo
      • design_controlled_medicinal_other
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaMOI UNIVERSITY CLINICAL RESEARCH CENTER
      • single_site_physical_addressCHANDARIA CANCER AND CHRONIC DISEASE CENTRE, NANDI ROAD
      • single_site_contact_personDR. NAFTALI BUSAKHALA
      • single_site_telephone0722496933
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states6
      • number_of_sites
      • multi_country_listKENYA: MOI UNIVERSITY CLINICAL RESEARCH CENTER UGANDA: UGANDA CANCER INSTITUTE ZIMBABWE: UNIVERSITY OF ZIMBABWE SOUTH AFRICA: WITWATERSRAND UNIVERSITY, TANZANIA: BUGANDO MEDICAL CENTER, MALAWI: UNC PROJECT
      • data_monitoring_committeeNo
      • total_enrolment_per_site10
      • total_participants_worldwide30
      • population_less_than_18_yearsNo
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentNo
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyNo
      • subjects_patientsYes
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingNo
      • subjects_women_using_contraceptionYes
      • subjects_pregnant_womenNo
      • subjects_nursing_womenNo
      • subjects_emergency_situationNo
      • subjects_incapable_consentNo
      • subjects_specify
      • subjects_othersNo
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      • investigator1_given_nameEVANGELINE
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      • investigator1_family_nameNJIRU
      • investigator1_qualificationMBCHB, MMED
      • investigator1_professional_address4606
      • investigator1_telephone0722624353
      • investigator1_emailoyungueva@yahoo.com
      • organisations_transferred_No
      • number_participants10
      • notification
      • approval_date01-04-2020
      • submitted1
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      • deleted_date(null)
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      • date_submitted05-03-2020
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      • initial_date_submitted(null)
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      • modified2024-07-18 10:41:25
      • created2019-08-23 16:45:54
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        • telephone0722496933
        • emailnbusakhala@yahoo.com
        • created2019-08-23 20:41:18
        • modified2020-03-05 10:07:02
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        • created2019-08-23 20:41:18
        • modified2020-03-05 10:07:02
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        • sponsorNational Cancer Institute Office of HIV and AIDS Malignancy (OHAM)
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        • address31 Center Drive, Room 3A33 Bethesda, MD, USA 20852-2440
        • telephone_number301-496-4995
        • fax_number
        • cell_number301-496-4995
        • email_addressNCIOHAMContact@mail.nih.gov
        • created2019-08-23 20:41:18
        • modified2020-03-05 10:07:02
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    • 2CORE/Utility/ObjectCollection.php
    • 3CORE/Utility/Debugger.php
    • 4CORE/Utility/String.php
    • 5CORE/Utility/ClassRegistry.php
    • 6CORE/Utility/Set.php
    • 7CORE/Utility/Sanitize.php
  • View(array)
    • 0CORE/View/HelperCollection.php
• app(array)
  • Behavior(array)
    • 0APP/Model/Behavior/SoftDeleteBehavior.php
  • Config(array)
    • 0APP/Config/core.php
    • 1APP/Config/bootstrap.php
    • 2APP/Config/routes.php
    • 3APP/Config/database.php
  • Controller(array)
    • 0APP/Controller/ApplicationsController.php
    • 1APP/Controller/AppController.php
  • Model(array)
    • 0APP/Model/AppModel.php
    • 1APP/Model/Application.php
    • 2APP/Model/User.php
    • 3APP/Model/TrialStatus.php
    • 4APP/Model/InvestigatorContact.php
    • 5APP/Model/Sponsor.php
    • 6APP/Model/SiteDetail.php
    • 7APP/Model/County.php
  • Other(array)
    • 0APP/webroot/index.php
• plugins(array)
  • CakePdf(array)
    • Config(array)
      • 0CakePdf/Config/bootstrap.php
      • 1CakePdf/Config/routes.php
  • CakeResque(array)
    • Config(array)
      • 0CakeResque/Config/bootstrap.php
    • Plugin(array)
      • 0CakeResque/Lib/CakeResque.php
      • 1CakeResque/vendor/kamisama/php-resque-ex/lib/Resque.php
      • 2CakeResque/vendor/kamisama/php-resque-ex/lib/Resque/Event.php
      • 3CakeResque/vendor/kamisama/php-resque-ex/lib/Resque/Exception.php
  • DebugKit(array)
    • Component(array)
      • 0DebugKit/Controller/Component/ToolbarComponent.php
    • Plugin(array)
      • 0DebugKit/Lib/DebugMemory.php
      • 1DebugKit/Lib/Panel/HistoryPanel.php
      • 2DebugKit/Lib/DebugPanel.php
      • 3DebugKit/Lib/Panel/SessionPanel.php
      • 4DebugKit/Lib/Panel/RequestPanel.php
      • 5DebugKit/Lib/Panel/SqlLogPanel.php
      • 6DebugKit/Lib/Panel/TimerPanel.php
      • 7DebugKit/Lib/Panel/LogPanel.php
      • 8DebugKit/Lib/Log/Engine/DebugKitLog.php
      • 9DebugKit/Lib/Panel/VariablesPanel.php
      • 10DebugKit/Lib/Panel/EnvironmentPanel.php
      • 11DebugKit/Lib/Panel/IncludePanel.php
      • 12DebugKit/Lib/DebugTimer.php
  • Media(array)
    • Config(array)
      • 0Media/Config/bootstrap.php
    • Plugin(array)
      • 0Media/Lib/mm/src/Mime/Type.php
      • 1Media/Lib/mm/src/Mime/Type/Magic/Adapter/Fileinfo.php
      • 2Media/Lib/mm/src/Mime/Type/Magic/Adapter.php
      • 3Media/Lib/mm/src/Mime/Type/Glob/Adapter/Memory.php
      • 4Media/Lib/mm/src/Mime/Type/Glob/Adapter.php
      • 5Media/Lib/mm/src/Media/Process.php
      • 6Media/Lib/mm/src/Media/Info.php
  • Search(array)
    • Component(array)
      • 0Search/Controller/Component/PrgComponent.php
    • Behavior(array)
      • 0Search/Model/Behavior/SearchableBehavior.php
  • Shim(array)
    • Config(array)
      • 0Shim/Config/bootstrap.php
  • Tools(array)
    • Config(array)
      • 0Tools/Config/bootstrap.php