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      • id1185
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      • abstract_of_study<div>\n A PHASE IIIB, MULTINATIONAL, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY TO EVALUATE PATIENT PREFERENCE FOR HOME</div>\n<div>\n ADMINISTRATION OF A FIXED-DOSE COMBINATION OF PERTUZUMAB AND TRASTUZUMAB FOR SUBCUTANEOUS ADMINISTRATION IN PARTICIPANTS WITH EARLY OR LOCALLY ADVANCED/ INFLAMMATORY HER2-POSITIVE BREAST CANCER</div>\n<div>\n  </div>\n<div>\n <div>\n PROTOCOL NUMBER: <strong>MO43110</strong></div>\n <div>\n  </div>\n <div>\n VERSION NUMBER: 1</div>\n <div>\n  </div>\n <div>\n TEST COMPOUND(S):</div>\n <ul>\n <li>\n Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous (PH FDC SC)administration</li>\n <li>\n Pertuzumab IV</li>\n <li>\n Trastuzumab IV</li>\n <li>\n Trastuzumab emtansine IV</li>\n </ul>\n <div>\n <u><strong>Objectives and Endpoints</strong></u></div>\n <div>\n  </div>\n <div>\n This study will evaluate the patient-reported preference of PH FDC SC administration in the home setting compared with the hospital setting during the cross-over period of adjuvant treatment in participants with early or locally advanced/inflammatory HER2+ breast cancer.</div>\n <div>\n  </div>\n <div>\n The administration of PH FDC SC in the home setting will be conducted by healthcare professionals (HCPs).</div>\n <div>\n  </div>\n <div>\n Specific primary and secondary objectives and corresponding endpoints for the study are outlined below.</div>\n <div>\n  </div>\n <div>\n Primary Objective </div>\n <ul>\n <li>\n To evaluate patient preference of PH FDC SC administration in the home setting during the cross-over period of the adjuvant phase of the study Corresponding endpoint:  Proportion of participants who preferred the administration of PH FDC SC in the home setting compared with the hospital setting in Question 1 of Patient Preference Questionnaire (PPQ) (Appendix 5)</li>\n </ul>\n <div>\n Secondary Objectives</div>\n <ul>\n <li>\n To evaluate the perception of HCPs of time/resource use and convenience of PH FDC SC compared to pertuzumab IV and trastuzumab IV (P+H IV) during the neoadjuvant phase of the study. Corresponding endpoint: Responses of HCPs to the Healthcare Professional Questionnaire (HCPQ) by individual questions in the neoadjuvant phase (Appendix 6 and Appendix 7)</li>\n <li>\n Collect pathological complete response (pCR) data post-surgery. Corresponding endpoint: Proportion of participants achieving pCR, defined a eradication of invasive disease in the breast and axilla (i.e., ypT0/Tis ypN0), according to local pathologist assessment following the AJCC criteria (FDA 2020)</li>\n <li>\n To evaluate Health-related Quality of Life (HRQoL) during the neoadjuvant phase of the study. Corresponding endpoint: HRQoL assessed by EORTC QLQ-C30 scores in the neoadjuvant phase (Appendix 8)</li>\n <li>\n To evaluate HRQoL with PH FDC SC administered during the adjuvant phase of the study. Corresponding endpoint: HRQoL assessed by EORTC QLQ-C30 scores in the participants treated with PH FDC SC during the adjuvant phase (Appendix 8)</li>\n <li>\n To evaluate the perception of HCPs of time/resource use of PH FDC SC during the adjuvant cross-over period. Corresponding endpoint: Responses of HCPs to the HCPQ by individual questions in the adjuvant cross-over period (Appendix 9 and Appendix 10)</li>\n <li>\n To evaluate HRQoL for participants treated with trastuzumab emtansine IV during the adjuvant phase. Corresponding endpoint: HRQoL assessed by EORTC QLQ-C30 scores in the participants treated with trastuzumab emtansine IV during the adjuvant phase (Appendix 8)</li>\n </ul>\n <div>\n Secondary Safety Objectives </div>\n <ul>\n <li>\n To evaluate the safety and tolerability of PH FDC SC and P+H IV during the neoadjuvant phase of the study. Corresponding endpoint: Incidence, nature and severity of all adverse events (AEs), Grade ≥ 3 AEs, SAEs, and cardiac AEs (including left ventricular ejection fraction [LVEF] events) with severity determined according to National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) v5.0 (Appendix 14 and Appendix 16), Incidence of premature withdrawal from the neoadjuvant treatment with PH FDC SC and P+H IV, Targeted vital signs and physical findings, Targeted clinical laboratory test results</li>\n <li>\n To evaluate the safety and tolerability of PH FDC SC administered in the home setting and hospital setting during the cross-over period and the entire adjuvant treatment period. Corresponding endpoint: Incidence, nature and severity of all AEs, Grade ≥ 3 AEs, SAEs and cardiac AEs (including LVEF events) with severity determined according to NCI CTCAE v5.0 (Appendix 14 and Appendix 16), Incidence of premature withdrawal from the adjuvant treatment with PH FDC SC, Targeted vital signs and physical findings, Targeted clinical laboratory test results</li>\n <li>\n To evaluate the safety and tolerability of trastuzumab emtansine IV during the adjuvant phase of the study. Corresponding endpoint: Incidence, nature and severity of all AEs Grade ≥ 3 AEs, SAEs and cardiac AEs (including LVEF events) with severity determined according to NCI CTCAE v5.0 (Appendix 14 and Appendix 16), Incidence of premature withdrawal from the treatment with trastuzumab emtansine IV, Targeted vital signs and physical findings, Targeted clinical laboratory test results</li>\n </ul>\n</div>\n<p>\n <u><strong>Study Design</strong></u></p>\n<div>\n This is a phase IIIb, multinational, multicenter, randomized, open-label study to evaluate the patient preference of PH FDC SC administration in the home setting compared with the hospital setting during the cross-over period of adjuvant treatment in participants with early or locally advanced/inflammatory HER2+ breast cancer.</div>\n<div>\n  </div>\n<div>\n This study will consist of two phases.</div>\n<ul>\n <li>\n During the neoadjuvant phase, participants will be randomized in a 1:2 ratio to receive treatment in the hospital with either P+H IV plus chemotherapy (Arm A) or PH FDC SC plus chemotherapy (Arm B). Participants in both cohorts are scheduled to undergo surgery after the completion of neoadjuvant therapy. This could be after 6 or 8 cycles depending on the chosen neoadjuvant scheme. After surgery, local pathologists interpreting surgical specimens will determine whether pCR has been achieved following the AJCC criteria (FDA 2020).</li>\n <li>\n During the adjuvant phase, participants who achieve pCR after surgery will be treated with 2 cycles of PH FDC SC in the hospital. Then, participants will be randomized in a 1:1 ratio to two treatment arms in a cross-over manner, Arm C (3 cycles of PH FDC SC treatment in the hospital followed by another 3 cycles of PH FDC SC treatment in the home setting) and Arm D (3 cycles of PH FDC SC in the home setting followed by 3 cycles of PH FDC SC in the hospital). To complete a total of 18 cycles of treatment with pertuzumab and trastuzumab in the (neo)adjuvant setting, the last cycles of PH FDC SC will be administered in the hospital or in the home setting, as selected by the participant at the end of cross-over period. Participants can request to change from home administration to hospital administration (and vice-versa) during the treatment continuation period, but not during the treatment cross-over period. Participants with pathological evidence of residual invasive carcinoma in the breast or axillary lymph nodes following completion of preoperative therapy and surgery will be treated with trastuzumab emtansine for 14 cycles (Arm E). Trastuzumab emtansine will be administered IV in the hospital as per prescribing information.</li>\n</ul>\n
      • study_title<div>\n A PHASE IIIB, MULTINATIONAL, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY TO EVALUATE PATIENT PREFERENCE FOR HOME ADMINISTRATION OF FIXED-DOSE COMBINATION OF PERTUZUMAB AND TRASTUZUMAB FOR SUBCUTANEOUS ADMINISTRATION IN PARTICIPANTS WITH EARLY OR LOCALLY ADVANCED/ INFLAMMATORY HER2-POSITIVE BREAST CANCER</div>\n
      • laymans_summary<div>\n <p>\n <u><strong>RATIONALE</strong></u></p>\n</div>\n<div>\n The purpose of this study is to evaluate the patient-reported preference for the pertuzumab and trastuzumab (PH) fixed-dose combination (FDC) for subcutaneous (SC) administration (PH FDC SC) in the home setting compared with the hospital setting in participants with early or locally advanced/inflammatory human epidermal growth factor receptor 2-positive (HER2+) breast cancer.</div>\n<div>\n  </div>\n<div>\n The SC delivery of biotherapeutics is well-established as a route of administration that is effective and well-tolerated across many therapeutic areas (Collins et al. 2020). It can offer several advantages over intravenous (IV) administration, including the convenience of self-administration, improved patient experience, reduced treatment burden and lower healthcare costs.</div>\n<div>\n  </div>\n<div>\n Moreover, the reduction in hospital time of the patient will reduce the patient's exposure to nosocomial pathogens and reduce the burden on healthcare systems.</div>\n<div>\n  </div>\n<div>\n <div>\n This study will evaluate the patient-reported preference for PH FDC SC administration in the home setting compared with the hospital setting during the cross-over period of adjuvant treatment in participants with early or locally advanced/inflammatory HER2+ breast cancer.</div>\n <div>\n  </div>\n <div>\n The administration of PH FDC SC in the home setting will be conducted by healthcare professionals (HCPs).</div>\n</div>\n<p>\n  </p>\n
      • short_titlePROHER
      • protocol_noECCT/23/01/01
      • version_no1
      • date_of_protocol02-02-2022
      • study_drugFixed-dose combination of pertuzumab and trastuzumab for subcutaneous (PH FDC SC) administration Pertuzumab IV Trastuzumab IV Trastuzumab emtansine IV
      • disease_conditionHER2-POSITIVE BREAST CANCER
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals1
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorYes
      • comparator_namePertuzumab, Trastuzumab, Trastuzumab emtansine
      • comparator_registeredNO
      • comparator_countriesThe products have been submitted for registration in Kenya.
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressfaith.wanjau@roche.con
      • 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_applicantFaith Wanjau
      • declaration_date107-11-2022
      • declaration_principal_investigatorFredrick Chite Asirwa
      • declaration_date207-11-2022
      • placebo_presentNo
      • study_objectives<div>\n <u><strong>Objectives and Endpoints</strong></u></div>\n<div>\n  </div>\n<div>\n This study will evaluate the patient-reported preference of PH FDC SC administration in the home setting compared with the hospital setting during the cross-over period of adjuvant treatment in participants with early or locally advanced/inflammatory HER2+ breast cancer.</div>\n<div>\n  </div>\n<div>\n The administration of PH FDC SC in the home setting will be conducted by healthcare professionals (HCPs).</div>\n<div>\n  </div>\n<div>\n Specific primary and secondary objectives and corresponding endpoints for the study are outlined below.</div>\n<div>\n  </div>\n<div>\n Primary Objective Corresponding Endpoint</div>\n<ul>\n <li>\n To evaluate patient preference of PH FDC SC administration in the home setting during the cross-over period of the adjuvant phase of the study</li>\n <li>\n Corresponding endpoint:  Proportion of participants who preferred the administration of PH FDC SC in the home setting compared with the hospital setting in Question 1 of Patient Preference Questionnaire (PPQ) (Appendix 5)</li>\n</ul>\n<div>\n Secondary Objectives</div>\n<ul>\n <li>\n To evaluate the perception of HCPs of time/resource use and convenience of PH FDC SC compared to pertuzumab IV and trastuzumab IV (P+H IV) during the neoadjuvant phase of the study. Corresponding endpoint: Responses of HCPs to the Healthcare Professional Questionnaire (HCPQ) by individual questions in the neoadjuvant phase (Appendix 6 and Appendix 7)</li>\n <li>\n Collect pathological complete response (pCR) data post-surgery. Corresponding endpoint: Proportion of participants achieving pCR, defined a eradication of invasive disease in the breast and axilla (i.e., ypT0/Tis ypN0), according to local pathologist assessment following the AJCC criteria (FDA 2020)</li>\n <li>\n To evaluate Health-related Quality of Life (HRQoL) during the neoadjuvant phase of the study. Corresponding endpoint: HRQoL assessed by EORTC QLQ-C30 scores in the neoadjuvant phase (Appendix 8)</li>\n <li>\n To evaluate HRQoL with PH FDC SC administered during the adjuvant phase of the study. Corresponding endpoint: HRQoL assessed by EORTC QLQ-C30 scores in the participants treated with PH FDC SC during the adjuvant phase (Appendix 8)</li>\n <li>\n To evaluate the perception of HCPs of time/resource use of PH FDC SC during the adjuvant cross-over period. Corresponding endpoint: Responses of HCPs to the HCPQ by individual questions in the adjuvant cross-over period (Appendix 9 and Appendix 10)</li>\n <li>\n To evaluate HRQoL for participants treated with trastuzumab emtansine IV during the adjuvant phase. Corresponding endpoint: HRQoL assessed by EORTC QLQ-C30 scores in the participants treated with trastuzumab emtansine IV during the adjuvant phase (Appendix 8)</li>\n</ul>\n<div>\n Secondary Safety Objectives </div>\n<ul>\n <li>\n To evaluate the safety and tolerability of PH FDC SC and P+H IV during the neoadjuvant phase of the study. Corresponding endpoint: Incidence, nature and severity of all adverse events (AEs), Grade ≥ 3 AEs, SAEs, and cardiac AEs (including left ventricular ejection fraction [LVEF] events) with severity determined according to National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) v5.0 (Appendix 14 and Appendix 16), Incidence of premature withdrawal from the neoadjuvant treatment with PH FDC SC and P+H IV, Targeted vital signs and physical findings, Targeted clinical laboratory test results</li>\n <li>\n To evaluate the safety and tolerability of PH FDC SC administered in the home setting and hospital setting during the cross-over period and the entire adjuvant treatment period. Corresponding endpoint: Incidence, nature and severity of all AEs, Grade ≥ 3 AEs, SAEs and cardiac AEs (including LVEF events) with severity determined according to NCI CTCAE v5.0 (Appendix 14 and Appendix 16), Incidence of premature withdrawal from the adjuvant treatment with PH FDC SC, Targeted vital signs and physical findings, Targeted clinical laboratory test results</li>\n <li>\n To evaluate the safety and tolerability of trastuzumab emtansine IV during the adjuvant phase of the study. Corresponding endpoint: Incidence, nature and severity of all AEs Grade ≥ 3 AEs, SAEs and cardiac AEs (including LVEF events) with severity determined according to NCI CTCAE v5.0 (Appendix 14 and Appendix 16), Incidence of premature withdrawal from the treatment with trastuzumab emtansine IV, Targeted vital signs and physical findings, Targeted clinical laboratory test results</li>\n</ul>\n
      • principal_inclusion_criteria<div>\n Inclusion Criteria:</div>\n<div>\n  </div>\n<div>\n Disease-specific criteria:</div>\n<ul>\n <li>\n Female or male with histologically confirmed, HER2-positive (HER2+) inflammatory, locally advanced or early-stage breast cancer who have received neoadjuvant pertuzumab and trastuzumab and have completed neoadjuvant chemotherapy and subsequently undergone surgery for their breast cancer.</li>\n <li>\n HER2+ breast cancer assessed at the local laboratory prior to initiation of neoadjuvant therapy. HER2+ status must be determined based on breast biopsy material obtained prior to neoadjuvant treatment and is defined as 3+ by immunohistochemistry (IHC) and/or positive by HER2 amplification by in situ hybridization (ISH) with a ratio of ≥2 for the number of HER2 gene copies to the number of chromosome 17 copies.</li>\n <li>\n Hormone receptor status of the primary tumour determined by local assessment. Hormone receptor status may be either positive or negative.</li>\n <li>\n Completed all neoadjuvant chemotherapy and surgery. Adjuvant radiotherapy may be planned or ongoing at study entry and adjuvant hormone therapy is allowed during the study. Note that study treatment cannot be initiated within <2 weeks of surgery but must be initiated ≤9 weeks from the last administration of systemic neoadjuvant therapy.</li>\n <li>\n No evidence of residual, locally recurrent or metastatic disease after completion of surgery. Patients with clinical suspicion of metastases must undergo radiological assessments per institutional practice to rule out distant disease.</li>\n <li>\n Wound healing after breast cancer surgery adequate per investigator's assessment to allow initiation of study treatment within ≤9 weeks of last systemic neoadjuvant therapy</li>\n <li>\n No adjuvant chemotherapy planned. Note that adjuvant hormonal treatment is allowed during the study.</li>\n</ul>\n<div>\n <u><strong>General criteria:</strong></u></div>\n<ul>\n <li>\n Ability to comply with the study protocol, in the investigator's judgment</li>\n <li>\n Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1</li>\n <li>\n Intact skin at planned site of subcutaneous injections (thigh)</li>\n <li>\n Left ventricular ejection fraction (LVEF) ≥55% measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within 28 days of study randomization</li>\n <li>\n No major surgical procedure unrelated to breast cancer within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment</li>\n <li>\n For women of childbearing potential: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating eggs, Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of <1% per year, or two effective non-hormonal contraceptive methods during the study treatment periods and for 7 months after the last dose of study treatment</li>\n <li>\n For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, men must remain abstinent or use a condom during the study treatment periods and for seven months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period</li>\n <li>\n A negative serum pregnancy test must be available prior to randomization for women of childbearing potential</li>\n</ul>\n
      • principal_exclusion_criteria<div>\n Exclusion Criteria:</div>\n<div>\n  </div>\n<div>\n Cancer-specific criteria:</div>\n<ul>\n <li>\n Stage IV (metastatic) breast cancer</li>\n <li>\n Current or prior history of active malignancy within the last five years. Appropriately treated non-melanoma skin cancer; in situ carcinomas, including cervix, colon, or skin; or Stage I uterine cancer within the last five years are allowed</li>\n <li>\n Previous systemic therapy for treatment or prevention of breast cancer, except neoadjuvant Perjeta, Herceptin and chemotherapy for current breast cancer</li>\n</ul>\n<div>\n General criteria:</div>\n<ul>\n <li>\n Investigational treatment within four weeks of enrolment</li>\n <li>\n Serious cardiac illness or medical conditions</li>\n <li>\n History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome</li>\n <li>\n Inadequate bone marrow, renal and impaired liver function</li>\n <li>\n Current severe, uncontrolled systemic disease that may interfere with planned treatment</li>\n <li>\n Pregnant or breastfeeding, or intending to become pregnant during the study or within seven months after the last dose of study treatment. Women of childbearing potential must have a negative serum pregnancy test result within seven days prior to initiation of study treatment</li>\n <li>\n Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in, and completion of, the study</li>\n <li>\n Known active liver disease, for example, active viral hepatitis infection, autoimmune hepatic disorders, or sclerosing cholangitis</li>\n <li>\n Concurrent, serious, uncontrolled infections, or known infection with human immunodeficiency virus (HIV)</li>\n <li>\n Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins</li>\n <li>\n Current chronic daily treatment with corticosteroids</li>\n</ul>\n
      • primary_end_points<div>\n <u><strong>Objectives and Endpoints</strong></u></div>\n<div>\n  </div>\n<div>\n This study will evaluate the patient-reported preference of PH FDC SC administration in the home setting compared with the hospital setting during the cross-over period of adjuvant treatment in participants with early or locally advanced/inflammatory HER2+ breast cancer.</div>\n<div>\n  </div>\n<div>\n The administration of PH FDC SC in the home setting will be conducted by healthcare professionals (HCPs).</div>\n<div>\n  </div>\n<div>\n Specific primary and secondary objectives and corresponding endpoints for the study are outlined below.</div>\n<div>\n  </div>\n<div>\n Primary Objective Corresponding Endpoint</div>\n<ul>\n <li>\n To evaluate patient preference of PH FDC SC administration in the home setting during the cross-over period of the adjuvant phase of the study</li>\n <li>\n Corresponding endpoint:  Proportion of participants who preferred the administration of PH FDC SC in the home setting compared with the hospital setting in Question 1 of Patient Preference Questionnaire (PPQ) (Appendix 5)</li>\n</ul>\n<div>\n Secondary Objectives</div>\n<ul>\n <li>\n To evaluate the perception of HCPs of time/resource use and convenience of PH FDC SC compared to pertuzumab IV and trastuzumab IV (P+H IV) during the neoadjuvant phase of the study. Corresponding endpoint: Responses of HCPs to the Healthcare Professional Questionnaire (HCPQ) by individual questions in the neoadjuvant phase (Appendix 6 and Appendix 7)</li>\n <li>\n Collect pathological complete response (pCR) data post-surgery. Corresponding endpoint: Proportion of participants achieving pCR, defined a eradication of invasive disease in the breast and axilla (i.e., ypT0/Tis ypN0), according to local pathologist assessment following the AJCC criteria (FDA 2020)</li>\n <li>\n To evaluate Health-related Quality of Life (HRQoL) during the neoadjuvant phase of the study. Corresponding endpoint: HRQoL assessed by EORTC QLQ-C30 scores in the neoadjuvant phase (Appendix 8)</li>\n <li>\n To evaluate HRQoL with PH FDC SC administered during the adjuvant phase of the study. Corresponding endpoint: HRQoL assessed by EORTC QLQ-C30 scores in the participants treated with PH FDC SC during the adjuvant phase (Appendix 8)</li>\n <li>\n To evaluate the perception of HCPs of time/resource use of PH FDC SC during the adjuvant cross-over period. Corresponding endpoint: Responses of HCPs to the HCPQ by individual questions in the adjuvant cross-over period (Appendix 9 and Appendix 10)</li>\n <li>\n To evaluate HRQoL for participants treated with trastuzumab emtansine IV during the adjuvant phase. Corresponding endpoint: HRQoL assessed by EORTC QLQ-C30 scores in the participants treated with trastuzumab emtansine IV during the adjuvant phase (Appendix 8)</li>\n</ul>\n<div>\n Secondary Safety Objectives </div>\n<ul>\n <li>\n To evaluate the safety and tolerability of PH FDC SC and P+H IV during the neoadjuvant phase of the study. Corresponding endpoint: Incidence, nature and severity of all adverse events (AEs), Grade ≥ 3 AEs, SAEs, and cardiac AEs (including left ventricular ejection fraction [LVEF] events) with severity determined according to National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) v5.0 (Appendix 14 and Appendix 16), Incidence of premature withdrawal from the neoadjuvant treatment with PH FDC SC and P+H IV, Targeted vital signs and physical findings, Targeted clinical laboratory test results</li>\n <li>\n To evaluate the safety and tolerability of PH FDC SC administered in the home setting and hospital setting during the cross-over period and the entire adjuvant treatment period. Corresponding endpoint: Incidence, nature and severity of all AEs, Grade ≥ 3 AEs, SAEs and cardiac AEs (including LVEF events) with severity determined according to NCI CTCAE v5.0 (Appendix 14 and Appendix 16), Incidence of premature withdrawal from the adjuvant treatment with PH FDC SC, Targeted vital signs and physical findings, Targeted clinical laboratory test results</li>\n <li>\n To evaluate the safety and tolerability of trastuzumab emtansine IV during the adjuvant phase of the study. Corresponding endpoint: Incidence, nature and severity of all AEs Grade ≥ 3 AEs, SAEs and cardiac AEs (including LVEF events) with severity determined according to NCI CTCAE v5.0 (Appendix 14 and Appendix 16), Incidence of premature withdrawal from the treatment with trastuzumab emtansine IV, Targeted vital signs and physical findings, Targeted clinical laboratory test results</li>\n</ul>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy0
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory0
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n This information has been provided in the respective Site-specific information/site-specific addendum attached.</p>\n
      • other_details_explanation<p>\n Not Applicable</p>\n
      • other_details_regulatory_notapproved<ul>\n <li>\n Croatia </li>\n <li>\n Czech Republic </li>\n <li>\n Roche also intends to submit the concerned Clinical Trial Application dossier for consideration in the USA</li>\n</ul>\n<div>\n  </div>\n
      • other_details_regulatory_approved<p>\n Argentina, Brazil, Canada, Chile, Costa Rica, Mexico, S. Africa, S.Korea, Singapore, Spain, Turkey, Bulgaria and Herzegovina, Croatia, Czech Republic, and Spain. Most of these are not in English, so they have also been attached to the notifications section.</p>\n
      • other_details_regulatory_rejected<p>\n Not applicable</p>\n
      • other_details_regulatory_halted<p>\n Not applicable</p>\n
      • estimated_durationThe total duration of study participation for each individual is expected to be approximately 1.5 to 2 years.
      • 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_comparatorPerjeta Phesgo Kadcyla
      • 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_states20
      • number_of_sites2
      • multi_country_listArgentina, Brazil, Canada, Chile, Costa Rica, Mexico, S. Africa, S.Korea, Singapore, Spain, Turkey, Bulgaria and Herzegovina, Croatia, Czech Republic, Spain. Roche also intends to submit the concerned Clinical Trial Application dossier for consideration in USA.
      • data_monitoring_committeeYes
      • total_enrolment_per_site30- AKUH\n20- ICI
      • total_participants_worldwide330
      • population_less_than_18_yearsNo
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      • investigator1_given_nameFredrick
      • investigator1_middle_nameChite
      • investigator1_family_nameAsirwa
      • investigator1_qualificationProfessor of Hematology and Oncology
      • investigator1_professional_addressInternational Cancer Institute, Nandi Road 8/10, Eldoret, Kenya, 8088-30100
      • investigator1_telephone+254 700 522 149
      • investigator1_emaildirector@intercancer.com
      • organisations_transferred_Yes
      • number_participants50
      • notification
      • approval_date12-05-2023
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        • professional_addressInternational Cancer Institute, Nandi Road 8/10, Eldoret, Kenya, 8088-30100
        • telephone+254 700 522 149
        • emaildirector@intercancer.com
        • created2022-11-03 12:02:44
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      • 1(array)
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        • given_nameMansoor
        • middle_name
        • family_nameSaleh
        • qualificationProfessor of Hematology and Oncology
        • professional_addressAga Khan University, Nairobi, 3rd Parklands Avenue, Nairobi-Kenya
        • telephone+254 709 93 1500
        • emailmansoor.saleh@aku.edu
        • created2022-11-07 15:55:26
        • modified2023-01-17 17:45:57
    • SiteDetail(array)
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        • site_nameAga Khan University, Nairobi
        • physical_address3rd Parklands Avenue, Off Limuru Road
        • contact_detailsP.O. Box 30270, Nairobi 00100
        • contact_personProf Mansoor Saleh
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        • site_nameInternational Cancer Institute
        • physical_addressNandi Road 8/10, Eldoret, Kenya, 8088-30100
        • contact_detailsP.O. Box 8088-30100, Eldoret Kenya
        • contact_personProf Fredrick Chite Asirwa
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        • id611
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        • sponsorHoffmann La Roche
        • sponsor_typeIndustry
        • contact_personGladys Mills
        • addressThe Atrium, 6th Floor Chaka Road, off Lenana Road P.O. Box 44212-00100 Nairobi, Kenya
        • telephone_number+233593813966
        • fax_number
        • cell_number+233593813966
        • email_addressgladys.mills@roche.com
        • created2022-11-03 12:02:44
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  • 1(array)
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      • abstract_of_study<div>\n <div>\n <strong>A PHASE II/III MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF MULTIPLE TARGETED THERAPIES AS TREATMENTS FOR PATIENTS WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) HARBORING ACTIONABLE SOMATIC MUTATIONS DETECTED IN BLOOD (BFAST: BLOOD FIRST ASSAY SCREENING TRIAL)</strong></div>\n</div>\n<div>\n  </div>\n<div>\n <div>\n PROTOCOL NUMBER: BO29554</div>\n <div>\n VERSION NUMBER: 7</div>\n</div>\n<div>\n  </div>\n<div>\n <div>\n TEST PRODUCT: Alectinib (RO5424802), Atezolizumab (RO5541267), Entrectinib (RO7102122), Cobimetinib (RO5514041), Vemurafenib (RO5185426), GDC-6036 (RO7435846)</div>\n</div>\n<div>\n  </div>\n<div>\n Lung cancer remains the leading cause of cancer death worldwide; it is the most common cancer in both men and women and is estimated to account for approximately 13% of all new cancers in 2016 (Miller et al. 2016). Non–small cell lung cancer (NSCLC), as a whole, is not rare (224,390 expected new cases in the United States in 2016) (Miller et al. 2016), and several treatments via a number of therapeutic mechanisms are approved for use. However, the disease is heterogeneous and comprises a number of rare or uncommon subgroups of patients, leaving considerable room for improvement in treating patients with a personalized approach.</div>\n<div>\n  </div>\n<div>\n Patients diagnosed with early-stage NSCLC have reasonable outcomes (5-year survival rate of 55%). However, the remaining 76% of the patient population who are diagnosed with regional or metastatic disease have poorer outcomes (5-year survival rates of 31% and 5% for regional and metastatic disease, respectively [Howlader et al. 2016]). Based on the Global Burden of Cancer Study (GLOBOCAN) 2012 data from the WHO Europe region, the overall age-standardized rate for lung cancer was 449 cases (313 cases in European Union) per 100,000 persons, with 36.5 deaths per 100,000 persons (International Agency for Cancer Research world population standard) (Ferlay et al. 2015). The GLOBOCAN database does not provide information on histology or cancer stage; thus, the proportion of the advanced or metastatic NSCLC could not be specifically determined for a European NSCLC population. NSCLC accounts for 80%-85% of all lung cancers in the Surveillance, Epidemiology and End Results (SEER) database; assuming a distribution similar to the data provided from SEER can be expected for the European Union, this would produce an expectation of 266 cases of NSCLC per 100,000 persons in the European Union per year.</div>\n<div>\n  </div>\n<div>\n Patients with advanced or metastatic NSCLC usually receive platinum-based doublet chemotherapy with or without a PD-L/PD-L1 inhibitor, unless they harbor tumors with activating EGFR, ALK, or ROS1 mutations and are treated with appropriately targeted therapy (based upon diagnostic selection) as first-line treatment (National Comprehensive Cancer Network [NCCN] 2016). These treatment options have produced response rates of up to 35% with chemotherapy (Schiller et al. 2002; Sandler et al. 2006; Scagliotti et al. 2008), 74% with crizotinib (ALK inhibitor; Xalkori®), and 65% with EGFR-targeted therapy (Rosell et al. 2012; Solomon et al. 2014). Additionally, the associated median progression-free survival (PFS) is approximately 6 months for chemotherapy and up to 14 months with targeted therapy, while the median overall survival (OS) is approximately 10 months with chemotherapy and up to 28 months with targeted therapy (Xalkori® and Tarceva® U.S. Prescribing Information). However, most patients will relapse as a result of inherent or acquired resistance and will require subsequent lines of therapy</div>\n<div>\n  </div>\n<div>\n The effectiveness of existing therapies declines in patients with advanced or metastatic disease who receive additional therapies beyond the first-line. While there are approved targeted therapies for previously treated patients with ALK- or EGFR-positive NSCLC, available approved treatment options for ALK- or EGFR-negative patients with previously treated advanced or metastatic NSCLC were limited to docetaxel, pemetrexed, and erlotinib prior to 2015. These agents have produced objective response rates (ORRs) of 5.5%-8.9% in pivotal trials in this patient population, with limited benefit in median PFS (range, 2-3 months) and median OS (range, 5.7-8.3 months) (Taxotere®, Alimta®, and Tarceva® U.S. Prescribing Information).</div>\n<div>\n  </div>\n<div>\n More recently, immunotherapy options such as atezolizumab (Tecentriq®), nivolumab (Opdivo) and pembrolizumab (Keytruda) have been approved in the United States, the European Union, and other countries for previously untreated (in the case of pembrolizumab) or previously treated advanced or metastatic NSCLC. In certain settings, patients are treated irrespective of biomarker information, while in others, patients are selected by a protein expression biomarker, largely regardless of driver mutation status (includes some, but not all patients with a specific mutation). The combination of ramucirumab (Cyramza®; VEGF-R2 antagonist) and docetaxel has also been recently approved in an unselected, previously treated NSCLC population. These recently approved agents have resulted in ORRs of ï‚£ 23% in unselected, previously treated NSCLC populations. While no single biomarker has, at this time, clearly discerned those patients who benefit from immunotherapies, it has been theorized that patients with high-mutation-load tumors are more likely to benefit thanas well as perhaps represent a distinct population from those patients who harbor driver mutations (Alexandrov et al. 2013; Rizvi et al. 2015).</div>\n<div>\n  </div>\n<div>\n <div>\n Patients will be assigned to the appropriate cohort based on their identified oncogenic somatic mutation(s). If more than one mutation is identified, the priority for cohort assignment will be as follows:</div>\n <ul>\n <li>\n Line of therapy (cohorts that allow patient enrollment for earlier lines of therapy given preference) where applicable</li>\n <li>\n Lesser prevalence of mutation or biomarker in the population as follows:</li>\n </ul>\n <div>\n ROS1 rearrangement (~1%): Cohort D (entrectinib) (Note: Cohort D has been closed to further enrollment)</div>\n <div>\n BRAF V600 mutation (~1%2%): Cohort E (vemurafenib, cobimetinib, atezolizumab)</div>\n <div>\n EGFR exon 20 mutation (~1%2%): Cohort F (atezolizumab, bevacizumab, carboplatin, pemetrexed)</div>\n <div>\n RET rearrangement (~1.8%): Cohort B (alectinib) (Note: Cohort B has been closed to further enrollment.)</div>\n <div>\n ALK rearrangement (~5%): Cohort A (alectinib) (Note: Cohort A has been closed to further enrollment.)</div>\n <div>\n KRAS G12C mutation (~8 12%): Cohort G (GDC-6036 vs. docetaxel) bTMB positive (~23%36%): Cohort C (atezolizumab vs. chemotherapy)</div>\n <div>\n (Note: Cohort C has been closed to further enrollment)</div>\n <ul>\n <li>\n Natural history follow-up (Note: as of 26 OCT 2020 , the enrollment into the natural history follow-up cohort has been paused, as the initial goal of enrolling approximately 1,000 patients has been met)</li>\n </ul>\n <div>\n Patients who are screened using the ctDNA assay but who do not enroll in a treatment cohort are eligible to begin natural history follow-up (if consent is given) to document their cancer therapies (or therapy types), treatment response, and survival status. Additional information on other data that were collected as part of initial blood screening process for these patients is available in the body of the protocol. Patients with an alteration relevant to the BFAST trial or other key alteration profiles of interest (e.g., KRAS+, HER2+, MET+, PIK3CA+, other EGFR alterations, other ALK alterations, other RET alterations, other BRAF alterations, or other  who pursue therapy or other management options outside of this study for any reason (e.g., failure to meet treatment-specific eligibility criteria, choosing not to enroll, physician decision to pursue alternative therapy, patient experiencing disease progression before they can enroll, etc.) will be the population of interest for this component of the study. Information will be obtained approximately every 3 months during routine doctor or healthcare appointments and/or telephone calls. For patients in the natural history follow-up, a blood sample will be collected at the time of disease progression for blood-based assay testing (if consent is given). These samples may be stored for future exploratory analyses.</div>\n <div>\n  </div>\n <div>\n Mandatory blood samples at baseline, during therapy (i.e., at each tumor assessment), and at progression of disease, as well as tissue (or results from tissue-based testing, when available or as required per protocol), will be collected in order to evaluate exploratory prognostic and/or predictive biomarkers, including but not limited to biomarkers related to driver oncogene signaling and NSCLC pathogenesis. For all patients, blood samples will be used as the only means of identifying driver mutations or TMB for inclusion in treatment cohorts, irrespective of tissue availability or tissue testing results. For patients who do not screen positive for an available cohort (or who are enrolled on the study but discontinue study treatment for reasons other than disease progression), or at the time of disease progression on study, treating physicians will have the option to receive access to a report of the FoundationOne Liquid Companion Diagnostic (F1LCDx) assay results (or Sponsor-designated assay results in China). To improve patient access to clinical trials and subject to informed consent, central F1LCDx results (or Sponsor-designated blood based NGS ctDNA assay results in China) for patients deemed not eligible for the enrollment in any active BFAST cohort, may be used to determine if patients are potentially eligible for other Sponsor's studies. The trial is designed to demonstrate clinical efficacy and safety in the target population, though dose-finding may be necessary in certain cohorts. Treatment will be assigned on the basis ofrelevant oncogenotype, will have cohort-specific inclusion/exclusion criteria, and unless otherwise specified, will continue until disease progression per Response Evaluation Criteria In Solid Tumors, Version 1.1 (RECIST v1.1), loss of clinical benefit (if applicable), unacceptable toxicity, patient or physician decision to discontinue, or death, whichever occurs first. If the</div>\n <div>\n patient discontinues treatment prior to disease progression (because of adverse event, withdrawal of consent to treatment, or other reason), tumor assessment data collection will continue until disease progression per RECIST v1.1, death, withdrawal of consent, or study closure by the Sponsor, whichever occurs first. Follow-up data capture, including survival and subsequent anti-cancer therapies, will continue for each patient until death, loss to follow-up, study discontinuation, or study closure, whichever occurs first. Information regarding the nature and the duration of subsequent therapies will be collected.</div>\n <div>\n  </div>\n</div>\n<div>\n <div>\n <u><strong>OBJECTIVES AND ENDPOINTS</strong></u></div>\n <div>\n  </div>\n <div>\n <strong>Primary Efficacy Objective:</strong></div>\n <div>\n To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed ORR based on confirmed objective response (indicated by two objective response assessments based on RECIST v1.1 separated by at least 4 weeks).</div>\n <div>\n  </div>\n <div>\n <strong>Secondary Efficacy Objective:</strong></div>\n <div>\n To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints:</div>\n <div>\n Investigator-assessed DOR, CBR, and PFS per RECIST v1.1</div>\n <div>\n IRF-assessed ORR, DOR, CBR, and PFS per RECIST v1.1</div>\n <div>\n OS.</div>\n <div>\n  </div>\n <div>\n <strong>Safety Objective:</strong></div>\n <div>\n To evaluate the safety and tolerability of alectinib. Corresponding Endpoints:</div>\n <div>\n Incidence, type, and severity of adverse events (based on the NCI CTCAE v4.0), including SAEs and AEs of special interest.</div>\n <div>\n Changes in vital signs, physical findings, and clinical laboratory results during and following administration of protocol-specified IMPs.</div>\n <div>\n  </div>\n <div>\n <strong>PRO Objective: </strong></div>\n <div>\n To evaluate the impact of alectinib on PROs in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints</div>\n <div>\n Proportion of patients who improved compared with baseline in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain as measured by SILC </div>\n <div>\n TTD in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain, as measured by SILC</div>\n <div>\n Mean change from baseline in HRQoL, patient functioning, and symptoms as measured by the EORTC QLQ-C30 and SILC</div>\n <div>\n  </div>\n <div>\n <strong>PRO Objective:</strong></div>\n <div>\n To evaluate and compare patients’ health status to generate utility scores for use in economic models for reimbursement. Corresponding endpoint: Health status as assessed by the EQ-5D-5L questionnaire.</div>\n <div>\n  </div>\n <div>\n <strong>Biomarker Objective:</strong></div>\n <div>\n To assess prognostic effect and pharmacodynamics of exploratory</div>\n <div>\n biomarkers in blood, and their association with disease status, mechanisms of resistance, and/or response to alectinib. Corresponding Endpoint: Relationship between circulating biomarkers related to alectinib efficacy.</div>\n <div>\n  </div>\n <div>\n <strong>Exploratory Objective:</strong></div>\n <div>\n To explore the anti-tumor effect of alectinib in patients with CNS disease identified at baseline. Corresponding Endpoints:</div>\n <div>\n Investigator-assessed ORR per RECIST v1.1 in patients with CNS disease</div>\n <div>\n Investigator-assessed DOR per RECIST v1.1 in patients with CNS disease</div>\n <div>\n Investigator-assessed CBR per RECIST v1.1 in patients with CNS disease</div>\n <div>\n  </div>\n <div>\n <strong>Exploratory Objective:</strong></div>\n <div>\n To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed TIR according to RECIST.</div>\n <div>\n  </div>\n <div>\n <div>\n <strong>Inclusion Criteria:</strong></div>\n <ul>\n <li>\n Histologically or cytologically confirmed diagnosis of unresectable Stage IIIb not amenable to treatment with combined modality chemoradiation (advanced) or Stage IV (metastatic) NSCLC</li>\n <li>\n Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2</li>\n <li>\n Measurable disease</li>\n <li>\n Adequate recovery from most recent systemic or local treatment for cancer</li>\n <li>\n Adequate organ function</li>\n <li>\n Life expectancy greater than or equal to (>/=) 12 weeks</li>\n <li>\n For female participants of childbearing potential and male participants, willingness to use acceptable methods of contraception</li>\n </ul>\n <div>\n <strong>Exclusion Criteria:</strong></div>\n <ul>\n <li>\n Inability to swallow oral medication</li>\n <li>\n Women who are pregnant or lactating</li>\n <li>\n Symptomatic, untreated CNS metastases</li>\n <li>\n History of malignancy other than NSCLC within 5 years prior to screening with the exception of malignancies with negligible risk of metastasis or death</li>\n <li>\n Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable angina</li>\n <li>\n Known human immunodeficiency virus (HIV) positivity or autoimmune deficiency syndrome (AIDS)-related illness</li>\n <li>\n Either a concurrent condition or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or confounds the ability to interpret data from the study</li>\n <li>\n Inability to comply with other requirements of the protocol</li>\n </ul>\n </div>\n</div>\n<p>\n  </p>\n
      • study_title<div>\n A PHASE II/III MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF MULTIPLE TARGETED THERAPIES AS TREATMENTS FOR PATIENTS WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) HARBORING ACTIONABLE SOMATIC MUTATIONS DETECTED IN BLOOD (BFAST: BLOOD FIRST ASSAY SCREENING TRIAL)</div>\n
      • laymans_summary<div>\n <div>\n This study will evaluate the efficacy and safety of multiple therapies that are selected using predictive biomarkers identified via a blood-based NGS assay in patients with advanced non-small cell lung cancer (NSCLC). Specific objectives and corresponding endpoints for the study are outlined for each cohort below.</div>\n <div>\n  </div>\n <div>\n This study will also characterize the natural history of patients with genomic alteration profiles of interest who do not enroll in any of the above treatment cohorts. Analyses will be exploratory in nature; there is no formal hypothesis testing in the natural history cohort.</div>\n</div>\n<div>\n  </div>\n<div>\n Study BO29554 (BFAST) is a Phase II/III, global, multicenter, open-label, multi-cohort study designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or in combination in patients with unresectable, advanced or metastatic NSCLC determined to harbor oncogenic somatic mutations (e.g., ALK, RET) or positive by tumor mutational burden (TMB) assay (above a prespecified cutoff) as identified by a blood-based NGS circulating tumor DNA (ctDNA) assay.</div>\n<div>\n  </div>\n<div>\n Male and female patients aged more than or equal to 18 years who meet the trial’s general inclusion/exclusion criteria will be eligible for blood-based screening. Blood specimens from patients meeting eligibility criteria for the blood-based screening part of the study will be prospectively tested for somatic alterations in a panel of oncogenes, including the targetable oncogenes and TMB.</div>\n<div>\n  </div>\n<div>\n The overarching structure of the BFAST study is an umbrella screening and interventional study, which will screen patient blood samples for the presence of potentially oncogenic somatic mutations and biomarker positivity via a blood-based NGS ctDNA assay, and will treat patients with a drug or drug regimen tailored to their results. Initially, three cohorts testing the efficacy and safety of therapy directed at specific mutations or biomarkers (ALK, RET, and biomarker positive for bTMB [bTMB-positive]) were implemented. Additional cohorts have been and will be added to address various identified somatic mutations or other biomarkers via future protocol amendments. Each cohort may have separate endpoints, screening, and treatment requirements.</div>\n
      • short_titleBFAST
      • protocol_noECCT/22/11/03
      • version_no7
      • date_of_protocol23-03-2022
      • study_drugAlectinib (RO5424802), Atezolizumab (RO5541267), Entrectinib (RO7102122), Cobimetinib (RO5514041), Vemurafenib (RO5185426), GDC-6036 (RO7435846)
      • disease_conditionNON-SMALL CELL LUNG CANCER (NSCLC)
      • product_type_biologicals1
      • product_type_proteins0
      • product_type_immunologicals1
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical0
      • product_type_medical_device0
      • product_type_chemical_name
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameDocetaxel
      • comparator_registeredThis is not a Roche product
      • comparator_countriesThis is not a Roche product
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressfaith.wanjau@roche.con
      • applicant_covering_letter1
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      • applicant_indemnity_cover1
      • applicant_opinion_letter1
      • applicant_approval_letter1
      • applicant_statement1
      • applicant_participating_countries(null)
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      • applicant_pan_african1
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      • declaration_applicantFaith Wanjau
      • declaration_date107-11-2022
      • declaration_principal_investigatorProf. Mansoor Saleh
      • declaration_date207-11-2022
      • placebo_presentNo
      • study_objectives<div>\n <strong>Primary Efficacy Objective:</strong> To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed ORR based on confirmed objective response (indicated by two objective response assessments based on RECIST v1.1 separated by at least 4 weeks).</div>\n<div>\n  </div>\n<div>\n <strong>Secondary Efficacy Objective:</strong> To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints:</div>\n<div>\n Investigator-assessed DOR, CBR, and PFS per RECIST v1.1</div>\n<div>\n IRF-assessed ORR, DOR, CBR, and PFS per RECIST v1.1</div>\n<div>\n OS.</div>\n<div>\n  </div>\n<div>\n <strong>Safety Objective</strong>: To evaluate the safety and tolerability of alectinib. Corresponding Endpoints:</div>\n<div>\n Incidence, type, and severity of adverse events (based on the NCI CTCAE v4.0), including SAEs and AEs of special interest.</div>\n<div>\n Changes in vital signs, physical findings, and clinical laboratory results during and following administration of protocol-specified IMPs.</div>\n<div>\n  </div>\n<div>\n <strong>PRO Objective:</strong>  To evaluate the impact of alectinib on PROs in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints</div>\n<div>\n Proportion of patients who improved compared with baseline in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain as measured by SILC </div>\n<div>\n TTD in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain, as measured by SILC</div>\n<div>\n Mean change from baseline in HRQoL, patient functioning, and symptoms as measured by the EORTC QLQ-C30 and SILC</div>\n<div>\n  </div>\n<div>\n <strong>PRO Objective</strong>: To evaluate and compare patients’ health status to generate utility scores for use in economic models for reimbursement. Corresponding endpoint: Health status as assessed by the EQ-5D-5L questionnaire.</div>\n<div>\n  </div>\n<div>\n <strong>Biomarker Objective</strong>: To assess prognostic effect and pharmacodynamics of exploratory</div>\n<div>\n biomarkers in blood, and their association with disease status, mechanisms of resistance, and/or response to alectinib. Corresponding Endpoint: Relationship between circulating biomarkers related to alectinib efficacy.</div>\n<div>\n  </div>\n<div>\n <strong>Exploratory Objective:</strong> To explore the anti-tumor effect of alectinib in patients with CNS disease identified at baseline. Corresponding Endpoints:</div>\n<div>\n Investigator-assessed ORR per RECIST v1.1 in patients with CNS disease</div>\n<div>\n Investigator-assessed DOR per RECIST v1.1 in patients with CNS disease</div>\n<div>\n Investigator-assessed CBR per RECIST v1.1 in patients with CNS disease</div>\n<div>\n  </div>\n<div>\n <strong>Exploratory Objective</strong>: To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed TIR according to RECIST.</div>\n<div>\n  </div>\n
      • principal_inclusion_criteria<ul>\n <li>\n Histologically or cytologically confirmed diagnosis of unresectable Stage IIIb not amenable to treatment with combined modality chemoradiation (advanced) or Stage IV (metastatic) NSCLC</li>\n <li>\n Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2</li>\n <li>\n Measurable disease</li>\n <li>\n Adequate recovery from most recent systemic or local treatment for cancer</li>\n <li>\n Adequate organ function</li>\n <li>\n Life expectancy greater than or equal to (>/=) 12 weeks</li>\n <li>\n For female participants of childbearing potential and male participants, willingness to use acceptable methods of contraception</li>\n</ul>\n
      • principal_exclusion_criteria<ul>\n <li>\n Inability to swallow oral medication</li>\n <li>\n Women who are pregnant or lactating</li>\n <li>\n Symptomatic, untreated CNS metastases</li>\n <li>\n History of malignancy other than NSCLC within 5 years prior to screening with the exception of malignancies with negligible risk of metastasis or death</li>\n <li>\n Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable angina</li>\n <li>\n Known human immunodeficiency virus (HIV) positivity or autoimmune deficiency syndrome (AIDS)-related illness</li>\n <li>\n Either a concurrent condition or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or confounds the ability to interpret data from the study</li>\n <li>\n Inability to comply with other requirements of the protocol</li>\n</ul>\n
      • primary_end_points<div>\n Primary Efficacy Objective: To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed ORR based on confirmed objective response (indicated by two objective response assessments based on RECIST v1.1 separated by at least 4 weeks).</div>\n<div>\n  </div>\n<div>\n Secondary Efficacy Objective: To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints:</div>\n<div>\n Investigator-assessed DOR, CBR, and PFS per RECIST v1.1</div>\n<div>\n IRF-assessed ORR, DOR, CBR, and PFS per RECIST v1.1</div>\n<div>\n OS.</div>\n<div>\n  </div>\n<div>\n Safety Objective:To evaluate the safety and tolerability of alectinib. Corresponding Endpoints:</div>\n<div>\n Incidence, type, and severity of adverse events (based on the NCI CTCAE v4.0), including SAEs and AEs of special interest.</div>\n<div>\n Changes in vital signs, physical findings, and clinical laboratory results during and following administration of protocol-specified IMPs.</div>\n<div>\n  </div>\n<div>\n PRO Objective:  To evaluate the impact of alectinib on PROs in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints</div>\n<div>\n Proportion of patients who improved compared with baseline in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain as measured by SILC </div>\n<div>\n TTD in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain, as measured by SILC</div>\n<div>\n Mean change from baseline in HRQoL, patient functioning, and symptoms as measured by the EORTC QLQ-C30 and SILC</div>\n<div>\n  </div>\n<div>\n PRO Objective: To evaluate and compare patients’ health status to generate utility scores for use in economic models for reimbursement. Corresponding endpoint: Health status as assessed by the EQ-5D-5L questionnaire.</div>\n<div>\n  </div>\n<div>\n Biomarker Objective: To assess prognostic effect and pharmacodynamics of exploratory</div>\n<div>\n biomarkers in blood, and their association with disease status, mechanisms of resistance, and/or response to alectinib. Corresponding Endpoint: Relationship between circulating biomarkers related to alectinib efficacy.</div>\n<div>\n  </div>\n<div>\n Exploratory Objective: To explore the anti-tumor effect of alectinib in patients with CNS disease identified at baseline. Corresponding Endpoints:</div>\n<div>\n Investigator-assessed ORR per RECIST v1.1 in patients with CNS disease</div>\n<div>\n Investigator-assessed DOR per RECIST v1.1 in patients with CNS disease</div>\n<div>\n Investigator-assessed CBR per RECIST v1.1 in patients with CNS disease</div>\n<div>\n  </div>\n<div>\n Exploratory Objective: To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed TIR according to RECIST.</div>\n<div>\n  </div>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy1
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic0
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n This has been provided in the Site-specific information/site-specific addendum attached.</p>\n<div>\n  </div>\n<div>\n  </div>\n
      • other_details_explanation<p>\n Not applicable</p>\n
      • other_details_regulatory_notapproved<ul>\n <li>\n Algeria</li>\n <li>\n Morocco</li>\n <li>\n Tunisia</li>\n</ul>\n
      • other_details_regulatory_approved<ul>\n <li>\n United States</li>\n <li>\n Japan</li>\n <li>\n France</li>\n <li>\n Thailand</li>\n <li>\n Republic of Korea</li>\n <li>\n Spain</li>\n <li>\n Canada</li>\n <li>\n Poland</li>\n <li>\n HongKong</li>\n <li>\n Belgium</li>\n <li>\n Germany</li>\n <li>\n Italy</li>\n <li>\n Australia</li>\n <li>\n Chile</li>\n <li>\n Brazil</li>\n <li>\n Israel</li>\n <li>\n Mexico</li>\n <li>\n Argentina</li>\n <li>\n Singapore</li>\n <li>\n Taiwan</li>\n <li>\n Newzealand</li>\n <li>\n Peru</li>\n <li>\n Costa Rica</li>\n <li>\n Turkey</li>\n <li>\n Russian Federation</li>\n <li>\n Serbia</li>\n <li>\n Panama</li>\n <li>\n China</li>\n</ul>\n
      • other_details_regulatory_rejected<p>\n Not applicable</p>\n
      • other_details_regulatory_halted<p>\n Not applicable</p>\n
      • estimated_duration7 years
      • 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_comparatorDocetaxel
      • design_controlled_other_medicinalNo
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherNo
      • design_controlled_medicinal_specify
      • single_site_member_stateYes
      • location_of_areaAga Khan University, Nairobi
      • single_site_physical_address3rd Parklands Avenue, Off Limuru Road
      • single_site_contact_personProf. Mansoor Saleh
      • single_site_telephone+254709931097
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_states31
      • number_of_sites
      • multi_country_listAlgeria\nMorocco\nTunisia\nUnited States\nJapan\nFrance\nThailand\nRepublic of Korea\nSpain\nCanada\nPoland\nHongKong\nBelgium\nGermany\nItaly\nAustralia\nChile\nBrazil\nIsrael\nMexico\nArgentina\nSingapore\nTaiwan\nNewzealand\nPeru\nCosta Rica\nTurkey\nRussian Federation\nSerbia\nPanama\nChina\n
      • data_monitoring_committeeYes
      • total_enrolment_per_site10
      • total_participants_worldwide1000
      • 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_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_nameMansoor
      • investigator1_middle_name
      • investigator1_family_nameSaleh
      • investigator1_qualificationProfessor of Hematology and Oncology
      • investigator1_professional_addressAga Khan University, Nairobi, 3rd Parklands Avenue, Nairobi-Kenya
      • investigator1_telephone+254 709 93 1500
      • investigator1_emailmansoor.saleh@aku.edu
      • organisations_transferred_Yes
      • number_participants10
      • notification
      • approval_date12-04-2023
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted25-11-2022
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments have been addressed
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2023-11-22 09:38:56
      • created2022-11-03 12:00:09
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id856
        • application_id1184
        • given_nameMansoor
        • middle_name
        • family_nameSaleh
        • qualificationProfessor of Hematology and Oncology
        • professional_addressAga Khan University, Nairobi, 3rd Parklands Avenue, Nairobi-Kenya
        • telephone+254 709 93 1500
        • emailmansoor.saleh@aku.edu
        • created2022-11-03 12:01:25
        • modified2022-11-25 09:01:56
    • SiteDetail(array)
      • 0(array)
        • id1326
        • application_id1184
        • county_id(null)
        • site_name
        • physical_address
        • contact_details
        • contact_person
        • site_capacity(null)
        • misc(null)
        • created2022-11-03 12:01:25
        • modified2022-11-25 09:01:56
        • County(empty)
    • Sponsor(array)
      • 0(array)
        • id610
        • application_id1184
        • sponsorHoffmann La Roche
        • sponsor_typeIndustry
        • contact_personNour Ashraf
        • addressThe Atrium, 6th Floor Chaka Road, off Lenana Road P.O. Box 44212-00100 Nairobi, Kenya
        • telephone_number+254 794 650436
        • fax_number
        • cell_number+20100 3300 246
        • email_addressnour.ashraf@roche.com
        • created2022-11-03 12:01:25
        • modified2022-11-25 09:01:56
  • 2(array)
    • Application(array)
      • id1178
      • user_id693
      • trial_status_id6
      • abstract_of_study<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>B</strong><strong>a</strong><strong>c</strong><strong>k</strong><strong>g</strong><strong>r</strong><strong>o</strong><strong>und</strong><strong>:</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n Sickle cell disease (SCD) is a serious and life-threatening inherited hemoglobin (Hb) disorder caused by a single amino acid substitution in the beta (β)-globin gene (β s c.20A>T; rs334). Sickle cell disease affects millions of people worldwide. The homozygous form (HbSS) occurs in most cases and represents approximately 88% to 96% in certain areas of Africa. Preliminary data indicate that mitapivat may reduce Hemoglobin S polymerization, sickling, and hemolysis. Therefore, in this study mitapivat is a therapeutic candidate for the treatment of adult patients with SCD with the potential to provide clinical benefit by both improvement of anemia and reduction in sickle cell pain crises (SCPCs).</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n The only current curative treatment approach for some patients with SCD is bone marrow transplant. However, a lack of histocompatible donors, concerns about transplantrelated morbidity and mortality, and pre-existing conditions (organ dysfunction or alloimmunization) often preclude patients from pursuing this treatment option. For decades, hydroxyurea was the only disease-modifying therapy available for patients with SCD. Hydroxyurea is indicated to reduce the frequency of painful crises; however, its use  is limited by its safety profile, which includes myelosuppression (neutropenia and thrombocytopenia) and gastrointestinal toxicity. Reduced fertility has been reported as a longterm adverse effect.</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>J</strong><strong>u</strong><strong>s</strong><strong>t</strong><strong>i</strong><strong>f</strong><strong>i</strong><strong>c</strong><strong>a</strong><strong>t</strong><strong>i</strong><strong>o</strong><strong>n</strong><strong>/</strong><strong>R</strong><strong>a</strong><strong>t</strong><strong>i</strong><strong>o</strong><strong>n</strong><strong>a</strong><strong>l</strong><strong>e</strong><strong>:</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n The use  of curative options for SCD is currently limited to a small subgroup of patients who are deemed fit for bone marrow transplantation and have available donors. The treatment options for SCD are not universally effective or globally available, tend to address only a single component of the disease, or are limited by their safety profile. Therefore, a significant unmet medical need exists for safe and effective therapies for the treatment of SCD that result in both an improvement in anemia and reduction in sickle cell–related crises.</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n Mitapivat is a small molecule, oral activator of wild-type (WT) and mutant forms of the RBC-specific form of pyruvate kinase (PKR). Activation of PKR has potential application in the treatment of hemolytic anemias, including SCD, which are characterized by increased metabolic demands or by defects in glycolysis that contribute to the shortened life span of the RBC. Decreases in PKR function, exemplified in patients with pyruvate kinase deficiency, leads to dysfunctional RBCs that are characterized by defective glycolysis, including a build-up of 2,3-DPG and PEP with decreased levels of ATP. However, there is evidence that the activation of the normal (WT) PKR enzyme can play a role in other hemolytic anemias such  as SCD.</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>Main Objectives: Phase 2:</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n 1. To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on:</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n • Anemia in subjects with sickle cell disease (SCD)</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n • Safety</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n Phase 3: 1. To determine the effect of mitapivat versus placebo on:</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n • Anemia in subjects with sickle cell disease (SCD)</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n • Sickle cell pain crises (SCPCs) in subjects with SCD</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>Secondary objectives:</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>Pha</strong><strong>se </strong><strong>2</strong><strong>:</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n 1. To evaluate the effect of 2 doses of mitapivat versus placebo on:</p>\n<ul>\n <li style=\"margin: 0px 0px 10px 29.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <img height=\"4\" src=\"file:///C:/Users/kimettjc/AppData/Local/Temp/msohtmlclip1/01/clip_image001.gif\" style=\"height: auto; max-width: 100%; vertical-align: middle; border: 0px;\" width=\"4\" />Anemia</li>\n <li style=\"margin: 0px 0px 10px 29.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <img height=\"4\" src=\"file:///C:/Users/kimettjc/AppData/Local/Temp/msohtmlclip1/01/clip_image002.gif\" style=\"height: auto; max-width: 100%; vertical-align: middle; border: 0px;\" width=\"4\" />Markers of hemolysis and erythropoiesis</li>\n <li style=\"margin: 0px 0px 10px 29.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <img height=\"4\" src=\"file:///C:/Users/kimettjc/AppData/Local/Temp/msohtmlclip1/01/clip_image003.gif\" style=\"height: auto; max-width: 100%; vertical-align: middle; border: 0px;\" width=\"4\" />Patient-reported fatigue</li>\n <li style=\"margin: 0px 0px 10px 29.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <img height=\"4\" src=\"file:///C:/Users/kimettjc/AppData/Local/Temp/msohtmlclip1/01/clip_image004.gif\" style=\"height: auto; max-width: 100%; vertical-align: middle; border: 0px;\" width=\"4\" />Sickle cell pain crises (SCPCs)</li>\n</ul>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n 2. To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat.</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>Pha</strong><strong>se </strong><strong>3</strong><strong>:</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n 1. To evaluate the effect of mitapivat versus placebo on:</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n • Anemia in subjects with SCD</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n • Markers of hemolysis</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n • Markers of erythropoiesis</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n • Patient-reported fatigue</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n • Additional clinical efficacy measures related to SCPC</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>Methods:</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>Ove</strong><strong>rall Study </strong><strong>d</strong><strong>e</strong><strong>s</strong><strong>i</strong><strong>g</strong><strong>n</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n This is a Phase 2/3, double-blind, randomized, placebo-controlled, global, multicenter study evaluating the efficacy and safety of mitapivat versus placebo in subjects with SCD using an operationally seamless design. The Phase 2 portion is a double-blind, randomized, placebo-controlled, dose-finding study evaluating 2 dose levels of mitapivat (50 mg BID and 100 mg BID) versus placebo to select the dose of mitapivat to be evaluated in the Phase 3 portion. The Phase 3 portion is a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of mitapivat at the selected Phase 3 dose versus placebo. Subjects who complete the Double-blind Period in eitherthe Phase 2 or Phase 3 portion will have the option to receive mitapivat in the Open-label Extension Period. A total of 267 subjects (69 in Phase 2 and 198 in Phase 3)</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n will be randomized in this study. The initiation of the Phase 3 portion will be based on prespecified go/no-go criteria and dose selection criteria. Subjects who participate in the</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n Phase 2 portion of the study are not eligible to participate in the Phase 3 portion of the study.</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>Study outcomes:</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n The primary outcome, or endpoint, for the phase 2 study is hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 10 through Week 12 compared with baseline and safety defined as adverse events (AEs) and serious adverse events (SAEs). The primary outcome for the phase 3 study is Hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 24 through Week 52 compared with baseline and annualized rate of sickle cell pain crises (SCPCs) in subjects with SCD.</p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <strong>S</strong><strong>tudy </strong><strong>du</strong><strong>r</strong><strong>a</strong><strong>t</strong><strong>i</strong><strong>o</strong><strong>n</strong><strong>:</strong></p>\n<p style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n The duration of participation of a subject in the Phase 2 portion is up to 4.5 years (236 weeks). The duration of participation of a subject in the Phase 3 portion is up to 5.3 years (276 weeks). The end of the study is defined as the time at which all subjects complete all study visits, are lost to follow-up, have withdrawn consent for further participation in the study, or when the Sponsor terminates the study.</p>\n
      • study_title<p>\n <span style=\"color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Mitapivat in Subjects With Sickle Cell Disease. Mitapivat - AG348-C-020</span></p>\n
      • laymans_summary<table class=\"table table-condensed\" style=\"max-width: 100%; border-collapse: collapse; border-spacing: 0px; width: 915.271px; margin-bottom: 20px; color: rgb(51, 51, 51); font-family: "Trebuchet MS", Tahoma, Verdana, Arial, sans-serif; font-size: 12.5px;\">\n <thead>\n <tr>\n <th class=\"table-label required\" style=\"padding: 4px 15px 4px 5px; line-height: 20px; text-align: left; vertical-align: bottom; border-top: 0px; color: rgb(0, 112, 0); width: 895.271px;\">\n <h5 style=\"margin: 10px 0px; font-family: inherit; line-height: 20px; color: inherit; text-rendering: optimizelegibility; font-size: 14px; text-align: center;\">\n Laymans Summary: <span class=\"sterix\" style=\"color: red;\">*</span></h5>\n </th>\n </tr>\n </thead>\n <tbody>\n <tr>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221);\">\n <p style=\"margin: 0px 0px 10px;\">\n Sickle cell disease (SCD) is an inherited blood disorder where the red blood cells, which carry oxygen around the body, develop abnormally and become rigid and shaped like a crescent (sickle shape). Sickle cell disease affects millions of people worldwide and is very common in certain areas of Africa. This study will look at a possible drug for treatment of Sickle cell disease called Mitapivat. Results from earlier studies with mitapivat shows that it may reduce the change of shape in red blood cells which makes them look like a sickle and causes the red blood cells to be destroyed resulting in a person with sickle cell disease getting low blood level (anemia). Therefore, in this study mitapivat is a drug candidate for the treatment of adult patients with sickle cell disease with the potential to provide clinical benefit by both improvement of anemia and reduction in sickle cell pain crisis.</p>\n <p style=\"margin: 0px 0px 10px;\">\n  </p>\n <p style=\"margin: 0px 0px 10px;\">\n This study has both a Phase 2 and a Phase 3. The main aim of the Phase 2 portion of the study is to define how mitapivat works in the short term, how safe it is and the right dose which will be selected for the Phase 3 portion of the study. The aim of the Phase 3 portion of the study is to assess the how well the selected dose of mitapivat works for treatment and how safe it when used in patients with sickle cell disease. This portion of the study is intended to show the extent to which mitapivat treatment reduces painful crisis because of blocked blood vessels and reduces anemia in sickle cell disease. In this Phase2/3 study, both the participant and most study staff including the doctors don’t know which treatment has been given to the participant (referred to as doubleblind). One group of study participants called the treatment group will receive the mitapivat and another group called the control group will receive a study treatment with no active ingredient called a placebo.</p>\n <p style=\"margin: 0px 0px 10px;\">\n  </p>\n <p style=\"margin: 0px 0px 10px;\">\n The study is being done in different countries around the world, in multiple study centers in participants with SCD. The Phase 2 portion dose-finding study will assess 2 dose levels of mitapivat (50 mg twice a day and 100 mg twice a day) versus placebo to select the dose of mitapivat to be evaluated in the Phase 3 portion. The Phase 3 portion is a double-blind, randomized, placebo-controlled study evaluating how effective and safe mitapivat is at the selected Phase 3 dose versus placebo. Participants who complete the Double-blind Period in the Phase 2/3 portion will have the option to receive mitapivat in the non-blinded (Open label) Extension Period. Approximately 267 participants (69 in Phase 2 and 198 in Phase 3) are planned to be enrolled in this study worldwide. In Kenya there are 7 sites ,3 sites in Nairobi,1 in western and 3 in Nyanza. Enrollment is competitive world wide.</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • short_titleAgios Study
      • protocol_noECCT/22/10/05
      • version_noAmendment 1 (V1.0)
      • date_of_protocol09-03-2022
      • study_drugMitavpivat Dr Nduba Siaya and Nairobi site
      • 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_nameMitapivat
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressPPDSubmissionsMembers.SM@ppd.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_applicantMillicent.Aketch
      • declaration_date128-10-2022
      • declaration_principal_investigatorDr Ogutu Bernhards
      • declaration_date228-10-2022
      • placebo_presentYes
      • study_objectives<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Main objective:</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Phase 2:</strong></p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 1. To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n : • Anemia in subjects with sickle cell disease (SCD). and</p>\n<ul font-size:=\"\" style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 10px 25px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <li style=\"line-height: 20px;\">\n Safety </li>\n</ul>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  </p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Safety Phase 3:</strong></p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 1. To determine the effect of mitapivat versus placebo on</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n : • Anemia in subjects with sickle cell disease (SCD)</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n • Sickle cell pain crises (SCPCs) in subjects with SCD</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Secondary objectives:</strong></p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Phase 2</strong>:</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 1. To evaluate the effect of 2 doses of mitapivat versus placebo on:</p>\n<ul>\n <li font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51);\" trebuchet=\"\">\n Anemia</li>\n <li font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51);\" trebuchet=\"\">\n Markers of hemolysis and erythropoiesis</li>\n <li font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51);\" trebuchet=\"\">\n Patient-reported fatigue</li>\n <li font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51);\" trebuchet=\"\">\n Sickle cell pain crises (SCPCs)</li>\n</ul>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 2. To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Phase 3</strong>:</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 1. To evaluate the effect of mitapivat versus placebo on:</p>\n<ul>\n <li font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51);\" trebuchet=\"\">\n Anemia in subjects with SCD</li>\n <li font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51);\" trebuchet=\"\">\n Markers of hemolysis Markers of erythropoiesis</li>\n <li font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51);\" trebuchet=\"\">\n Patient-reported fatigue</li>\n <li font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51);\" trebuchet=\"\">\n Additional clinical efficacy measures related to SCPC</li>\n</ul>\n
      • principal_inclusion_criteria<p font-size:=\"\" style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 1. Age ≥16 years; subjects age 16 or 17 years must physically have completed puberty.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 2. Documented diagnosis of SCD (HbSS, HbSC, HbS/β0-thalassemia, HbS/β+ thalassemia, or other sickle cell syndrome variants).</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  3. At least 2 sickle cell pain crises (SCPCs) and no more than 10 SCPCs in the past 12 months.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  4. Hemoglobin ≥5.5 and ≤10.5 g/dL.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  5. If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days before starting study drug.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  6. Women capable of becoming pregnant and men with partners who are women that are capable of becoming pregnant must agree to use  2 forms of contraception.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 7. Other protocol-defined inclusion criteria may apply</p>\n
      • principal_exclusion_criteria<p font-size:=\"\" style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 1. Pregnant or breastfeeding.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px 5.9pt; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 2. Receiving regularly scheduled transfusions.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  3. Hepatobiliary disorders including but not limited to significant liver disease or gallbladder disease.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  4. Severe kidney disease.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  5. Prior exposure to gene therapy or prior bone marrow or stem cell transplantation.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  6. Currently receiving treatment for SCD (eg, voxelotor, crizanlizumab, L glutamine), with the exception of hydroxyurea. The last dose of such  therapies must have been administered at least 90 days before starting study drug.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  7. Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before starting study drug.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  8. Received treatment on another investigational trial within 90 days prior to start of study drug or plans to participate in another investigational drug trial.</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n  9. Taking medications that are strong inhibitors of CYP3A4/5 or strong inducers of CYP3A4 that cannot be stopped in an acceptable timeframe before starting study drug (timeframe will be discussed with your doctor).</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 10. Other protocol defined exclusion criteria may apply</p>\n
      • primary_end_points<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Phase 2 Primary Endpoints</strong>:</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 1. Percentage of participants with hemoglobin (Hb) response</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 2. Percentage of participants with treatment emergent adverse events (AEs) and treatment emergent serious adverse events (SAEs)</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Timepoint(s) of evaluation of this end point:</strong></p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Phase 2 primary endpoint of percentage of participants with Hb response: Week 12</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n Phase 2 primary endpoint of percentage of participants with treatment emergent AEs and treatment emergent SAEs: Up to Week 12</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Phase 3 Primary Endpoints</strong>:</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 1. Percentage of participants with hemoglobin (Hb) response</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n 2. Annualized rate of Sickle Cell Pain Crises (SCPCs)</p>\n<p font-size:=\"\" style=\"margin: 0px 0px 10px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <strong>Timepoint(s) of evaluation of this end point</strong>:</p>\n<ul font-size:=\"\" style=\"padding-right: 0px; padding-left: 0px; margin: 0px 0px 10px 25px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <li style=\"line-height: 20px;\">\n Phase 3 primary endpoint of percentage of participants with Hb response: Week 52</li>\n <li style=\"line-height: 20px;\">\n Phase 3 primary endpoint of annualized rate of sickle cell pain crises:Up to Week 52</li>\n</ul>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence0
      • scope_dose_response1
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
      • trial_therapeutic_exploratory1
      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n <strong>KEMRI/CRDR clinical research Site</strong></p>\n<p>\n Site activities will take place within the KEMRI/CRDR clinical research annex. This facility has several clinical rooms available for consenting, nursing procedures, clinical exams and dosing. There are also additional facilities that include an inpatient ward, staff work areas and a monitoring space, a pharmacy, laboratory and kitchen for preparing participant meals.</p>\n<p>\n Site staff include the principal investigator, 4 medical officers, 2 pharmacists, 1 pharmtech, 5 nurses, 5 quality assurance officers, 3 clinical officers and 6 community health workers.</p>\n<p>\n <strong>Kisumu/SiayaSite</strong></p>\n<p>\n Site activities are located in Kisumu/Siaya and Nairobi Counties. Kisumu hosts the main IP storage site, administrative offices of the PI and co-investigators, procurement and Human Resource functions are housed at theKEMRI Kisian Campus. Recruitment, follow-up of study participants will occur in Siaya. KEMRI has a modern research annex at the Siaya county hospital with capacity to conduct phase I to Phase III studies. After community mobilization, screening and enrollment, IP dispensation will occur at the Siaya Clinical Research Annexe.</p>\n<p>\n Site investigators responsible for day to day running of the project include: Medical Officer 2, Pharmacist 1, Pharm tech 2, Nurses 5, Quality Assurance Officer 2, Quality Control 1, Clinical Officer 2, Community Interviewers 4.</p>\n<p>\n N/A</p>\n<p>\n All the 5 sites have been submitted.</p>\n
      • other_details_explanation<p>\n <strong font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">N/A</strong><span font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">, trial is being conducted in the USA</span></p>\n
      • other_details_regulatory_notapproved<table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" font-size:=\"\" style=\"max-width: 100%; border-collapse: collapse; border-spacing: 0px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <tbody>\n <tr>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 186px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px;\">\n  </p>\n </td>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 153px; height: 13px;\">\n <table border=\"1\" cellpadding=\"1\" cellspacing=\"1\" style=\"width:500px;\">\n <tbody>\n <tr>\n <td>\n Country </td>\n <td>\n Date submited </td>\n <td>\n status </td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n kenya </td>\n <td>\n 01 Sep 2022_ 2 sites </td>\n <td>\n Pending approval </td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n Kenya </td>\n <td>\n 14 Oct  2022 _ 1 site </td>\n <td>\n Pending Apprval</td>\n <td>\n  </td>\n </tr>\n <tr>\n <td>\n Egypt </td>\n <td>\n 13 Jun 2022</td>\n <td>\n Pending  Approval</td>\n <td>\n  </td>\n </tr>\n </tbody>\n </table>\n <p>\n  </p>\n </td>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 61px; height: 13px;\">\n  </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_regulatory_approved<p>\n  </p>\n<table class=\"table table-condensed\" font-size:=\"\" style=\"max-width: 100%; border-collapse: collapse; border-spacing: 0px; width: 915.271px; margin-bottom: 20px; color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">\n <tbody>\n <tr>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221);\">\n <table border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"max-width: 100%; background-color: transparent; border-collapse: collapse; border-spacing: 0px;\">\n <tbody>\n <tr>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 110px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Regualtory</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 103px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Approval Date</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 186px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Number of site per Country</p>\n </td>\n </tr>\n <tr>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 110px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Canada</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 103px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 16 Nov  2021</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 186px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 4</p>\n </td>\n </tr>\n <tr>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 110px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n United Kingdom</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 103px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 13 Sep 2021</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 186px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 7</p>\n </td>\n </tr>\n <tr>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 110px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Belgium</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 103px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 16 Feb 2022</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 186px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 8</p>\n </td>\n </tr>\n <tr>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 110px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n France</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 103px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 27 Jan 2022</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 186px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 6</p>\n </td>\n </tr>\n <tr>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 110px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Germany</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 103px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 07 Apr 2022</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 186px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 4</p>\n </td>\n </tr>\n <tr>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 110px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Italy</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 103px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 23 Feb 2022</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 186px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 8</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 148px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Regulatory Authority</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 90px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Approved Date</p>\n </td>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 161px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Number of site per country</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 148px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Netherlands</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 90px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 23 Dec 2021</p>\n </td>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 161px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 148px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Brazil</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 90px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 21 Jan 2022</p>\n </td>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 161px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 8</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 148px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n Israel</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 90px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 09 Aug 2021</p>\n </td>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 161px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 4</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 148px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n United States of America</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 90px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 26 May 2022</p>\n </td>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 161px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px 0.55pt;\">\n 23</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 148px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px;\">\n Turkey</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 90px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px;\">\n 04 Jul 2022 </p>\n </td>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 161px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px;\">\n 5</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 148px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px;\">\n Saudia Arabia</p>\n </td>\n <td colspan=\"2\" style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 90px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px;\">\n 06Sep 2022</p>\n </td>\n <td style=\"vertical-align: top; padding: 4px 5px; line-height: 20px; border-top-style: solid; border-top-color: rgb(221, 221, 221); width: 161px; height: 13px;\">\n <p style=\"margin: 0px 0px 10px;\">\n 3</p>\n </td>\n </tr>\n </tbody>\n </table>\n <p style=\"margin: 0px 0px 10px;\">\n Nigeria _ 22 Aug 2022 - sites _6 </p>\n <p style=\"margin: 0px 0px 10px;\">\n Kenya _ 06 Sep  2022 _ sites approved 2 out of 7 .</p>\n <div>\n  </div>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_regulatory_rejected<p>\n <span font-size:=\"\" style=\"color: rgb(51, 51, 51); font-family: \" trebuchet=\"\">No Regulatory authority nor Ethics Committee has rejected this trial</span></p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration9 years 10 months 0 days
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherYes
      • design_controlled_specifyThere is an open label extension period following completion of the double blind period.
      • 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_states17
      • number_of_sites7
      • multi_country_listBelgium Brazil Canada Egypt France Germany Israel Italy Kenya Lebanon Netherlands Nigeria Oman Saudi Arabia Turkey\nUnited Kingdom United States
      • data_monitoring_committeeYes
      • total_enrolment_per_siteNo maximum nor minimum enrolment per site as enrolment is competitive world wide
      • total_participants_worldwide267 for both phases(69 in Phase 2 and 198 in Phase 3)
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_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_consentYes
      • subjects_specifyFor subjects under 18 Years of age written informed assent/consent will be obtained from parents and child assent. It must be obtained before any study-related procedures are conducted
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameBernhards
      • investigator1_middle_nameRagama
      • investigator1_family_nameOgutu
      • investigator1_qualificationMedical Doctor
      • investigator1_professional_addressStrathmore University Medical Centre_CREATES Madaraka Estate, Ole Sangale Road P.O Box 59857-00200 Nairobi
      • investigator1_telephone+254 733812613
      • investigator1_emailogutu6@gmail.com
      • organisations_transferred_Yes
      • number_participantsEnrolment is competitive world wide
      • notification
      • approval_date26-02-2023
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted16-12-2022
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe Approval is based on review of a similar study ECCT/22/10/02, alongside response of PI to reviewer comments.\n
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-04-18 01:59:18
      • created2022-10-14 11:33:51
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id853
        • application_id1178
        • given_nameVidelis
        • middle_nameN
        • family_nameNduba
        • qualificationMedical Doctor
        • professional_addressKEMRI-CRDR , Kenyata National Hospital
        • telephone+254724522474
        • emailvnduba@gmail.com
        • created2022-10-14 11:35:08
        • modified2022-12-16 22:48:30
    • SiteDetail(array)
      • 0(array)
        • id1322
        • application_id1178
        • county_id47
        • site_nameKEMRI/CRDR
        • physical_addressKenyatta National Hospital Off Hospital Road, CRDR
        • contact_detailsTel:+254790484654, P.O Box 47855-00100
        • contact_personProf. Videlis Nduba
        • site_capacity(null)
        • misc(null)
        • created2022-10-14 11:35:08
        • modified2022-12-16 22:48:30
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 1(array)
        • id1324
        • application_id1178
        • county_id41
        • site_nameKEMRI Siaya Clinical Research Annex
        • physical_addressKEMRI Clinical research Annex,Siaya County Hospital,
        • contact_detailsTel: +254722205901, P.O Box 144-40600
        • contact_personProf. Videlis Nduba
        • site_capacity(null)
        • misc(null)
        • created2022-10-31 08:28:02
        • modified2022-12-16 22:48:30
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
    • Sponsor(array)
      • 0(array)
        • id607
        • application_id1178
        • sponsorAgios Pharmaceuticals, Inc.
        • sponsor_typeIndustry
        • contact_personJamie Cohen
        • address88 Sidney Street Cambridge, MA 02139-4169 USA
        • telephone_number+1 617-844-6657
        • fax_number+1 617-588-0455
        • cell_number+1 617-844-6657
        • email_addressJamie.cohen@agios.com
        • created2022-10-14 11:35:08
        • modified2022-12-16 22:48:30
  • 3(array)
    • Application(array)
      • id1175
      • user_id693
      • trial_status_id6
      • abstract_of_study<p align=\"center\" style=\"margin-left:224.7pt;\">\n <strong>Ab</strong><strong>stract of </strong><strong>the  study: </strong></p>\n<p style=\"margin-left:5.9pt;\">\n <strong>B</strong><strong>a</strong><strong>c</strong><strong>k</strong><strong>g</strong><strong>r</strong><strong>o</strong><strong>und</strong><strong>:</strong></p>\n<p style=\"margin-left:5.9pt;\">\n Sickle cell disease (SCD) is a serious and life-threatening inherited hemoglobin (Hb) disorder caused by a single amino acid substitution in the beta (β)-globin gene (β s c.20A>T; rs334). Sickle cell disease affects millions of people worldwide. The homozygous form (HbSS) occurs in most cases and represents approximately 88% to 96% in certain areas of Africa. Preliminary data indicate that mitapivat may reduce Hemoglobin S polymerization, sickling, and hemolysis. Therefore, in this study mitapivat is a therapeutic candidate for the treatment of adult patients with SCD with the potential to provide clinical benefit by both improvement of anemia and reduction in sickle cell pain crises (SCPCs).</p>\n<p style=\"margin-left:5.9pt;\">\n The only current curative treatment approach for some patients with SCD is bone marrow transplant. However, a lack of histocompatible donors, concerns about transplantrelated morbidity and mortality, and pre-existing conditions (organ dysfunction or alloimmunization) often preclude patients from pursuing this treatment option. For decades, hydroxyurea was the only disease-modifying therapy available for patients with SCD. Hydroxyurea is indicated to reduce the frequency of painful crises; however, its use  is limited by its safety profile, which includes myelosuppression (neutropenia and thrombocytopenia) and gastrointestinal toxicity. Reduced fertility has been reported as a longterm adverse effect.</p>\n<p style=\"margin-left:5.9pt;\">\n <strong>J</strong><strong>u</strong><strong>s</strong><strong>t</strong><strong>i</strong><strong>f</strong><strong>i</strong><strong>c</strong><strong>a</strong><strong>t</strong><strong>i</strong><strong>o</strong><strong>n</strong><strong>/</strong><strong>R</strong><strong>a</strong><strong>t</strong><strong>i</strong><strong>o</strong><strong>n</strong><strong>a</strong><strong>l</strong><strong>e</strong><strong>:</strong></p>\n<p style=\"margin-left:5.9pt;\">\n The use  of curative options for SCD is currently limited to a small subgroup of patients who are deemed fit for bone marrow transplantation and have available donors. The treatment options for SCD are not universally effective or globally available, tend to address only a single component of the disease, or are limited by their safety profile. Therefore, a significant unmet medical need exists for safe and effective therapies for the treatment of SCD that result in both an improvement in anemia and reduction in sickle cell–related crises.</p>\n<p style=\"margin-left:5.9pt;\">\n Mitapivat is a small molecule, oral activator of wild-type (WT) and mutant forms of the RBC-specific form of pyruvate kinase (PKR). Activation of PKR has potential application in the treatment of hemolytic anemias, including SCD, which are characterized by increased metabolic demands or by defects in glycolysis that contribute to the shortened life span of the RBC. Decreases in PKR function, exemplified in patients with pyruvate kinase deficiency, leads to dysfunctional RBCs that are characterized by defective glycolysis, including a build-up of 2,3-DPG and PEP with decreased levels of ATP. However, there is evidence that the activation of the normal (WT) PKR enzyme can play a role in other hemolytic anemias such  as SCD.</p>\n<p style=\"margin-left:5.9pt;\">\n <strong>Ma</strong><strong>in </strong><strong>O</strong><strong>b</strong><strong>j</strong><strong>e</strong><strong>c</strong><strong>t</strong><strong>i</strong><strong>v</strong><strong>e</strong><strong>s</strong>: <strong>Pha</strong><strong>se </strong><strong>2</strong><strong>:</strong></p>\n<p style=\"margin-left:5.9pt;\">\n 1. To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on:</p>\n<p style=\"margin-left:5.9pt;\">\n • Anemia in subjects with sickle cell disease (SCD)</p>\n<p style=\"margin-left:5.9pt;\">\n • Safety</p>\n<p style=\"margin-left:5.9pt;\">\n Phase 3: 1. To determine the effect of mitapivat versus placebo on:</p>\n<p style=\"margin-left:5.9pt;\">\n • Anemia in subjects with sickle cell disease (SCD)</p>\n<p style=\"margin-left:5.9pt;\">\n • Sickle cell pain crises (SCPCs) in subjects with SCD</p>\n<p style=\"margin-left:5.9pt;\">\n Secondary objectives:</p>\n<p style=\"margin-left:5.9pt;\">\n <strong>Pha</strong><strong>se </strong><strong>2</strong><strong>:</strong></p>\n<p style=\"margin-left:5.9pt;\">\n 1. To evaluate the effect of 2 doses of mitapivat versus placebo on:</p>\n<p style=\"margin-left:29.9pt;\">\n <img height=\"4\" src=\"file:///C:/Users/kimettjc/AppData/Local/Temp/msohtmlclip1/01/clip_image001.gif\" width=\"4\" />Anemia</p>\n<p style=\"margin-left:29.9pt;\">\n <img height=\"4\" src=\"file:///C:/Users/kimettjc/AppData/Local/Temp/msohtmlclip1/01/clip_image002.gif\" width=\"4\" />Markers of hemolysis and erythropoiesis</p>\n<p style=\"margin-left:29.9pt;\">\n <img height=\"4\" src=\"file:///C:/Users/kimettjc/AppData/Local/Temp/msohtmlclip1/01/clip_image003.gif\" width=\"4\" />Patient-reported fatigue</p>\n<p style=\"margin-left:29.9pt;\">\n <img height=\"4\" src=\"file:///C:/Users/kimettjc/AppData/Local/Temp/msohtmlclip1/01/clip_image004.gif\" width=\"4\" />Sickle cell pain crises (SCPCs)</p>\n<p style=\"margin-left:5.9pt;\">\n 2. To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat.</p>\n<p style=\"margin-left:5.9pt;\">\n <strong>Pha</strong><strong>se </strong><strong>3</strong><strong>:</strong></p>\n<p style=\"margin-left:5.9pt;\">\n 1. To evaluate the effect of mitapivat versus placebo on:</p>\n<p style=\"margin-left:5.9pt;\">\n • Anemia in subjects with SCD</p>\n<p style=\"margin-left:5.9pt;\">\n • Markers of hemolysis</p>\n<p style=\"margin-left:5.9pt;\">\n • Markers of erythropoiesis</p>\n<p style=\"margin-left:5.9pt;\">\n • Patient-reported fatigue</p>\n<p style=\"margin-left:5.9pt;\">\n • Additional clinical efficacy measures related to SCPC</p>\n<p style=\"margin-left:5.9pt;\">\n <strong>M</strong><strong>e</strong><strong>t</strong><strong>h</strong><strong>o</strong><strong>d</strong><strong>s</strong><strong>:</strong></p>\n<p style=\"margin-left:5.9pt;\">\n <strong>Ove</strong><strong>rall Study </strong><strong>d</strong><strong>e</strong><strong>s</strong><strong>i</strong><strong>g</strong><strong>n</strong></p>\n<p style=\"margin-left:5.9pt;\">\n This is a Phase 2/3, double-blind, randomized, placebo-controlled, global, multicenter study evaluating the efficacy and safety of mitapivat versus placebo in subjects with SCD using an operationally seamless design. The Phase 2 portion is a double-blind, randomized, placebo-controlled, dose-finding study evaluating 2 dose levels of mitapivat (50 mg BID and 100 mg BID) versus placebo to select the dose of mitapivat to be evaluated in the Phase 3 portion. The Phase 3 portion is a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of mitapivat at the selected Phase 3 dose versus placebo. Subjects who complete the Double-blind Period in eitherthe Phase 2 or Phase 3 portion will have the option to receive mitapivat in the Open-label Extension Period. A total of 267 subjects (69 in Phase 2 and 198 in Phase 3)</p>\n<p style=\"margin-left:5.9pt;\">\n will be randomized in this study. The initiation of the Phase 3 portion will be based on prespecified go/no-go criteria and dose selection criteria. Subjects who participate in the</p>\n<p style=\"margin-left:5.9pt;\">\n Phase 2 portion of the study are not eligible to participate in the Phase 3 portion of the study.</p>\n<p style=\"margin-left:5.9pt;\">\n <strong>S</strong><strong>tudy </strong><strong>o</strong><strong>u</strong><strong>tc</strong><strong>o</strong><strong>m</strong><strong>e</strong><strong>s</strong><strong>:</strong></p>\n<p style=\"margin-left:5.9pt;\">\n The primary outcome, or endpoint, for the phase 2 study is hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 10 through Week 12 compared with baseline and safety defined as adverse events (AEs) and serious adverse events (SAEs). The primary outcome for the phase 3 study is Hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 24 through Week 52 compared with baseline and annualized rate of sickle cell pain crises (SCPCs) in subjects with SCD.</p>\n<p style=\"margin-left:5.9pt;\">\n <strong>S</strong><strong>tudy </strong><strong>du</strong><strong>r</strong><strong>a</strong><strong>t</strong><strong>i</strong><strong>o</strong><strong>n</strong><strong>:</strong></p>\n<p style=\"margin-left:5.9pt;\">\n The duration of participation of a subject in the Phase 2 portion is up to 4.5 years (236 weeks). The duration of participation of a subject in the Phase 3 portion is up to 5.3 years (276 weeks). The end of the study is defined as the time at which all subjects complete all study visits, are lost to follow-up, have withdrawn consent for further participation in the study, or when the Sponsor terminates the study.</p>\n<p>\n  </p>\n
      • study_title<p>\n A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Mitapivat in Subjects With Sickle Cell Disease. Mitapivat - AG348-C-020</p>\n
      • laymans_summary<p>\n Sickle cell disease (SCD) is an inherited blood disorder where the red blood cells, which carry oxygen around the body, develop abnormally and become rigid and shaped like a crescent (sickle shape). Sickle cell disease affects millions of people worldwide and is very common in certain areas of Africa. This study will look at a possible drug for treatment of Sickle cell disease called Mitapivat. Results from earlier studies with mitapivat shows that it may reduce the change of shape in red blood cells which makes them look like a sickle and causes the red blood cells to be destroyed resulting in a person with sickle cell disease getting low blood level (anemia). Therefore, in this study mitapivat is a drug candidate for the treatment of adult patients with sickle cell disease with the potential to provide clinical benefit by both improvement of anemia and reduction in sickle cell pain crisis.</p>\n<p>\n  </p>\n<p>\n This study has both a Phase 2 and a Phase 3. The main aim of the Phase 2 portion of the study is to define how mitapivat works in the short term, how safe it is and the right dose which will be selected for the Phase 3 portion of the study. The aim of the Phase 3 portion of the study is to assess the how well the selected dose of mitapivat works for treatment and how safe it when used in patients with sickle cell disease. This portion of the study is intended to show the extent to which mitapivat treatment reduces painful crisis because of blocked blood vessels and reduces anemia in sickle cell disease. In this Phase2/3 study, both the participant and most study staff including the doctors don’t know which treatment has been given to the participant (referred to as doubleblind). One group of study participants called the treatment group will receive the mitapivat and another group called the control group will receive a study treatment with no active ingredient called a placebo.</p>\n<p>\n  </p>\n<p>\n The study is being done in different countries around the world, in multiple study centers in participants with SCD. The Phase 2 portion dose-finding study will assess 2 dose levels of mitapivat (50 mg twice a day and 100 mg twice a day) versus placebo to select the dose of mitapivat to be evaluated in the Phase 3 portion. The Phase 3 portion is a double-blind, randomized, placebo-controlled study evaluating how effective and safe mitapivat is at the selected Phase 3 dose versus placebo. Participants who complete the Double-blind Period in the Phase 2/3 portion will have the option to receive mitapivat in the non-blinded (Open label) Extension Period. Approximately 267 participants (69 in Phase 2 and 198 in Phase 3) are planned to be enrolled in this study worldwide. In Kenya there are 7 sites ,3 sites in Nairobi,1 in western and 3 in Nyanza. Enrollment is competitive world wide. Abstract</p>\n
      • short_titleAgios Study
      • protocol_noECCT/22/10/02
      • version_noAmendment 1 (V1.0)
      • date_of_protocol09-03-2022
      • study_drugMitapivat _ Dr Oyieko Janet
      • 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_nameMitapivat
      • product_type_medical_device_name
      • comparatorNo
      • comparator_name
      • comparator_registered
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressPPDSubmissionsMembers.SM@ppd.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_applicantMillicent Aketch
      • declaration_date114-10-2022
      • declaration_principal_investigatorDr Ogutu Bernhards
      • declaration_date214-10-2022
      • placebo_presentYes
      • study_objectives<p>\n * Main objective:</p>\n<p>\n <strong>Phase 2:</strong></p>\n<p>\n 1. To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on</p>\n<p>\n : • Anemia in subjects with sickle cell disease (SCD). and</p>\n<ul>\n <li>\n Safety </li>\n</ul>\n<p>\n  </p>\n<p>\n <strong>Safety Phase 3:</strong></p>\n<p>\n 1. To determine the effect of mitapivat versus placebo on</p>\n<p>\n : • Anemia in subjects with sickle cell disease (SCD)</p>\n<p>\n • Sickle cell pain crises (SCPCs) in subjects with SCD</p>\n<p>\n <strong>Secondary objectives:</strong></p>\n<p>\n <strong>Phase 2</strong>:</p>\n<p>\n 1. To evaluate the effect of 2 doses of mitapivat versus placebo on:</p>\n<p>\n Anemia</p>\n<p>\n Markers of hemolysis and erythropoiesis</p>\n<p>\n Patient-reported fatigue</p>\n<p>\n Sickle cell pain crises (SCPCs)</p>\n<p>\n 2. To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat.</p>\n<p>\n <strong>Phase 3</strong>:</p>\n<p>\n 1. To evaluate the effect of mitapivat versus placebo on:</p>\n<p>\n Anemia in subjects with SCD</p>\n<p>\n Markers of hemolysis Markers of erythropoiesis</p>\n<p>\n Patient-reported fatigue</p>\n<p>\n Additional clinical efficacy measures related to SCPC</p>\n
      • principal_inclusion_criteria<p style=\"margin-left:5.9pt;\">\n 1. Age ≥16 years; subjects age 16 or 17 years must physically have completed puberty.</p>\n<p style=\"margin-left:5.9pt;\">\n 2. Documented diagnosis of SCD (HbSS, HbSC, HbS/β0-thalassemia, HbS/β+ thalassemia, or other sickle cell syndrome variants).</p>\n<p>\n  3. At least 2 sickle cell pain crises (SCPCs) and no more than 10 SCPCs in the past 12 months.</p>\n<p>\n  4. Hemoglobin ≥5.5 and ≤10.5 g/dL.</p>\n<p>\n  5. If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days before starting study drug.</p>\n<p>\n  6. Women capable of becoming pregnant and men with partners who are women that are capable of becoming pregnant must agree to use  2 forms of contraception.</p>\n<p>\n 7. Other protocol-defined inclusion criteria may apply</p>\n
      • principal_exclusion_criteria<p style=\"margin-left:5.9pt;\">\n 1. Pregnant or breastfeeding.</p>\n<p style=\"margin-left:5.9pt;\">\n 2. Receiving regularly scheduled transfusions.</p>\n<p>\n  3. Hepatobiliary disorders including but not limited to significant liver disease or gallbladder disease.</p>\n<p>\n  4. Severe kidney disease.</p>\n<p>\n  5. Prior exposure to gene therapy or prior bone marrow or stem cell transplantation.</p>\n<p>\n  6. Currently receiving treatment for SCD (eg, voxelotor, crizanlizumab, L glutamine), with the exception of hydroxyurea. The last dose of such  therapies must have been administered at least 90 days before starting study drug.</p>\n<p>\n  7. Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before starting study drug.</p>\n<p>\n  8. Received treatment on another investigational trial within 90 days prior to start of study drug or plans to participate in another investigational drug trial.</p>\n<p>\n  9. Taking medications that are strong inhibitors of CYP3A4/5 or strong inducers of CYP3A4 that cannot be stopped in an acceptable timeframe before starting study drug (timeframe will be discussed with your doctor).</p>\n<p>\n 10. Other protocol defined exclusion criteria may apply</p>\n
      • primary_end_points<p>\n <strong>Phase 2 Primary Endpoints</strong>:</p>\n<p>\n 1. Percentage of participants with hemoglobin (Hb) response</p>\n<p>\n 2. Percentage of participants with treatment emergent adverse events (AEs) and treatment emergent serious adverse events (SAEs)</p>\n<p>\n <strong>Timepoint(s) of evaluation of this end point:</strong></p>\n<p>\n Phase 2 primary endpoint of percentage of participants with Hb response: Week 12</p>\n<p>\n Phase 2 primary endpoint of percentage of participants with treatment emergent AEs and treatment emergent SAEs: Up to Week 12</p>\n<p>\n <strong>Phase 3 Primary Endpoints</strong>:</p>\n<p>\n 1. Percentage of participants with hemoglobin (Hb) response</p>\n<p>\n 2. Annualized rate of Sickle Cell Pain Crises (SCPCs)</p>\n<p>\n <strong>Timepoint(s) of evaluation of this end point</strong>:</p>\n<ul>\n <li>\n Phase 3 primary endpoint of percentage of participants with Hb response: Week 52</li>\n <li>\n Phase 3 primary endpoint of annualized rate of sickle cell pain crises:Up to Week 52</li>\n</ul>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic1
      • scope_bioequivalence1
      • 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_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n Kombewa Clinical Research Centre</p>\n<p>\n The KEMRI/WRP Kombewa Clinical Research Center (KCRC) is designed for large clinical trials and has a full clinical laboratory including microbiology capability. KCRC is part of The Walter Reed Project (WRP), which is a 40-year collaboration between the Kenya Medical Research Institute, (KEMRI) and the Walter Reed Army Institute of Research (WRAIR).</p>\n<p>\n The US Army Medical Research Unit in Kenya (USAMRU-K) is a WRAIR attachment stationed in Kenya with headquarters in Nairobi and field stations in Kericho and Kisumu. WRP-Kisumu conducts a wide spectrum of field and laboratory work including numerous clinical research trials. The study will be conducted at the KCRC and recruitment will occur at the Kombewa County hospital as well as in the surrounding health facilities. </p>\n<p>\n The KEMRI/WRP Clinical Research Centre in Kombewa is staffed by KEMRI/WRP qualified research personnel, some of whom will be involved with recruitment of study subjects and conduct of the study. The KCRC is located opposite the Kombewa County Hospital in Kisumu West District of Nyanza Province in Western Kenya. It is located about 40 kilometres west of Kisumu town and has previously been used as a site for many clinical trials and epidemiological studies involving both adults and children on malaria, trypanosomiasis, leishmaniasis, entomology, HIV/AIDS and arboviruses.</p>\n<p>\n INVESTIGATORS AND COORDINATORS: ROLES AND RESPONSIBILITIES</p>\n<p>\n Dr. Janet Oyieko, Principal Investigator Kombewa Clinical Research Centre: will be responsible for the overall conduct of the trial at this study site, administrative actions between WRP, Institutional Review Boards, and the sponsor, oversight of field activities and care accorded to participants. She contributed to the site protocol addendum development and may contribute to the writing of the scientific report(s). </p>\n<p>\n Dr. Jack Hutter, Associate Investigator: will be responsible for the site administrative conduct of the trial, oversight of field activities. He contributed to the protocol addendum development and may contribute to writing of scientific report(s).</p>\n<p>\n Dr. Walter Otieno, Associate Investigator: will be responsible for the clinical conduct of the trial, the care provided to participants, oversight of field activities. He contributed to the protocol addendum development and may contribute to the writing of scientific report(s).</p>\n<p>\n Dr. Valentine Sing’oei, Associate Investigator: will be responsible for the clinical conduct of the trial, the care provided to participants, oversight of field activities. She may contribute to the writing of scientific report(s).</p>\n<p>\n Dr. Michal Ohaga, Associate Investigator: will be responsible for the clinical conduct of the trial, the care provided to participants, oversight of field activities. She may contribute to the writing of scientific report(s).</p>\n<p>\n Irene Onyango- Regulatory Affairs oversight will be responsible for communication with IRBs and ECs.</p>\n<p>\n Millicent Achola - Clinical Research Coordinator; responsible for overall study coordination while working in a team environment under the direction of the investigators. Coordinating the recruiting, screening, and enrolling of study participants; arranging follow-up visits; completing and ensuring the accuracy of CRFs and regulatory documents; and ensuring the adherence to GCP guidelines.</p>\n
      • other_details_explanation<p>\n <strong>N/A</strong>, trial is being conducted in the USA</p>\n
      • other_details_regulatory_notapproved<table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n <tbody>\n <tr>\n <td style=\"width:186px;height:13px;\">\n <p>\n Kenya </p>\n </td>\n <td style=\"width:153px;height:13px;\">\n <p>\n 01 Sep  2022 </p>\n </td>\n <td style=\"width:61px;height:13px;\">\n <p>\n 2 additional sites submitted </p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n  </p>\n
      • other_details_regulatory_approved<table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n <tbody>\n <tr>\n <td style=\"width:110px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Regualtory</p>\n </td>\n <td colspan=\"2\" style=\"width:103px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Approval Date</p>\n </td>\n <td colspan=\"2\" style=\"width:186px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Number of site per Country</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:110px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Canada</p>\n </td>\n <td colspan=\"2\" style=\"width:103px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 16 Nov  2021</p>\n </td>\n <td colspan=\"2\" style=\"width:186px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 4</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:110px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n United Kingdom</p>\n </td>\n <td colspan=\"2\" style=\"width:103px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 13 Sep 2021</p>\n </td>\n <td colspan=\"2\" style=\"width:186px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 7</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:110px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Belgium</p>\n </td>\n <td colspan=\"2\" style=\"width:103px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 16 Feb 2022</p>\n </td>\n <td colspan=\"2\" style=\"width:186px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 8</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:110px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n France</p>\n </td>\n <td colspan=\"2\" style=\"width:103px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 27 Jan 2022</p>\n </td>\n <td colspan=\"2\" style=\"width:186px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 6</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:110px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Germany</p>\n </td>\n <td colspan=\"2\" style=\"width:103px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 07 Apr 2022</p>\n </td>\n <td colspan=\"2\" style=\"width:186px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 4</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:110px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Italy</p>\n </td>\n <td colspan=\"2\" style=\"width:103px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 23 Feb 2022</p>\n </td>\n <td colspan=\"2\" style=\"width:186px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 8</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:148px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Regulatory Authority</p>\n </td>\n <td colspan=\"2\" style=\"width:90px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Approved Date</p>\n </td>\n <td style=\"width:161px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Number of site per country</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:148px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Netherlands</p>\n </td>\n <td colspan=\"2\" style=\"width:90px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 23 Dec 2021</p>\n </td>\n <td style=\"width:161px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 1</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:148px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Brazil</p>\n </td>\n <td colspan=\"2\" style=\"width:90px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 21 Jan 2022</p>\n </td>\n <td style=\"width:161px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 8</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:148px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n Israel</p>\n </td>\n <td colspan=\"2\" style=\"width:90px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 09 Aug 2021</p>\n </td>\n <td style=\"width:161px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 4</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:148px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n United States of America</p>\n </td>\n <td colspan=\"2\" style=\"width:90px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 26 May 2022</p>\n </td>\n <td style=\"width:161px;height:13px;\">\n <p style=\"margin-left:.55pt;\">\n 23</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:148px;height:13px;\">\n <p>\n Turkey</p>\n </td>\n <td colspan=\"2\" style=\"width:90px;height:13px;\">\n <p>\n 04 Jul 2022 </p>\n </td>\n <td style=\"width:161px;height:13px;\">\n <p>\n 5</p>\n </td>\n </tr>\n <tr>\n <td colspan=\"2\" style=\"width:148px;height:13px;\">\n <p>\n Saudia Arabia</p>\n </td>\n <td colspan=\"2\" style=\"width:90px;height:13px;\">\n <p>\n 06Sep 2022</p>\n </td>\n <td style=\"width:161px;height:13px;\">\n <p>\n 3</p>\n </td>\n </tr>\n </tbody>\n</table>\n<p>\n Nigeria _ 22 Aug 2022 - sites _6 </p>\n<p>\n Kenya _ 06 Sep  2022 _ sites approved 2 out of 7 .</p>\n
      • other_details_regulatory_rejected<p style=\"margin-left:5.9pt;\">\n No Regulatory authority nor Ethics Committee has rejected this trial</p>\n
      • other_details_regulatory_halted<p>\n N/A</p>\n
      • estimated_duration9 years 10 months 0 days
      • design_controlled_randomisedYes
      • design_controlled_openNo
      • design_controlled_single_blindNo
      • design_controlled_double_blindYes
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherYes
      • design_controlled_specifyThere is an open label extension period following completion of the double blind period.
      • 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_states17
      • number_of_sites7
      • multi_country_listBelgium Brazil Canada Egypt France Germany Israel Italy Kenya Lebanon Netherlands Nigeria Oman Saudi Arabia Turkey\nUnited Kingdom United States\n
      • data_monitoring_committeeYes
      • total_enrolment_per_siteNo maximum nor minimum enrolment per site as enrolment is competitive world wide
      • total_participants_worldwide267 for both phases(69 in Phase 2 and 198 in Phase 3)
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenNo
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_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_consentYes
      • subjects_specifyFor subjects under 18 Years of age written informed assent/consent will be obtained from parents and child assent. It must be obtained before any study-related procedures are conducted
      • subjects_othersNo
      • subjects_others_specify
      • investigator1_given_nameBernhards
      • investigator1_middle_nameRagama
      • investigator1_family_nameOgutu
      • investigator1_qualificationMedical Doctor
      • investigator1_professional_addressStrathmore University Medical Centre_CREATES Madaraka Estate, Ole Sangale Road P.O Box 59857-00200 Nairobi
      • investigator1_telephone+254 733812613
      • investigator1_emailogutu6@gmail.com
      • organisations_transferred_Yes
      • number_participantsEnrolment is competitive world wide
      • notification
      • approval_date10-02-2023
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted14-10-2022
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonThe reviewer comments have been reviewed internally and considered adequate.
      • final_report(null)
      • implication_results(null)
      • quantity_imported(null)
      • quantity_dispensed(null)
      • quantity_destroyed(null)
      • quantity_exported(null)
      • balance_site(null)
      • final_date(null)
      • modified2025-04-17 23:41:34
      • created2022-09-27 09:23:19
      • total_sites(null)
      • ecitizen_invoice(null)
    • InvestigatorContact(array)
      • 0(array)
        • id852
        • application_id1175
        • given_nameJanet
        • middle_nameN
        • family_nameOyieko
        • qualificationPediatrician
        • professional_addressKEMRI_CCR
        • telephone+254721996988
        • emailJanet.Oyieko@gmail.com
        • created2022-09-27 09:24:50
        • modified2022-10-14 14:51:43
    • SiteDetail(array)
      • 0(array)
        • id1315
        • application_id1175
        • county_id42
        • site_name Kombewa Clinical Research Centre
        • physical_addressKombewa, Opposite Kombewa Sub-County Hospital
        • contact_details +254721996988
        • contact_personDr Janet Oyieko
        • site_capacity(null)
        • misc(null)
        • created2022-09-27 09:24:50
        • modified2022-10-14 14:51:43
        • County(array)
          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 1(array)
        • id1316
        • application_id1175
        • county_id42
        • site_nameVictoria Biomedical Research Institute
        • physical_addressButere County Hospital, Postal Code 40100, Kisumu, Kenya
        • contact_detailsTel: +254 720 597654 P.O. Box 7180
        • contact_personDr. Lucas Otieno Tina
        • site_capacity(null)
        • misc(null)
        • created2022-09-27 12:42:07
        • modified2022-10-14 14:51:43
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          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
      • 2(array)
        • id1317
        • application_id1175
        • county_id47
        • site_nameKEMRI/CRDR
        • physical_address Kenyatta National Hospital Off Hospital Road, CRDR
        • contact_detailsTel:+254790484654, P.O Box 47855-00100
        • contact_personProf. Videlis Nduba
        • site_capacity(null)
        • misc(null)
        • created2022-09-27 12:42:07
        • modified2022-10-14 14:51:43
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 3(array)
        • id1318
        • application_id1175
        • county_id41
        • site_nameKEMRI Siaya Clinical Research Annex
        • physical_address KEMRI Clinical research Annex,Siaya County Hospital,
        • contact_detailsTel: +254722205901, P.O Box 144-40600
        • contact_personProf. Videlis Nduba
        • site_capacity(null)
        • misc(null)
        • created2022-09-27 12:42:07
        • modified2022-10-14 14:51:43
        • County(array)
          • id41
          • county_nameSiaya
          • created2012-06-15 10:26:56
          • modified2012-06-15 10:26:56
      • 4(array)
        • id1319
        • application_id1175
        • county_id47
        • site_nameGertrude’s Children’s Hospital
        • physical_addressGertrude’s Children’s Hospital, 34 Muthaiga Road
        • contact_details+254 721245721
        • contact_personProf. Jessie Githanga
        • site_capacity(null)
        • misc(null)
        • created2022-09-27 12:42:07
        • modified2022-10-14 14:51:43
        • County(array)
          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
      • 5(array)
        • id1320
        • application_id1175
        • county_id42
        • site_nameKEMRI Kondele Children\'s Hospital
        • physical_addressKondele Children\'s Hospital
        • contact_details+254714481488
        • contact_personDr Godfrey Allan Otieno
        • site_capacity(null)
        • misc(null)
        • created2022-09-27 12:42:07
        • modified2022-10-14 14:51:43
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          • id42
          • county_nameKisumu
          • created2012-06-15 10:27:02
          • modified2012-06-15 10:27:02
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        • id1321
        • application_id1175
        • county_id47
        • site_nameStrathmore University Medical Centre
        • physical_addressStrathmore University Medical Centre, Ole Sangale Rd
        • contact_details+254733813613
        • contact_personDr Bernhards Ogutu
        • site_capacity(null)
        • misc(null)
        • created2022-09-27 12:42:07
        • modified2022-10-14 14:51:43
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          • id47
          • county_nameNairobi City
          • created2012-06-15 10:27:40
          • modified2012-06-15 10:27:40
    • Sponsor(array)
      • 0(array)
        • id606
        • application_id1175
        • sponsorAgios Pharmaceuticals, Inc.
        • sponsor_typeIndustry
        • contact_personJamie Cohen
        • address88 Sidney Street Cambridge, MA 02139-4169 USA
        • telephone_number+1 617-844-6657
        • fax_number+1 617-588-0455
        • cell_number+1 617-844-6657
        • email_addressJamie.cohen@agios.com
        • created2022-09-27 09:24:50
        • modified2022-10-14 14:51:43
  • 4(array)
    • Application(array)
      • id1168
      • user_id81
      • trial_status_id5
      • abstract_of_study<address>\n Malaria continues to be a major public health problem in developing countries. Insecticide resistance and mosquito behavioral adaptations contribute to sustain transmission, even after scale-up of key vector control interventions. Mass administration of ivermectin, a drug capable of killing malaria vector that feed upon treated subjects is a potential new tool against residual transmission. This trial will assess the efficacy and safety of this new intervention. The design is cluster-randomized, parallel groups, open label and assessor blinded. The main outcome measures are malaria incidence in an active pediatric cohort of children 5-15 years old and incidence of adverse events in the treated population. The active cohort is followed for six months and receives a malaria test every visit. The treatment cohort is followed for four months and receives a single dose of ivermectin (400 mcg/Kg) monthly for three months or a single dose of albendazole (400 mg) as control.</address>\n<p>\n  </p>\n<p>\n  </p>\n<p>\n  </p>\n
      • study_title<p>\n A Phase III cluster-randomized, open-label, clinical trial to study the safety and efficacy of ivermectin mass drug administration to reduce malaria transmission in Kwale, Kenya<strong><em>.  </em></strong></p>\n<p>\n  </p>\n
      • laymans_summary<p>\n <strong>LAY SUMMARY</strong></p>\n<p>\n Lay Title</p>\n<p>\n Evaluation of ivermectin mass drug treatment to reduce malaria transmission in Coastal Kenya.</p>\n<p>\n  </p>\n<p>\n What is the problem/background?</p>\n<p>\n Malaria is transmitted by mosquitoes. Malaria has been reduced in Kenya using bed-nets and spraying of insecticides that kill mosquitoes, but malaria still exists in many places including in Kwale. Mosquitoes can adapt, become resistant to insecticides, and change their behavior to bite at times when people are not under their bed-net as well as on animals. We need to find a way to fight mosquitoes in addition to the bed nets, that can control mosquitoes that bite outdoors and when people are not under their nets. Ivermectin is a drug commonly used as to treat worms, however if a mosquito bites a human or animal who has been treated with ivermectin it will not survive for a long time and may not be able to spread malaria. Administering ivermectin to as many people as possible at the same time in a community, might be a new way to control the mosquitoes and needs to be tested. We also want to know if treating humans and cattle with ivermectin works better than just treating humans, this is because mosquitoes also like to feed on cattle.</p>\n<p>\n  </p>\n<p>\n What questions are we trying to answer?</p>\n<p>\n The study is designed to answer the following questions: is malaria transmission reduced by distributing ivermectin to all human, or humans and cattle,  once a month for three months during the rainy season? Is it safe? The study will be divided in geographic areas called clusters and all residents of each cluster will be allocated to three possible treatments:</p>\n<p style=\"margin-left:27.0pt;\">\n 1) Ivermectin 400mcg/Kg will be given to all eligible humans whilst all cattle in these clusters will be left untreated;</p>\n<p style=\"margin-left:27.0pt;\">\n 2) Ivermectin 400mcg/Kg will be given to all eligible humans and ivermectin 200mcg/Kg will be given to all cattle in these clusters;</p>\n<p style=\"margin-left:27.0pt;\">\n 3) Albendazole 400mg (control) will be given to all eligible humans whilst cattle will be left untreated.</p>\n<p>\n  </p>\n<p style=\"margin-left:21.3pt;\">\n Where is the study taking place, how many people does it involve and how are they selected?</p>\n<p>\n The study will take place in the sub-counties of Msambweni and Lungalunga in Kwale county, Kenya. All residents of the study areas will be eligible for inclusion unless they weigh less than 15kg, are pregnant or are taking certain drugs. In total, approximately 45,000 participants will be recruited with support from the Kwale county community health services platform. The study area will be divided into geographic units called clusters, residents of each cluster will be visited monthly for 3 months during the long rains to receive the treatment and will be followed up for any side effects to assess if the drug is safe (safety). In each cluster we will recruit a group of 25-35 children 5-15 years old. These children will be followed up to assess whether the drug has an impact on malaria (efficacy group). The children will be followed-up monthly through household visits for six months. Every month a study member will take a drop of blood by finger prick for a malaria rapid test and record whether it was negative or positive, if the child is found to have malaria the study team will provide treatment. One month after the last round of treatment, a random sample of people of all-ages living in the study area will be selected to collect a drop of blood on filter paper for determining the proportion of people who have malaria in each group (cross sectional study). In addition, we believe ivermectin may also help control other parasites, for this reason we will randomly select a smaller group of participants (1,044) and examine them for skin lesions caused by other parasites (neglected tropical diseases -NTDs-). Because the effect of ivermectin depends on its blood concentrations, we will ask 160 randomly selected people 18 years or older to provide drops of blood on filter paper which we will analyze in the laboratory for amount of drug. Participants experiencing side-effects of ivermectin such as dizziness may be asked to give a small blood sample to look for two specific genetic variations that can influence ivermectin concentrations in the body.</p>\n<p>\n  </p>\n<p>\n What does the study involve for those who are in it?</p>\n<p>\n Participants will be asked to take ivermectin or albendazole once every month for three months. They will also be requested to answer a few questions about any possible adverse events caused by the drug, or any symptoms experienced in between visits, as well as their healthcare seeking behavior, during four months in total. Women who participate in the treatment group and become pregnant in between visits, will not receive treatment again, but their pregnancy will be followed monthly up to term. The children recruited to the efficacy group will be tested for malaria by finger prick monthly for 6 months. Those who are positive for malaria will receive antimalarial treatment according to national guidelines. The participants in the NTD sub-sample will be examined for skin lesions. The participants in the cross-sectional study will be tested for malaria by finger prick and those who are positive will be treated with anti-malarials. All blood sampling will be done by fingerprick. The amount of blood taken with finger pricks is very small and will be less than a spoonful for the entire study.</p>\n<p>\n What are the benefits and risks/costs of the study for those involved? </p>\n<p>\n Both ivermectin and albendazole are dewormers that are regularly used in deworming campaigns done in Kenya. The ivermectin dose chosen for this clinical trial is higher than what is usually used in Kenya. However, it is approved in a few countries in the European Union. Ivermectin will be used more often than usual because people will be treated once every month and this could potentially lead to build up of the drug in the body, however there is evidence that this is unlikely to occur. Ivermectin should not be taken during pregnancy, for this reason we will ask all women who are old enough to be pregnant (13+) if they agree to a pregnancy test. The test will be a urine test done by the woman in private, the results will not be shared with anyone else. If a woman becomes pregnant in between treatments, they will not be given any more drug and their pregnancy will be followed up to term. There is also risk that drugs that people take regularly can interact with ivermectin, we will ask participants whether they take any medication regularly and exclude them if appropriate.</p>\n<p>\n Other risks to be considered are those arising from taking blood samples (i.e.; small risk of infection, temporary pain or bruising from finger prick). Additionally, there could be a social risk derived from women of child bearing age being asked and tested for pregnancy.</p>\n<p>\n The study will involve no cost for the participants.</p>\n<p>\n  </p>\n<p>\n How will the study benefit society? </p>\n<p>\n This study will benefit society by finding out if mass drug administration of ivermectin can be used as a new way to decrease malaria in addition to bed nets.</p>\n<p>\n  </p>\n<p>\n When does the study start and finish?</p>\n<p>\n The first round of MDA will occur during the long rains season of 2023, participants will be recruited and consented a few days or weeks in advance. Participation of the safety group will end one month after the last dose, whereas the efficacy group will continue up to 6 months after the first dose. For women becoming pregnant during the study, participation will continue for a maximum of 9 months after the third round of treatment. Participants selected to be part of the NTD sub-study will be examined during the safety and efficacy household visits. People in the cross-sectional study will only be part of the study for one household visit, one month after the last dose of study drug. Those participating in the smaller study about ivermectin concentrations will need to be available for a period of five days, the first of which will require a day at a hospital site.</p>\n<p>\n  </p>\n
      • short_titleBOHEMIA Safety and Efficacy
      • protocol_noECCT/23/02/06
      • version_no2.0
      • date_of_protocol19-12-2022
      • study_drugIvermectin Tablets USP, 3mg
      • disease_conditionMalaria
      • product_type_biologicals0
      • product_type_proteins0
      • product_type_immunologicals0
      • product_type_vaccines0
      • product_type_hormones0
      • product_type_toxoid0
      • product_type_chemical1
      • product_type_medical_device0
      • product_type_chemical_nameIvermectin 3mg
      • product_type_medical_device_name
      • comparatorYes
      • comparator_nameAlbendazole 400mg
      • comparator_registeredYes
      • comparator_countries
      • ecct_not_applicable0
      • ecct_ref_number
      • email_addressCGMRCCSC@kemri-wellcome.org
      • applicant_covering_letter1
      • applicant_protocol1
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      • 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
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      • 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_applicantMarta Ferreira Maia
      • declaration_date124-05-2023
      • declaration_principal_investigatorMarta Ferreira Maia
      • declaration_date224-05-2023
      • placebo_presentNo
      • study_objectives<p>\n Primary Objective:</p>\n<p>\n To determine the safety (in humans) and efficacy of ivermectin MDA (administered to humans or humans and livestock simultaneously) for the prevention of malaria.</p>\n<p>\n Secondary Objectives</p>\n<ul>\n <li>\n To assess the efficacy of the intervention using complementary methods (efficacy);\n <ul>\n <li>\n Time to first positive rapid diagnostic test (RDT) in children in the cohort;</li>\n <li>\n Molecular force of infection in a subset of children in the cohort;</li>\n <li>\n Malaria prevalence in all ages one month after the last dose; and</li>\n <li>\n Multiplicity of infection in all ages one month after the last dose.</li>\n </ul>\n </li>\n <li>\n To assess the safety of the intervention with complementary methods (safety);\n <ul>\n <li>\n Observed tolerability of the dose;</li>\n <li>\n Rate of SUSARs; and</li>\n <li>\n AEs and SAEs by organ system.</li>\n </ul>\n </li>\n <li>\n To assess the pharmacokinetics (PK) of the proposed ivermectin dose/regime in its relationship with efficacy and safety outcomes (efficacy and safety);</li>\n <li>\n To assess the impact of ivermectin mass drug administration (MDA) at the proposed regimen on the prevalence of selected ectoparasitic neglected tropical diseases (NTDs);</li>\n <li>\n To assess the relationship between malaria incidence in children 5-15 years old and community prevalence one month post last dose (this serves for prevalence outcomes and paves the way for future studies using prevalence as outcome which is much less resource-consuming than incidence). </li>\n</ul>\n<p>\n Exploratory Objectives:</p>\n<ul>\n <li>\n To assess the relationship between self-reported pregnancy status, last menstrual period (LMP), and the results of pregnancy tests in women of reproductive age participating in the study.</li>\n <li>\n To assess all-cause mortality in intervention and control arms.</li>\n <li>\n To estimate the prevalence of relevant CYP (Cytochrome P 450) and P-gp (<em>P-Glycoprotein)</em> variations in the target population and subjects suffering from CNS-AEs (central nervous system adverse events).</li>\n</ul>\n<p>\n  </p>\n
      • principal_inclusion_criteria<p>\n <strong>Inclusion criteria for those receiving ivermectin or albendazole (safety cohort):</strong></p>\n<ul>\n <li>\n Residents of the study area</li>\n <li>\n Weighing more than 15kg</li>\n <li>\n Adult able to provide written consent</li>\n <li>\n Minors aged 12 to 17 able to provide assent</li>\n <li>\n Minors whose parent/guardians are able to provide consent for them</li>\n <li>\n Agreement to adhere to study visits and procedures</li>\n <li>\n A negative pregnancy test for women 13-49 years old</li>\n</ul>\n<p>\n <strong>Inclusion criteria for those recruited to the cross-sectional malaria infection survey</strong></p>\n<ul>\n <li>\n Children in the age of highest burden at the time of enrollment (5 to under 15 years old)</li>\n <li>\n Residents of the study area</li>\n <li>\n Parent/guardian’s able to provide consent for them</li>\n <li>\n Minors aged 12 to 15 able to provide assent</li>\n</ul>\n<p>\n <strong>For cross sectionals</strong></p>\n<ul>\n <li>\n Residents of the area</li>\n <li>\n Parent/guardian’s consent for minors</li>\n <li>\n Ability to provide assent for minors aged 12 to 17</li>\n <li>\n Written consent from adults</li>\n</ul>\n<p>\n  </p>\n
      • principal_exclusion_criteria<p>\n <strong>Exclusion criteria for those receiving ivermectin or albendazole (safety cohort):</strong></p>\n<ul>\n <li>\n Known hypersensitivity to ivermectin or albendazole</li>\n <li>\n Risk of <em>Loa Loa</em> exposure assessed by travel history to Angola, Cameroon, Chad, Central African Republic, Congo, DR Congo, Equatorial Guinea, Ethiopia, Gabon, Nigeria or Sudan</li>\n <li>\n Pregnant women </li>\n <li>\n Lactating women in the first week postpartum</li>\n <li>\n Children < 15 kg</li>\n <li>\n Currently participating in another clinical trial</li>\n <li>\n Severely ill either self-reported or in the eyes of the investigator, e.g. defined as need for clinical care, or active or progressive disease interfering with activities of daily living. If in doubt, these criteria can be confirmed after a call with either the site PI/MD/safety officer against a pre-defined list</li>\n <li>\n Currently under treatment with inhibitors of CYP3A or P-gp or other drugs that can interfere with the study (examples given in <strong>Table 7</strong>)</li>\n</ul>\n<p>\n Table 7. Concurrent treatment used as exclusion criteria for the treatment/safety cohort</p>\n<table align=\"center\" border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width:100.0%;\" width=\"100%\">\n <tbody>\n <tr>\n <td style=\"width:25.34%;\">\n <p>\n <strong>Class</strong></p>\n </td>\n <td style=\"width:19.42%;\">\n <p>\n <strong>Drug</strong></p>\n </td>\n <td style=\"width:55.24%;\">\n <p>\n <strong>Rationale</strong></p>\n </td>\n </tr>\n <tr>\n <td rowspan=\"5\" style=\"width:25.34%;\">\n <p>\n Antiarrhytmic/ Antihypertensive</p>\n </td>\n <td style=\"width:19.42%;\">\n <p>\n Quinidine</p>\n </td>\n <td rowspan=\"14\" style=\"width:55.24%;\">\n <p style=\"margin-left:4.75pt;\">\n May increase ivermectin exposure by inhibiting its metabolism and excretion or competing with CYPs or the P-gp.</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:19.42%;\">\n <p>\n Amiodarone</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:19.42%;\">\n <p>\n Diltiazem</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:19.42%;\">\n <p>\n Spironolactone</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:19.42%;\">\n <p>\n Verapamil</p>\n </td>\n </tr>\n <tr>\n <td rowspan=\"2\" style=\"width:25.34%;\">\n <p>\n Antibiotic- Macrolides</p>\n </td>\n <td style=\"width:19.42%;\">\n <p>\n Clarithromycin</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:19.42%;\">\n <p>\n Erythromycin</p>\n </td>\n </tr>\n <tr>\n <td rowspan=\"2\" style=\"width:25.34%;\">\n <p>\n Antifungal agents</p>\n </td>\n <td style=\"width:19.42%;\">\n <p>\n Itraconazole</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:19.42%;\">\n <p>\n Ketoconazole</p>\n </td>\n </tr>\n <tr>\n <td rowspan=\"2\" style=\"width:25.34%;\">\n <p>\n Inmunosupressants</p>\n </td>\n <td style=\"width:19.42%;\">\n <p>\n Cyclosporine</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:19.42%;\">\n <p>\n Tacrolimus</p>\n </td>\n </tr>\n <tr>\n <td rowspan=\"2\" style=\"width:25.34%;\">\n <p>\n Anti HIV therapy</p>\n </td>\n <td style=\"width:19.42%;\">\n <p>\n Indinavir</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:19.42%;\">\n <p>\n Ritonavir</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:25.34%;\">\n <p>\n Anticoagulant</p>\n </td>\n <td style=\"width:19.42%;\">\n <p>\n Warfarin</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:25.34%;\">\n <p>\n H-2 blockers</p>\n </td>\n <td style=\"width:19.42%;\">\n <p>\n Cimetidine</p>\n </td>\n <td rowspan=\"2\" style=\"width:55.24%;\">\n <p>\n May increase albendazole metabolite levels by inhibiting its metabolism and excretion</p>\n </td>\n </tr>\n <tr>\n <td style=\"width:25.34%;\">\n <p>\n Steroids</p>\n </td>\n <td style=\"width:19.42%;\">\n <p>\n Dexamethasone</p>\n </td>\n </tr>\n </tbody>\n</table>\n<div style=\"clear:both;\">\n  </div>\n<p>\n  </p>\n<p>\n <strong>Exclusion criteria for those enrolled in the active pediatric cohort (efficacy cohort)</strong></p>\n<ul>\n <li>\n Non-residents</li>\n <li>\n Currently enrolled in another clinical trial.</li>\n</ul>\n<p>\n  </p>\n<p>\n <strong>Exclusion criteria for those recruited to the cross-sectional malaria infection survey</strong></p>\n<ul>\n <li>\n Non-residents</li>\n</ul>\n<p>\n  </p>\n
      • primary_end_points<p>\n Primary efficacy: malaria infection incidence in children 5-15 years old (active pediatric cohort) confirmed by malaria rapid diagnostic test (RDT) and PCR performed monthly regardless of symptoms during household visits.</p>\n<p>\n Primary safety: rate of AEs and serious adverse events (SAEs) and difference between ivermectin and albendazole</p>\n
      • scope_diagnosis0
      • scope_prophylaxis0
      • scope_therapy0
      • scope_safety1
      • scope_efficacy1
      • scope_pharmacokinetic1
      • scope_pharmacodynamic0
      • scope_bioequivalence0
      • scope_dose_response0
      • scope_pharmacogenetic0
      • scope_pharmacogenomic0
      • scope_pharmacoecomomic0
      • scope_others0
      • scope_others_specify
      • trial_human_pharmacology0
      • trial_administration_humans0
      • trial_bioequivalence_study0
      • trial_other0
      • trial_other_specify
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      • trial_therapeutic_confirmatory1
      • trial_therapeutic_use0
      • design_controlledYes
      • site_capacity(null)
      • staff_numbers<p>\n The trial will be conducted in Kwale county. The operations headquarters is in KEMRI Kwale office (KEMRI Centre for Vector Disease Control). KEMRI CVDC has adequate office space as well as lab space allocated by the Kwale county hospital. The study is currently renovating the facility at the hospital to permit field samples to be received and packed before transport to KWTRP main lab in Kilifi for processing. In addition, the Kwale county hospital has provided a space in its pharmacy for the study IP storage. The space is adequate in size, features, and access control for study staff. At KEMRI CVDC there is also an archive for ICF review and storage. The study also has a field station in Pongwe kikoneni whereby field officers will be provided with documentation and materials when needed. The study will receive support from the KWTRP clinical trials facility unit as well as the community liaison group. The project staff will include:</p>\n<p>\n - Dr Marta Maia  (co-PI) - Experience in clinical trials using ivermectin. Experience managing large field-based projects.</p>\n<p>\n - Dr Joseph Mwangangi (co-PI) - Experienced researcher in malaria vector control interventions</p>\n<p>\n - Yvonne Kamau (Pharmacist) - qualified pharmacist with experience in clinical trials using ivermectin. </p>\n<p>\n -  Aurelia Brazeal (Resarch Medical Officer) - qualified MD with experience in clinical trials</p>\n<p>\n - Mercy Kariuki (Project manager) - experience in running projects with complex logistics</p>\n<p>\n - Leah Musyoka (Project manager assistant) - experience in trials conducted in Kwale (TUMIKIA and STOP)</p>\n<p>\n - Isaiah Omondi (Data manager) - experienced data manager, preivously employed at KEMRI CGHR</p>\n<p>\n - Lawrence Babu (Data manager) - experienced managing data from clinical trials</p>\n<p>\n - Lydia Kasiwa (Community liaison officer) - experienced community liaison officer part of KEMRI CLG</p>\n<p>\n - Philip Muema (Administrator) - longstanding administrator of KEMRI CVDC</p>\n<p>\n - Pharmacy technicians (2) - to be named</p>\n<p>\n - Clinical officers (2) - to be named</p>\n<p>\n - Archivists (10) - to be named</p>\n<p>\n - Laboratory supervisor (1) - to be named</p>\n<p>\n - Laboratory technician (2) - to be named</p>\n<p>\n - Senior field assistants (4) - to be named</p>\n<p>\n - Field assistants (16) - to be named</p>\n<p>\n - Field workers (around 300)</p>\n<p>\n In case of emergency, all cases will be referred to Msambweni county hospital (level 5 governmental health facility).</p>\n
      • other_details_explanation<p>\n Kwale county has the highest malaria burden in coastal Kenya. Transmission is highly heterogenous with known hotspots presenting with moderate to high transmission despite high access to preventive measures including LLINs and ACTs. It also has a large population of cattle which makes it a valuable site for one-health interventions.</p>\n<p>\n Using MDA of endectocides such as ivermectin to reduce malaria transmission offers several potential advantages:</p>\n<ol>\n <li>\n It would target malaria vectors feeding on treated humans regardless of the place and time of biting, effectively targeting residual transmission driven by mosquitoes that feed outside times and spaces protected by core vector control tools.</li>\n <li>\n It would target malaria vectors that feed on livestock and that are not exposed to insecticide within the home, effectively targeting zoophagic-driven residual transmission.</li>\n <li>\n It holds additional potential to tackle insecticide resistance given that ivermectin’s mechanism of action differs from public health insecticides currently in use.</li>\n <li>\n It offers an opportunity for the integrated prevention of malaria and NTDs, which may help achieve efficiencies.</li>\n <li>\n Broader ivermectin delivery to livestock would have positive externalities on households, by reducing the burden of intestinal helminths and ecto-parasites in dominant domesticated herds; this can in turn increase income, food security, and liberate resources for re-investment in household improvement and human healthcare.</li>\n</ol>\n<p>\n  </p>\n
      • other_details_regulatory_notapproved<p>\n The trial has been approved by all other regulatory authorities..</p>\n
      • other_details_regulatory_approved<p>\n Autoridade Nacional Reguladora de Medicamentos (ANARME), Mozambique</p>\n<p>\n Ref 8309/380/DNF</p>\n<p>\n Date: 10 December 2021</p>\n<p>\n  </p>\n<p>\n Ethics Committees that have granted approval:</p>\n<p>\n KEMRI SERU - January 20th, 2023</p>\n<p>\n KEMRI ACUC - October 6th, 2022</p>\n<p>\n WHO ERC - February 1st, 2023</p>\n<p>\n  </p>\n
      • other_details_regulatory_rejected
      • other_details_regulatory_halted
      • estimated_duration1 year
      • design_controlled_randomisedYes
      • design_controlled_openYes
      • design_controlled_single_blindYes
      • design_controlled_double_blindNo
      • design_controlled_parallel_groupYes
      • design_controlled_cross_overNo
      • design_controlled_otherNo
      • design_controlled_specify
      • design_controlled_comparatorAlbendazole 400 mg
      • design_controlled_other_medicinalYes
      • design_controlled_placeboNo
      • design_controlled_medicinal_otherYes
      • design_controlled_medicinal_specifyCoartem® (Arthemeter/Lumenfantrine) will be offered for treatment of malaria
      • single_site_member_stateYes
      • location_of_areaKwale county, subcounties Lungalunga and Msambweni
      • single_site_physical_addressPongwe-Kikoneni and Ramisi, Kwale
      • single_site_contact_personJoseph Mwangangi
      • single_site_telephone+254 713112168
      • multiple_sites_member_stateNo
      • multiple_countriesYes
      • multiple_member_statesOne
      • number_of_sites
      • multi_country_listMozambique
      • data_monitoring_committeeYes
      • total_enrolment_per_sitemaximum of 45\'000 participants
      • total_participants_worldwidemaximum of 45\'000 participants
      • population_less_than_18_yearsYes
      • population_uteroNo
      • population_preterm_newbornNo
      • population_newbornNo
      • population_infant_and_toddlerNo
      • population_childrenYes
      • population_adolescentYes
      • population_above_18Yes
      • population_adultYes
      • population_elderlyYes
      • gender_female1
      • gender_male1
      • subjects_healthyYes
      • subjects_patientsNo
      • subjects_vulnerable_populationsYes
      • subjects_women_child_bearingYes
      • 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_nameMarta
      • investigator1_middle_nameFerreira
      • investigator1_family_nameMaia
      • investigator1_qualificationDVM, PhD
      • investigator1_professional_address230-80108 Kilifi
      • investigator1_telephone_254791639964
      • investigator1_emailmmaia@kemri-wellcome.org
      • organisations_transferred_Yes
      • number_participantsmaximum of 45\'000 participants
      • notification
      • approval_date25-06-2023
      • submitted1
      • deleted0
      • deleted_date(null)
      • deactivated0
      • date_submitted24-05-2023
      • is_child0
      • unsubmitted0
      • initial_date_submitted(null)
      • admin_stopped0
      • admin_stopped_reason(null)
      • approved2
      • approved_reasonReviewer comments have been addressed.
      • final_report<p align=\"center\" style=\"margin-left:-14.2pt;\">\n <strong>Efficacy and safety of ivermectin to reduce malaria transmission in Kwale, a district with high coverage of insecticide treated nets in coastal Kenya: the BOHEMIA cluster randomized trial</strong></p>\n<p style=\"margin-left:-14.2pt;\">\n  </p>\n<p style=\"margin-left:-14.2pt;\">\n <em>Background</em></p>\n<p style=\"margin-left:-14.2pt;\">\n Malaria control and elimination is threatened by the spread of insecticide resistance and behavioral adaptation of vectors. We hypothesized that mass drug administration with ivermectin, a broad-spectrum antiparasitic drug that also kills mosquitoes feeding on treated subjects, can reduce malaria transmission.</p>\n<p style=\"margin-left:-14.2pt;\">\n <em>Methods</em></p>\n<p style=\"margin-left:-14.2pt;\">\n We conducted a cluster randomized trial in Kwale, a highly endemic county in coastal Kenya with high coverage and usage of insecticide-treated nets. A total of 84 clusters were equally randomized to intervention or control arms. In the intervention arm, a single 400 mcg/kg dose of ivermectin was administered once a month for three months at the beginning of the short rains to all eligible participants. In the control arm, albendazole (400 mg) was administered following the same schedule. A cohort of children aged 5-15 years was tested for malaria monthly for 6 months following the first mass drug administration round. Our primary outcomes were cumulative malaria infection incidence and adverse event rates. Analysis was done using generalized estimating equations following intention-to-treat. The trial design was reviewed and approved by the Vector Control Advisory Group at WHO.</p>\n<p style=\"margin-left:-14.2pt;\">\n <em>Results</em></p>\n<p style=\"margin-left:-14.2pt;\">\n A total of 28,932 participants from 84 clusters were recruited. The arms were similar at baseline. Six months after the first treatment round, the malaria infection incidence was 2.66 infections/child-year-at-risk in the control arm and 2.20 in the ivermectin arm, the adjusted incidence rate ratio was 0.74 (95% CI, 0.58-0.95, P = 0.017). The rate of severe adverse events per 10,000 treatments was not significantly different between arms (IRR = 0.63; 95%CI 0.21-1.91).</p>\n<p style=\"margin-left:-14.2pt;\">\n <em>Conclusions</em></p>\n<p style=\"margin-left:-14.2pt;\">\n Three rounds of a single dose of ivermectin resulted in an additional 26% reduction in malaria infection incidence among children 5-15 living in an area with high bed net coverage and usage. There were no safety concerns. (Funded by Unitaid; ClinicalTrials.gov number, NCT04966702)</p>\n
      • implication_results<p style=\"margin-left:-14.2pt;\">\n <em>Implications</em></p>\n<p style=\"margin-left:-14.2pt;\">\n Prevention, in the form of vector control, is the most cost-effective approach to malaria control and elimination. Optimizing resource allocation to achieve and sustain high LLIN coverage is key to reducing the burden of clinical malaria and relieve health care systems. However, no single intervention will achieve malaria elimination in all settings, and successful scale-up of household-centered interventions such as LLIN provides an evolutionary advantage to malaria vectors that are resistant to currently used insecticides, bite outdoors, have crepuscular activity, or feed alternatively upon livestock. MDA with ivermectin would be a completely new, drug-based, approach to vector control leveraging a mechanism of action distinct from that of the currently used public health insecticides. This innovative method not only enhances vector control but provides remarkable collateral benefits on co-endemic neglected tropical diseases such as scabies, soil-transmitted helminths and filariae, particularly when combined with existing delivery systems.</p>\n<p style=\"margin-left:-14.2pt;\">\n This trial provides robust evidence to support the use of ivermectin as a complementary strategy for malaria control and prevention in mesoendemic areas with perennial transmission. </p>\n
      • quantity_importedIvermectin 3mg-350,000 tablets, Albendazole 400mg-40,000 tablets, Coartem 20/120-58,272-3,000 tablets, Coartem 80/480-3,000 tablets.
      • quantity_dispensedIvermectin 3mg-157,009 tablets Albendazole 400mg-30,208 tablets, Coartem 20/120-46,838 tablets, Coartem 80/480-2,832 tablets,
      • quantity_destroyedIvermectin 3mg-192,620tablets, Coartem 20/120-532 tablets, Coartem 80/480-150 tablets.
      • quantity_exportedIvermectin 3mg-400 tablets
      • balance_siteIvermectin 3mg-0 tablets, Albendazole 400mg-9,788 tablets-donated, Coartem 20/120-10,854 tablets-donated, Coartem 80/480-0 tablets.
      • final_date0000-00-00
      • modified2025-03-13 13:56:15
      • created2022-09-06 08:28:06
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        • given_nameMarta
        • middle_nameFerreira
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        • qualificationDVM, PhD
        • professional_addressKEMRI Centre for Geographic Medicine Research – Coast, Kilifi, Kenya
        • telephone+254 791639964
        • emailmmaia@kemri-wellcome.org
        • created2023-02-08 19:20:40
        • modified2023-05-24 07:12:40
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        • given_nameJoseph
        • middle_name
        • family_nameMwangangi
        • qualificationMSc, PhD
        • professional_addressKEMRI Centre for Geographic Medicine Research – Coast, Kilifi, Kenya
        • telephone+254 713112168
        • emailjmwangangi@kemri-wellcome.org
        • created2023-02-13 09:56:14
        • modified2023-05-24 07:12:40
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        • created2023-02-08 19:20:40
        • modified2023-05-24 07:12:40
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        • id641
        • application_id1168
        • sponsorISGlobal
        • sponsor_typeResearch Institution
        • contact_personCarlos Chaccour
        • addressCarrer Rosselló 132, 5º 2ª E-08036 Barcelona, Spain
        • telephone_number+34932275400
        • fax_number
        • cell_number+34666293112
        • email_addresscarlos.chaccour@isglobal.org
        • created2023-02-08 19:20:40
        • modified2023-05-24 07:12:40
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    • 4CORE/Routing/Router.php
    • 5CORE/Routing/Route/CakeRoute.php
    • 6CORE/Routing/Route/PluginShortRoute.php
  • Utility(array)
    • 0CORE/Utility/Hash.php
    • 1CORE/Utility/Inflector.php
    • 2CORE/Utility/ObjectCollection.php
    • 3CORE/Utility/Debugger.php
    • 4CORE/Utility/String.php
    • 5CORE/Utility/ClassRegistry.php
    • 6CORE/Utility/Set.php
    • 7CORE/Utility/Sanitize.php
  • View(array)
    • 0CORE/View/HelperCollection.php
• app(array)
  • Behavior(array)
    • 0APP/Model/Behavior/SoftDeleteBehavior.php
  • Config(array)
    • 0APP/Config/core.php
    • 1APP/Config/bootstrap.php
    • 2APP/Config/routes.php
    • 3APP/Config/database.php
  • Controller(array)
    • 0APP/Controller/ApplicationsController.php
    • 1APP/Controller/AppController.php
  • Model(array)
    • 0APP/Model/AppModel.php
    • 1APP/Model/Application.php
    • 2APP/Model/User.php
    • 3APP/Model/TrialStatus.php
    • 4APP/Model/InvestigatorContact.php
    • 5APP/Model/Sponsor.php
    • 6APP/Model/SiteDetail.php
    • 7APP/Model/County.php
  • Other(array)
    • 0APP/webroot/index.php
• plugins(array)
  • CakePdf(array)
    • Config(array)
      • 0CakePdf/Config/bootstrap.php
      • 1CakePdf/Config/routes.php
  • CakeResque(array)
    • Config(array)
      • 0CakeResque/Config/bootstrap.php
    • Plugin(array)
      • 0CakeResque/Lib/CakeResque.php
      • 1CakeResque/vendor/kamisama/php-resque-ex/lib/Resque.php
      • 2CakeResque/vendor/kamisama/php-resque-ex/lib/Resque/Event.php
      • 3CakeResque/vendor/kamisama/php-resque-ex/lib/Resque/Exception.php
  • DebugKit(array)
    • Component(array)
      • 0DebugKit/Controller/Component/ToolbarComponent.php
    • Plugin(array)
      • 0DebugKit/Lib/DebugMemory.php
      • 1DebugKit/Lib/Panel/HistoryPanel.php
      • 2DebugKit/Lib/DebugPanel.php
      • 3DebugKit/Lib/Panel/SessionPanel.php
      • 4DebugKit/Lib/Panel/RequestPanel.php
      • 5DebugKit/Lib/Panel/SqlLogPanel.php
      • 6DebugKit/Lib/Panel/TimerPanel.php
      • 7DebugKit/Lib/Panel/LogPanel.php
      • 8DebugKit/Lib/Log/Engine/DebugKitLog.php
      • 9DebugKit/Lib/Panel/VariablesPanel.php
      • 10DebugKit/Lib/Panel/EnvironmentPanel.php
      • 11DebugKit/Lib/Panel/IncludePanel.php
      • 12DebugKit/Lib/DebugTimer.php
  • Media(array)
    • Config(array)
      • 0Media/Config/bootstrap.php
    • Plugin(array)
      • 0Media/Lib/mm/src/Mime/Type.php
      • 1Media/Lib/mm/src/Mime/Type/Magic/Adapter/Fileinfo.php
      • 2Media/Lib/mm/src/Mime/Type/Magic/Adapter.php
      • 3Media/Lib/mm/src/Mime/Type/Glob/Adapter/Memory.php
      • 4Media/Lib/mm/src/Mime/Type/Glob/Adapter.php
      • 5Media/Lib/mm/src/Media/Process.php
      • 6Media/Lib/mm/src/Media/Info.php
  • Search(array)
    • Component(array)
      • 0Search/Controller/Component/PrgComponent.php
    • Behavior(array)
      • 0Search/Model/Behavior/SearchableBehavior.php
  • Shim(array)
    • Config(array)
      • 0Shim/Config/bootstrap.php
  • Tools(array)
    • Config(array)
      • 0Tools/Config/bootstrap.php