Phase 1/2 Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of Marzeptacog alfa (activated) in Treatment of Episodic Bleeding in Subjects with Inherited Bleeding Disorders.
试验速览
- 阶段
- 1/2 期
- 状态
- Other
- 入组人数
- 24
- 试验地点
- 5
- 主要终点
- Phase 1 by Cohort
研究概览
简要总结
Phase 1/2 Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy of Marzeptacog alfa (activated) in Treatment of Episodic Bleeding in Subjects with Inherited Bleeding Disorders.
Marzeptacog alfa (activated) (MarzAA), a novel activated recombinant Factor VII (rFVIIa) variant, to address the unmet need for medical management of Factor VII deficiency (FVIID), Glanszmann thrombasthenia (GT), and Hemophilia A with inhibitors on emicizumab prophylaxis (HAwI-E)
研究设计
- 研究类型
- Interventional
- 分配方式
- Not Applicable
- 盲法
- Not Applicable
入排标准
- 年龄范围
- 12.00 Year(s) 至 90.00 Year(s)（—）
- 性别
- All
入选标准
- •Study candidates must meet all the following inclusion criteria to be eligible for participation in this study: 1) Confirmed diagnosis of cohort: a) Confirmed diagnosis of congential Factor VII deficiency (FVIID) b) Confirmed diagnosis of congenital Glanzmann thrombasthenia (GT) (ie, platelet function analyzer, mutational analysis) c) Confirmed diagnosis of congenital Hemophilia A with inhibitors on emicizumab (HAwI-E) treated with the same dose of emicizumab 2) History of bleeding with an (a) Annualized bleeding rate (ABR) of ≥8 for FVIID.
- •(b) Annualized bleeding rate (ABR) of ≥8 for GT.
- •(c) Annualized bleeding rate (ABR) of ≥1 for HAwI-E 3) Agreement to use highly effective birth control throughout the study if the subject has childbearing potential 4) If female, the subject must meet the following criteria (a) Not currently be breastfeeding (b) Not plan on becoming pregnant during the study.
- •(c) Be surgically sterile, or at least 2 years postmenopausal, or have a negative serum pregnancy test during Screening.
- •Subject’s ability to rapidly assess a bleeding episode and respond appropriately 6) Affirmation of informed consent with signature confirmation and assent for children from age 12 to 17 years before any study-related activities 7) Subject’s ability to administer MarzAA SC at home.
排除标准
- •Subjects who meet any of the following criteria will not be eligible for participation in this study: 1) Cohort 1: genotype of FVIID subjects with following mutations: a) P.A354V-p.464Hfs b) P.Ser112-Stop (homozygous) c) Ala294Val + Del C d) 100GLN ARG shift e) Ser103 Gly Note: documentation of historic genotype would be acceptable.
- •Inability to discontinue and washout any prophylactic (except Hemlibra) or episodic treatment for 5 days and 10 days for platelet transfusion prior to dosing 3) Previous participation in a clinical study involving SC administration of wt-rFVIIa (NovoSeven or MOD-5014) or any study using a modified amino-acid sequence FVIIa (other than MarzAA) such as: NN1731 or BAY86-
- •Note: Prior participation in a study of intravenous (IV) LR769, rFVIIa-FP (CSL689), or MarzAA is permissible.
- •Previous participation in a clinical study with treatment within the previous 30 days or ≤5 half-lives (of the investigation product) or absence of clinical effect, whichever is longer 5) Known positive antibody to FVIIa or variants thereof detected during screening or prior to Day 1 6) Known hypersensitivity to pd-FVIIa, pd-FVII, wt-rFVIIa, or MarzAA or any of the excipients or related products 7) Treatment with anticoagulants or antiplatelet therapy within 1 week of enrollment or anticipated need during the study 8) Planned elective surgery within 12 months following study entry 9) History of clinically relevant coagulation blood disorders 10) CD 4 T cell count of <200 cells/mm3 11) Platelet count <50,000 /μL based on screening laboratory assessments 12) Current or history of advanced atherosclerotic disease (ie, known history of coronary artery disease, ischemic stroke, etc), or deep venous thrombosis (DVT) within 24 months of dosing or considered to be at a high risk of venous thromboembolic event (VTE) or pulmonary embolism as judged by the Investigator 13) Compromised hepatic or renal function: a) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≥5 × the upper limit of normal (ULN) b) Total bilirubin level ≥2 mg/dL (>35 μmol/L) unless there is a known history of Gilbert’s syndrome c) Serum creatinine level >1.25 × ULN 14) Inability or medical, psychosocial, or familial issues that might prevent full participation and cooperation with the procedures and requirements of the clinical study as determined by the potential subject and physician/Investigator 15) Weight ≥105 kg (231 lbs).
结局指标
主要结局
Phase 1 by Cohort
时间窗: For Phase 1:- Blood samples for PK will be obtained at predose and at specified time intervals post dosing at Phase 1A, 1B, 1C, 1D, 1F and 1E. PK analysis to determine the dosing for phase 2 | For Phase 2:- e-Diaries provided to subject where potential bleeds can be recorded. The bleeds are adjudicated and assessed for effective hemostasis at 24 hours
1- Pharmacokinetics of ascending SC doses of MarzAA by dose level/stage and confirm the Phase 2 dose
时间窗: For Phase 1:- Blood samples for PK will be obtained at predose and at specified time intervals post dosing at Phase 1A, 1B, 1C, 1D, 1F and 1E. PK analysis to determine the dosing for phase 2 | For Phase 2:- e-Diaries provided to subject where potential bleeds can be recorded. The bleeds are adjudicated and assessed for effective hemostasis at 24 hours
Phase 2 by Cohort
时间窗: For Phase 1:- Blood samples for PK will be obtained at predose and at specified time intervals post dosing at Phase 1A, 1B, 1C, 1D, 1F and 1E. PK analysis to determine the dosing for phase 2 | For Phase 2:- e-Diaries provided to subject where potential bleeds can be recorded. The bleeds are adjudicated and assessed for effective hemostasis at 24 hours
2- Percentage of bleed treatments resulting in effective hemostasis at 24 hours.
时间窗: For Phase 1:- Blood samples for PK will be obtained at predose and at specified time intervals post dosing at Phase 1A, 1B, 1C, 1D, 1F and 1E. PK analysis to determine the dosing for phase 2 | For Phase 2:- e-Diaries provided to subject where potential bleeds can be recorded. The bleeds are adjudicated and assessed for effective hemostasis at 24 hours
次要结局
- Phase 1 by Cohort(1-Pharmacokinetics of IV and SC MarzAA)
- Phase 2 by Cohort(1-The time to cessation of bleeding after the initial dose)
- 1-Use and amount of rescue therapy needed in treatment failures(2-Pharmacokinetics and pharmacodynamics of MarzAA in the bleeding state)
- 1-Occurrence of clinical thromboembolic events (TEs)(2-Occurrence of ADA and whether they are neutralizing or cross-reactive to FVIIa or FVII or variants there of.)