A Phase 3 Open-Label, Multicenter Study of the Safety, Efficacy, and Pharmacokinetics of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein (rFVIIIFc-VWF-XTEN; BIVV001) in Previously Treated Patients ≥12 Years of Age With Severe Hemophilia A
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 159
- 试验地点
- 46
- 主要终点
- Estimated Annualized Bleeding Rate (ABR) in Arm A: Prophylaxis
研究概览
简要总结
Primary Objective:
- To evaluate the efficacy of BIVV001 as a prophylaxis treatment in prophylaxis treatment arm.
Secondary Objectives:
- To evaluate the efficacy of BIVV001 as a prophylaxis treatment.
- To evaluate the efficacy of BIVV001 in the treatment of bleeding episodes.
- To evaluate BIVV001 consumption for the prevention and treatment of bleeding episodes.
- To evaluate the effect of BIVV001 prophylaxis on joint health outcomes.
- To evaluate the effect of BIVV001 prophylaxis on Quality of Life outcomes.
- To evaluate the efficacy of BIVV001 for perioperative management.
- To evaluate the safety and tolerability of BIVV001 treatment.
- To assess the pharmacokinetics (PK) of BIVV001 based on the 1-stage activated partial thromboplastin time (aPTT) and 2-stage chromogenic coagulation factor VIII (FVIII) activity assays.
详细描述
Participants in prophylaxis arm received a weekly prophylactic dose of BIVV001 for 52 weeks. Participants in on-demand arm received BIVV001 on demand for 26 weeks followed by a switch to weekly prophylaxis for another 26 weeks.
The Sponsor planned to perform a long-term safety trial. Enrollment in this open-label extension study would be offered to participants completing the treatment period based on eligibility criteria.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Arm A: Prophylaxis
Participants who were on a prophylaxis treatment with a FVIII product prior to study EFC16293 including participants who rolled over from study OBS16221, received BIVV001 50 international units per kilogram (IU/kg) intravenous (IV) injection once-weekly (QW) for 52 weeks in the current study. Study OBS16221 participants with 6 months historical data on prophylaxis treatment with a marketed FVIII product prior to enrollment were analyzed as a subgroup (named as: Arm A: Historical Prophylaxis [OBS16221]) in the outcome measure analysis.
干预措施: efanesoctocog alfa (BIVV001) (Biological)
Arm B: On-Demand Then Prophylaxis
Participants who were on an on-demand treatment regimen with a FVIII product prior to study EFC16293, including participants who rolled over from study OBS16221, received BIVV001 50 IU/kg IV injection as an on-demand treatment (as needed for the treatment of bleeding episodes) from Week 1 to Week 26 in current study. At Week 26, participants in Arm B were switched to prophylaxis treatment, and received BIVV001 50 IU/kg, IV injection QW until Week 52.
干预措施: efanesoctocog alfa (BIVV001) (Biological)
结局指标
主要结局
Estimated Annualized Bleeding Rate (ABR) in Arm A: Prophylaxis
时间窗: Baseline to Week 52
ABR is annualized number of treated bleeding episodes (BE) per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered less than or equal to (\<=) 72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated BE during efficacy period (EP)/number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This outcome measure (OM) presents estimated results (i.e., results estimated by fitting negative binomial \[NB\] regression model on data collected during EP).
Observed Annualized Bleeding Rate in Arm A: Prophylaxis
时间窗: Baseline to Week 52
ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered \<=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP\*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents observed results (i.e., descriptive statistics values based on the data which was collected during EP).
次要结局
- Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Non-inferiority Analysis(Historical prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 prophylaxis: Baseline up to Week 52 of current study EFC16293)
- Observed Annualized Bleeding Rate During the Efficacy Period in Prophylaxis - Non-inferiority Analysis(Historical prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 Prophylaxis: Baseline up to Week 52 of current study EFC16293)
- Estimated Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis(Historical Prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 Prophylaxis: Baseline up to Week 52 of current study EFC16293)
- Change From Baseline in Hemophilia Joint Health Score (HJHS) Domain Score at Week 52 in Arm A: Prophylaxis(Baseline, Week 52)
- Annualized Bleeding Rate: Intra-participant Comparison of Arm B Participants(Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Number of Injections of BIVV001 Required to Treat a Bleeding Episode(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Total Dose of BIVV001 Required to Treat Bleeding Episode(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Percentage of Participants Achieving Factor VIII (FVIII) Activity Levels Above 1%, 5%, 10%, 15%, and 20% in Arm A: Prophylaxis(Baseline to Week 52)
- Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery(During the perioperative period (any time during Baseline up to Week 52))
- Number of Participants With Occurrence of Embolic and Thrombotic Events(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Pharmacokinetics: Clearance (CL)(Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline))
- Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau)(Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26 (Day 183))
- Pharmacokinetics: Time Above Predefined (10 and 40%) FVIII Activity Levels(Pre-dose and 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline))
- Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Percentage of Participants With Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Total Annualized BIVV001 Consumption Per Participant(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Total BIVV001 Consumption From Day -1 to 14 During Perioperative Period for Major Surgery(Day -1 to Day 14)
- Change From Baseline in Hemophilia-specific Health-related Quality of Life Questionnaire for Adults Total Score at Week 52 in Arm A: Prophylaxis(Baseline, Week 52)
- Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery(During the perioperative period (any time during Baseline up to Week 52))
- Estimated Blood Loss During Major Surgery(Day 0 (i.e., day of surgery))
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAE)(Arm A: From Baseline (Day 1) up to 3 weeks post last dose of BIVV001 (i.e., up to Week 55); Arm B: On-demand: Baseline to Week 26 and Arm B: Prophylaxis: From Week 26 up to 3 weeks post last dose of BIVV001 in Week 52 (i.e., up to Week 55))
- Observed Annualized Bleeding Rate During the Efficacy Period in Arm A: Prophylaxis - Superiority Analysis(Historical Prophylaxis: From 6 months (prior to entry into study EFC16293) until the day before enrollment in EFC16293; BIVV001 Prophylaxis: Baseline up to Week 52 of current study EFC16293)
- Change From Baseline in Hemophilia-specific Health-related Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Week 52 in Arm A: Prophylaxis(Baseline, Week 52)
- Change From Baseline in Patient Reported Outcomes Measurements Information Systems (PROMIS) Pain Intensity 3a Score at Week 52 in Arm A: Prophylaxis(Baseline, Week 52)
- Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at Week 52 in Arm A: Prophylaxis(Baseline, Week 52)
- Annualized Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)(Baseline (15 minutes post-dose on Day 1) and 15 minutes post-dose on Week 52)
- Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Annualized Bleeding Rate for All Bleeding Episodes(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Pharmacokinetics: Elimination Half-life (t1/2z)(pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26)
- Physicians' Global Assessment of Participant's Response to BIVV001 Treatment(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Pharmacokinetics: Total Clearance at Steady State (CLss)(Pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26)
- Change From Baseline in Patient Reported Outcomes Measurements Information Systems Short Form (PROMIS-SF) Physical Function (PF) 6b at Week 52 in Arm A: Prophylaxis(Baseline, Week 52)
- Investigators' or Surgeons' Assessment of Participant's Hemostatic Response to BIVV001 Treatment(Baseline to Week 52)
- Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery(During the perioperative period (any time during Baseline up to Week 52))
- Total Dose Required to Maintain Hemostasis From Day -1 to Day 0 During Perioperative Period for Major Surgery(Day -1 to Day 0 (day of surgery))
- Number of Participants With Neutralizing Antibodies (Development of Inhibitors) Directed Against Factor VIII(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Estimated Annualized Joint Bleeding Rate (AJBR)(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Observed Annualized Joint Bleeding Rate (AJBR)(Arm A: Baseline to Week 52; Arm B: On-demand - Baseline to Week 26, Prophylaxis - Week 26 to 52)
- Total Number of Target Joint Resolved in Participants at Week 52 in Arm A: Prophylaxis(Week 52)
- Pharmacokinetics: Accumulation Index (AI)(Pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26)
- Pharmacokinetics: Volume of Distribution at Steady State (Vss)(Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26 (Day 183))
- Pharmacokinetics: Mean Residence Time (MRT)(Pre-dose, 0.25, 3, 24, 72, 168, 240 and 336 hours post-dose on Day 1 (Baseline); pre-dose, 0.25, 3, 24, 72, 168, 240, and 336 hours post-dose on Week 26 (Day 183))
- Pharmacokinetics: Incremental Recovery (IR)(Pre-dose, 0.25 hours post-dose on Day 1 (Baseline); pre-dose, 0.25 hours post-dose on Week 26 (Day 183))
- Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)(Pre-dose at Baseline (Day 1) and Week 52)