A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Patients Without Inhibitors
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 152
- 试验地点
- 39
- 主要终点
- Annualized Bleeding Rate (ABR) for Treated Bleeds
研究概览
简要总结
This is a randomized, global, multicenter, open-label, Phase 3 clinical study in participants with severe hemophilia A without inhibitors against Factor VIII (FVIII) who are 12 years or older. The study evaluates two prophylactic emicizumab regimens versus no prophylaxis in this population with emphasis on efficacy, safety, and pharmacokinetics.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Body weight >/= 40 kilogram (kg) at the time of screening
- •Diagnosis of severe congenital hemophilia A
- •Documentation of the details of prophylactic or episodic FVIII treatment and of number of bleeding episodes for at least the last 24 weeks
- •Adequate hematologic function
- •Adequate hepatic function
- •Adequate renal function
- •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of less than (<) 1 percent (%) per year during the treatment period and for at least 5 elimination half-lives (24 weeks) after the last dose of study drug
排除标准
- •Inherited or acquired bleeding disorder other than hemophilia A
- •Previous or current treatment for thromboembolic disease or signs of thromboembolic disease
- •Conditions that may increase risk of bleeding or thrombosis
- •History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection
- •Known human immunodeficiency virus (HIV) infection with cluster of differentiation (CD) 4 count <200 cells per microliter (cells/mcL) within 24 weeks prior to screening. Participants with HIV infection who has CD4 greater than (>) 200 and meet all other criteria are eligible
- •Use of systemic immunomodulators at enrollment or planned use during the study, with the exception of anti-retroviral therapy
- •Participants who are at high risk for thrombotic microangiopathy (TMA) (for example, have a previous medical or family history of TMA), in the investigator's judgment
- •Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose additional risk, or would, in the opinion of the investigator, preclude the participant's safe participation in and completion of the study
- •Planned surgery (excluding minor procedures) during the study
- •Receipt of emicizumab in a prior investigational study; an investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration; a non-hemophilia-related investigational drug concurrently, within last 30 days or 5 half-lives, whichever is shorter
- •Pregnant or lactating, or intending to become pregnant during the study
研究组 & 干预措施
Arm C (Control): No Prophylaxis, Then Emicizumab
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial. After completing 24 weeks of no prophylaxis (i.e., episodic FVIII treatment) on study, then they were given the opportunity to switch to emicizumab prophylaxis of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
干预措施: Emicizumab (Drug)
Arm C (Control): No Prophylaxis, Then Emicizumab
Participants who had received episodic treatment with FVIII prior to study entry were randomized to continue episodic FVIII treatment when they started the trial. After completing 24 weeks of no prophylaxis (i.e., episodic FVIII treatment) on study, then they were given the opportunity to switch to emicizumab prophylaxis of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
干预措施: Factor VIII (FVIII) (Drug)
Arm A: Emicizumab 1.5 mg/kg QW
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
干预措施: Emicizumab (Drug)
Arm A: Emicizumab 1.5 mg/kg QW
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 milligrams per kilogram (mg/kg) subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
干预措施: Factor VIII (FVIII) (Drug)
Arm B: Emicizumab 3 mg/kg Q2W
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
干预措施: Emicizumab (Drug)
Arm B: Emicizumab 3 mg/kg Q2W
Participants who had received episodic treatment with FVIII prior to study entry were randomized to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 3 mg/kg emicizumab SC once every 2 weeks (Q2W). Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
干预措施: Factor VIII (FVIII) (Drug)
Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
干预措施: Emicizumab (Drug)
Arm D: Emicizumab 1.5 mg/kg QW (Pre-study FVIII Prophylaxis)
Participants who had received FVIII prophylaxis prior to study entry were enrolled to receive emicizumab prophylaxis at a dose of 3 mg/kg subcutaneously (SC) once per week (QW) for 4 weeks, followed by maintenance dosing of 1.5 mg/kg emicizumab SC QW. Upon implementation of protocol version 4 (20-Dec-2019), treatment duration was extended. During this study prolongation, each participant was given the option to choose a preferred emicizumab dosing regimen among those permitted and continue on that dosing regimen until discontinuation from the study.
干预措施: Factor VIII (FVIII) (Drug)
结局指标
主要结局
Annualized Bleeding Rate (ABR) for Treated Bleeds
时间窗: From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks)
The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was assessed using a negative binomial (NB) regression model, which accounts for different follow-up times, with the number of bleeds as a function of randomization and the time that each participant stays in the study (i.e., length of the efficacy period) included as an offset in the model. The model also includes the number of bleeds (\<9 or ≥9) in the last 24 weeks prior to study entry as a stratification factor. A bleed is considered a "treated bleed" if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a "treatment for bleed", irrespective of the time between treatment and the preceding bleed. Bleeds due to surgery/procedure are excluded.
次要结局
- Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants From the Non-Interventional Study Population Previously Treated With FVIII Prophylaxis (NISP)(Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for Dnisp-FVIII Prophylaxis: 30.07 [5.0-45.1] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for Dnisp-Emicizumab Prophylaxis: 33.71 [20.1-48.6] weeks))
- Annualized Bleeding Rate (ABR) for All Bleeds(From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks))
- Annualized Bleeding Rate (ABR) for Treated Joint Bleeds(From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks))
- Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds(From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks))
- Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds(From Baseline to at least 24 weeks (median [min-max] efficacy periods for Arm C: 24.00 [14.4-25.0] weeks; Arm A: 29.57 [17.3-49.6] weeks; Arm B: 31.29 [3.3-50.6] weeks; Arm D: 33.14 [18.4-48.6] weeks))
- Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants From the Non-Interventional Study Population Previously Treated With Factor VIII (FVIII) Prophylaxis (NISP)(Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for Dnisp-FVIII Prophylaxis: 30.07 [5.0-45.1] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for Dnisp-Emicizumab Prophylaxis: 33.71 [20.1-48.6] weeks))
- Intra-Participant Comparison of ABR for Treated Bleeds on Study Versus Pre-Study in Participants From the NIS Population Previously Treated With Episodic FVIII (NISE)(Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for A+Bnise-FVIII Episodic: 25.71 [15.4-40.9] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for A+Bnise-Emicizumab: 34.71 [24.1-50.6] weeks))
- Intra-Participant Comparison of ABR for All Bleeds on Study Versus Pre-Study in Participants From the NIS Population Previously Treated With Episodic FVIII (NISE)(Efficacy periods: At least 24 weeks prior to study entry (median [min-max] for A+Bnise-FVIII Episodic: 25.71 [15.4-40.9] weeks); and From Baseline to at least 24 weeks on study (median [min-max] for A+Bnise-Emicizumab: 34.71 [24.1-50.6] weeks))
- Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Subscore for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25(Baseline, Week 25)
- Haem-A-QoL Questionnaire Total Score for Adult Participants (≥18 Years of Age) in the Randomized Population at Week 25(Baseline, Week 25)
- European Quality of Life 5-Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score in the Randomized Population at Week 25(Baseline, Week 25)
- EQ-5D-5L Questionnaire Index Utility Score in the Randomized Population at Week 25(Baseline, Week 25)
- Hemophilia-Specific Quality of Life - Short Form (Haemo-QoL-SF) Questionnaire Score in Adolescent Participants (12 to 17 Years of Age) in the Randomized Population at Week 25(Week 25)
- Percentage of Participants With at Least One Adverse Event During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Percentage of Participants With at Least One Grade ≥3 Adverse Event During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Percentage of Participants With at Least One Adverse Event Leading to Withdrawal From Treatment During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Percentage of Participants With at Least One Adverse Event of Changes From Baseline in Vital Signs During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Percentage of Participants With at Least One Adverse Event of Changes From Baseline in Physical Examination Findings During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Percentage of Participants With at Least One Adverse Event of Abnormal Laboratory Values During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Percentage of Participants With at Least One Local Injection-Site Reaction During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Percentage of Participants With at Least One Thromboembolic Event During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Percentage of Participants With at Least One Thrombotic Microangiopathy During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Percentage of Participants With at Least One Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reaction During the First 24 Weeks of the Study, Primary Analysis(From Baseline to at least 24 weeks (median [min-max] safety periods for Arm C (Control): 24.00 [14.4-25.0] weeks; Arm A: 30.00 [21.4-49.6] weeks; Arm B: 31.29 [24.4-50.6] weeks; Arm C (Emi): 7.57 [0.3-26.3] weeks; Arm D: 33.71 [18.4-49.6] weeks))
- Safety Summary of the Percentage of Emicizumab-Treated Participants With at Least One Adverse Event During the Study(From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks))
- Long-Term Efficacy of Emicizumab: Model-Based Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants(From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks))
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants(From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks))
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks)
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks)
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for All Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks)
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds, All Bleeds, Treated Spontaneous Bleeds, Treated Joint Bleeds, and Treated Target Joint Bleeds, All Emicizumab Participants(From start of emicizumab treatment to study completion, dose up-titration, or change of dosing regimen (median [min-max] efficacy period for all emicizumab participants: 228.14 [7.3-288.3] weeks))
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks)
- Percentage of Participants With De Novo Development of Factor VIII (FVIII) Inhibitors(From Baseline to discontinuation from study (median [min-max] observation period for all emicizumab participants: 262.3 [14.4-288.3] weeks))
- Trough Plasma Concentration (Ctrough) of Emicizumab(Predose at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181, 193, 205, 217, 229, 241, 253, 265, and 277)
- Long-Term Efficacy of Emicizumab: Mean Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks)
- Long-Term Efficacy of Emicizumab: Median Calculated Annualized Bleeding Rates (ABR) for Treated Spontaneous Bleeds Per 12-Week Intervals Over Time, All Emicizumab Participants(1-12, 13-24, 25-36, 37-48, 49-60, 61-72, 73-84, 85-96, 97-108, 109-120, 121-132, 133-144, 145-156, 157-168, 169-180, 181-192, 193-204, 205-216, 217-228, 229-240, 241-252, 253-264, 265-276, and 277-288 weeks)
- Percentage of Participants With Anti-Emicizumab Antibodies at Any Time Post-Baseline During the Study(From Baseline to discontinuation from study (median [min-max] observation period for all emicizumab participants: 262.3 [14.4-288.3] weeks))