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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 85
- 试验地点
- 12
- 主要终点
- Mean Calculated Annualized Bleeding Rate for Treated Bleeds
研究概览
简要总结
This multicenter, open-label, Phase 3 study with randomized and non-randomized arms is designed to investigate the efficacy, safety, and pharmacokinetics of emicizumab in participants with hemophilia A regardless of factor VIII (FVIII) inhibitor status. Participants greater than or equal to (≥)12 years old who received episodic therapy with FVIII or bypassing agents prior to study entry and experienced at least 5 bleeds over the prior 24 weeks will be randomized in a 2:2:1 ratio to the following regimens: Arm A: Emicizumab prophylaxis at 3 milligrams per kilogram (mg/kg) once every week (QW) subcutaneously (SC) for 4 weeks, followed by 1.5 mg/kg QW SC; Arm B: Emicizumab prophylaxis at 3 mg/kg QW SC for 4 weeks, followed by 6 mg/kg once every 4 weeks (Q4W) SC; and Arm C: No prophylaxis (control arm). In addition, pediatric participants less than (<)12 years old with hemophilia A and FVIII inhibitors who received episodic therapy with bypassing agents prior to study entry will be enrolled to Arm D: Emicizumab prophylaxis at 3 mg/kg QW SC for 4 weeks, followed by 1.5 mg/kg QW SC.
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
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion Criteria for Arms A, B, and C:
- •Diagnosis of severe congenital hemophilia A or hemophilia A with FVIII inhibitors
- •Aged 12 years or older at the time of informed consent
- •Body weight ≥40 kilograms (kg) at the time of screening
- •Participants without FVIII inhibitors (<0.6 Bethesda unit per milliliter [BU/mL]) who completed successful immune tolerance induction (ITI) must have done so at least 5 years before screening and have no evidence of inhibitor recurrence (permanent or temporary)
- •Documentation of the details of episodic therapy (FVIII or bypassing agents) and of number of bleeding episodes for at least the last 24 weeks and ≥5 bleeds in the last 24 weeks prior to study entry
- •Adequate hematologic, hepatic, and renal function
- •For women of child bearing potential: agreement to remain abstinent or use a protocol defined contraceptive measure during the treatment period and for at least 5 elimination half-lives (24 weeks) after the last dose of study drug
- •Inclusion Criteria for Arm D:
- •Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor (i.e., ≥5 BU/mL)
- •Children <12 years old at time of informed consent
- •Body weight >3 kg at time of informed consent
- •Requires treatment with bypassing agents
- •Adequate hematologic, hepatic, and renal function
- •For female participants who are of childbearing potential, follow the same contraception criteria as listed above for Arms A, B, and C
排除标准
- •Exclusion Criteria for Arms A, B, and C:
- •Inherited or acquired bleeding disorder other than hemophilia A
- •At high risk for thrombotic microangiopathy, in the investigator's judgment
- •History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator's judgment
- •Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
- •Other 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 immuno-deficiency virus (HIV) infection with cluster of differentiation 4 (CD4) count <200 cells/microliter (cells/mcL) within 24 weeks prior to screening. Participants with HIV infection who have CD4 >200 cells/mcL 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
- •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 such as tooth extraction or incision and drainage) 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
- •Exclusion Criteria for Arm D:
- •Inherited or acquired bleeding disorder other than hemophilia A
- •Ongoing (or plan to receive during the study) ITI therapy or prophylaxis treatment with FVIII
- •Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
- •Other diseases 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 infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV)
- •At high risk for thrombotic microangiopathy, in the investigator's judgment
- •Use of systemic immunomodulators at enrollment or planned use during the study
- •Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study
- •Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood products (or any standard-of-care treatment for a life-threatening condition)
- •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
- •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
- •Pregnant or lactating, or intending to become pregnant during the study
研究组 & 干预措施
Arm D: Emicizumab Prophylaxis at 1.5 mg/kg QW
Participants <12 years old with hemophilia A and FVIII inhibitors who are enrolled to Arm D will receive prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for first 4 weeks, followed by 1.5 mg/kg via SC injection QW for at least 24 weeks. After 24 weeks treatment, participants will be allowed to continue emicizumab until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants will continue to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.
干预措施: Emicizumab (Drug)
Arm C (Control): No Prophylaxis, Then Emicizumab
Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who are randomized to Arm C will not receive any prophylactic treatment for at least 24 weeks. After 24 weeks, participants will have the opportunity to switch to receive emicizumab prophylaxis at 3 mg/kg QW via SC injection for 4 weeks, followed by 6 mg/kg Q4W until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants will continue to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.
干预措施: Emicizumab (Drug)
Arm A: Emicizumab Prophylaxis at 1.5 mg/kg QW
Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who are randomized to Arm A will receive prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for first 4 weeks, followed by 1.5 mg/kg via SC injection Q4W for at least 24 weeks. After 24 weeks treatment, participants will be allowed to continue emicizumab until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants will continue to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.
干预措施: Emicizumab (Drug)
Arm B: Emicizumab Prophylaxis at 6 mg/kg Q4W
Participants ≥12 years old with hemophilia A (with or without FVIII inhibitors) who are randomized to Arm B will receive prophylactic emicizumab at a dose of 3 mg/kg via SC injection QW for first 4 weeks, followed by 6 mg/kg via SC injection Q4W for at least 24 weeks. After 24 weeks treatment, participants will be allowed to continue emicizumab until marketing authorization as part of this study or a separate extension study, as long as they derive clinical benefit. Participants will continue to receive standard-of-care treatments on an episodic basis for the treatment of breakthrough bleeds during the study.
干预措施: Emicizumab (Drug)
结局指标
主要结局
Mean Calculated Annualized Bleeding Rate for Treated Bleeds
时间窗: From Baseline to at least 24 weeks
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Median Calculated Annualized Bleeding Rate for Treated Bleeds
时间窗: From Baseline to at least 24 weeks
The number of treated bleeds over the efficacy period is presented here as a calculated annualized bleeding rate (ABR) that was annualized for each participant using the following formula: ABR = (number of bleeds/number of days during the efficacy period) x 365.25. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
Model-Based Annualized Bleeding Rate for Treated Bleeds
时间窗: From Baseline to at least 24 weeks
The number of treated bleeds over the efficacy period was estimated as an annualized bleeding rate (ABR) using a negative binomial regression model, which accounts for different follow-up times. A treated bleed was defined as a bleed that was directly followed by a hemophilia medication reported to be a "treatment for bleed". The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location were counted as one bleed if the second bleed occurred within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure were excluded.
次要结局
- Median Calculated Annualized Bleeding Rate for All Bleeds(From Baseline to at least 24 weeks)
- Arms A, B, and C: Adjusted Mean Haem-A-QoL Questionnaire Total Score at Week 25 in Participants ≥18 Years of Age(Baseline and Week 25)
- Model-Based Annualized Bleeding Rate for All Bleeds(From Baseline to at least 24 weeks)
- Arms A, B, and C: Change From Baseline in EQ-5D-5L Index Utility Score at Week 25(Baseline and Week 25)
- Arm D: Change From Baseline in Haemo-QoL-SF Questionnaire Physical Health and Total Scores at Week 25 in Participants 8 to 12 Years of Age(Baseline and Week 25)
- Arm D: Change From Baseline in the Caregiver-Reported Adapted Health-Related Quality of Life for Hemophilia Patients With Inhibitors (Adapted Inhib-QoL) Including Aspects of Caregiver Burden Questionnaire Score Over Time(Baseline (Week 1) and Weeks 17, 29, 37, and 49, every 12 weeks during extension phase, and study completion (up to 48 months))
- Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds(From Baseline to at least 24 weeks)
- Model-Based Annualized Bleeding Rate for Treated Target Joint Bleeds(From Baseline to at least 24 weeks)
- Arms A, B, and C: Adjusted Mean Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Physical Health Domain Score at Week 25 in Participants ≥18 Years of Age(Baseline and Week 25)
- Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Total Score for Participants ≥18 Years of Age(Baseline and Week 25)
- Mean Calculated Annualized Bleeding Rate for All Bleeds(From Baseline to at least 24 weeks)
- Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds(From Baseline to at least 24 weeks)
- Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds(From Baseline to at least 24 weeks)
- Model-Based Annualized Bleeding Rate for Treated Joint Bleeds(From Baseline to at least 24 weeks)
- Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds(From Baseline to at least 24 weeks)
- Number of Participants With Thromboembolic Events by Severity, According to the WHO Toxicity Grading Scale(From Baseline until end of study (up to 85 months))
- Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds(From Baseline to at least 24 weeks)
- Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for All Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study(Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days))
- Arms A, B, and C: Adjusted Mean European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Questionnaire Visual Analog Scale (VAS) Score at Week 25(Baseline and Week 25)
- Arms A, B, and C: Change From Baseline in EQ-5D-5L Questionnaire VAS Score at Week 25(Baseline and Week 25)
- Number of Participants With Injection-Site Reactions by Severity, According to the WHO Toxicity Grading Scale(From Baseline until end of study (up to 85 months))
- Change From Baseline in Respiratory Rate Over Time(Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months))
- Mean Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds(From Baseline to at least 24 weeks)
- Median Calculated Annualized Bleeding Rate for Treated Target Joint Bleeds(From Baseline to at least 24 weeks)
- Intra-Participant Comparison of the Calculated Annualized Bleeding Rate for Treated Bleeds With Emicizumab Prophylaxis On-Study Versus With Previous Episodic Therapy Pre-Study(Efficacy periods: At least 24 weeks prior to study entry (mean [min-max] for A+B NIS-Previous Episodic Therapy: 183 [169-221] days); and From Baseline to at least 24 weeks on study (mean [min-max] for A+B NIS-Emicizumab: 363 [324-422] days))
- Arms A, B, and C: Change From Baseline to Week 25 in Haem-A-QoL Questionnaire Physical Health Domain Score for Participants ≥18 Years of Age(Baseline and Week 25)
- Arms A, B, and C: Adjusted Mean EQ-5D-5L Index Utility Score at Week 25(Baseline and Week 25)
- Change From Baseline in Systolic Blood Pressure Over Time(Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months))
- Arms A, B, and C: Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score at Baseline and Week 25 in Participants 12 to 17 Years of Age(Baseline and Week 25)
- Number of Participants With Adverse Events by Severity, According to the World Health Organization (WHO) Toxicity Grading Scale(From Baseline until end of study (up to 85 months))
- Number of Participants With Adverse Events Leading to Study Drug Discontinuation(From Baseline until end of study (up to 85 months))
- Number of Participants With Serum Chemistry Laboratory Abnormalities by Highest WHO Grade Post-Baseline, According to the WHO Toxicity Grading Scale(From Baseline until end of study (up to 85 months))
- Number of Participants With Hematology Laboratory Abnormalities by Highest WHO Grade Post-Baseline, According to the WHO Toxicity Grading Scale(From Baseline until end of study (up to 85 months))
- Change From Baseline in Body Temperature Over Time(Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months))
- Number of Participants With Anti-Emicizumab Antibodies(QW: Pre-dose at Weeks 1, 5, 9, 13, 17, 21, 25, 33, 41, 49, and every 12 weeks thereafter until study completion; Q4W: Pre-dose at Weeks 1, 5, 9, 13, 17, 21, 25, and every 12 weeks thereafter until study completion (up to 85 months))
- Number of Participants With Thrombotic Microangiopathy by Severity, According to the WHO Toxicity Grading Scale(From Baseline until end of study (up to 85 months))
- Change From Baseline in Pulse Rate Over Time(Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months))
- Change From Baseline in Diastolic Blood Pressure Over Time(Baseline, Weeks 5, 25, 49, and at study completion (up to 85 months))
- Number of Participants With Severe Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions(From Baseline until end of study (up to 85 months))
- Plasma Trough Concentration (Ctrough) of Emicizumab(QW: Predose at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, and every 12 weeks thereafter to study completion; Q4W: Predose at Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, and every 12 weeks thereafter to study completion (up to 85 months))