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Efficacy, Safety, and Pharmacokinetic Study of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Participants (HAVEN 5)

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ClinicalTrials.gov Identifier: NCT03315455
Recruitment Status : Enrolling by invitation
First Posted : October 20, 2017
Last Update Posted : September 12, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE October 17, 2017
First Posted Date  ICMJE October 20, 2017
Last Update Posted Date September 12, 2019
Actual Study Start Date  ICMJE April 26, 2018
Estimated Primary Completion Date December 17, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 10, 2019)
  • Model-Based Annualized Bleeding Rate for Treated Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
    The model-based annualized bleeding rate (ABR) will be estimated using a negative binomial regression model.
  • Median Calculated Annualized Bleeding Rate for Treated Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
  • Mean Calculated Annualized Bleeding Rate for Treated Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
Original Primary Outcome Measures  ICMJE
 (submitted: October 17, 2017)
Numbers of Treated Bleeds Over Time [ Time Frame: From Baseline up to 24 weeks ]
Change History Complete list of historical versions of study NCT03315455 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2019)
  • Model-Based Annualized Bleeding Rate for All Bleeds (Whether Treated or Not Treated With Coagulation Factors) [ Time Frame: From Baseline to at least 24 weeks ]
    The model-based annualized bleeding rate (ABR) will be estimated using a negative binomial regression model.
  • Median Calculated Annualized Bleeding Rate for All Bleeds (Whether Treated or Not Treated With Coagulation Factors) [ Time Frame: From Baseline to at least 24 weeks ]
  • Mean Calculated Annualized Bleeding Rate for All Bleeds (Whether Treated or Not Treated With Coagulation Factors) [ Time Frame: From Baseline to at least 24 weeks ]
  • Model-Based Annualized Bleeding Rate for Spontaneous Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
    The model-based annualized bleeding rate (ABR) will be estimated using a negative binomial regression model.
  • Median Calculated Annualized Bleeding Rate for Spontaneous Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
  • Mean Calculated Annualized Bleeding Rate for Spontaneous Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
  • Model-Based Annualized Bleeding Rate for Joint Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
    The model-based annualized bleeding rate (ABR) will be estimated using a negative binomial regression model.
  • Median Calculated Annualized Bleeding Rate for Joint Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
  • Mean Calculated Annualized Bleeding Rate for Joint Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
  • Model-Based Annualized Bleeding Rate for Target Joint Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
    The model-based annualized bleeding rate (ABR) will be estimated using a negative binomial regression model.
  • Median Calculated Annualized Bleeding Rate for Target Joint Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
  • Mean Calculated Annualized Bleeding Rate for Target Joint Bleeds [ Time Frame: From Baseline to at least 24 weeks ]
  • Intra-Participant Comparison of the Model-Based Annualized Bleeding Rate (ABR) for Treated Bleeds on Study Versus Pre-Study [ Time Frame: Up to 24 weeks before study entry (will be assessed retrospectively at Baseline), from Baseline to at least 24 weeks on study ]
  • Intra-Participant Comparison of the Model-Based ABR for All Bleeds (Whether Treated or not Treated by Coagulation Factors) on Study Versus Pre-Study [ Time Frame: Up to 24 weeks before study entry (will be assessed retrospectively at Baseline), from Baseline to at least 24 weeks on study ]
  • Arms A, B, and C: Change from Baseline in Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score in Participants ≥18 Years of Age at Week 25 [ Time Frame: Baseline and Week 25 ]
  • Arms A, B, and C: Change from Baseline in Haem-A-QoL Questionnaire Physical Health Domain Score in Participants ≥18 Years of Age at Week 25 [ Time Frame: Baseline and Week 25 ]
  • Arms A, B, and C: Change from Baseline in Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Total Score in Participants 12 to 17 Years of Age at Week 25 [ Time Frame: Baseline and Week 25 ]
  • Arms A, B, and C: Change from Baseline in European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Index Utility Score at Week 25 [ Time Frame: Baseline and Week 25 ]
  • Arms A, B, and C: Change from Baseline in EQ-5D-5L Questionnaire Visual Analog Scale (VAS) Score at Week 25 [ Time Frame: Baseline and Week 25 ]
  • Arm D: Change from Baseline in Haemo-QoL-SF Questionnaire Score in Participants 8 to 12 Years of Age at Week 25 [ Time Frame: 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 [ Time Frame: Baseline (Week 1) and Weeks 17, 29, 37, and 49, and study completion (up to approximately 42 months) ]
  • Number of Participants with Adverse Events by Severity, According to the World Health Organization (WHO) Toxicity Grading Scale [ Time Frame: From Baseline until end of study (up to approximately 42 months) ]
  • Number of Participants with Adverse Events Leading to Study Drug Discontinuation [ Time Frame: From Baseline until end of study (up to approximately 42 months) ]
  • Number of Participants with Thromboembolic Events by Severity, According to the WHO Toxicity Grading Scale [ Time Frame: From Baseline until end of study (up to approximately 42 months) ]
  • Number of Participants with Thrombotic Microangiopathy by Severity, According to the WHO Toxicity Grading Scale [ Time Frame: From Baseline until end of study (up to approximately 42 months) ]
  • Number of Participants with Injection-Site Reactions by Severity, According to the WHO Toxicity Grading Scale [ Time Frame: From Baseline until end of study (up to approximately 42 months) ]
  • Number of Participants with Severe Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions [ Time Frame: From Baseline until end of study (up to approximately 42 months) ]
  • Number of Participants with Serum Chemistry Laboratory Abnormalities by Highest WHO Grade Post-Baseline, According to the WHO Toxicity Grading Scale [ Time Frame: From Baseline until end of study (up to approximately 42 months) ]
  • Number of Participants with Hematology Laboratory Abnormalities by Highest WHO Grade Post-Baseline, According to the WHO Toxicity Grading Scale [ Time Frame: From Baseline until end of study (up to approximately 42 months) ]
  • Change from Baseline in Body Temperature Over Time [ Time Frame: Baseline, Weeks 1, 25, and 49, and at study completion (up to approximately 42 months) ]
  • Change from Baseline in Pulse Rate Over Time [ Time Frame: Baseline, Weeks 1, 25, and 49, and at study completion (up to approximately 42 months) ]
  • Change from Baseline in Respiratory Rate Over Time [ Time Frame: Baseline, Weeks 1, 25, and 49, and at study completion (up to approximately 42 months) ]
  • Change from Baseline in Systolic Blood Pressure Over Time [ Time Frame: Baseline, Weeks 1, 25, and 49, and at study completion (up to approximately 42 months) ]
  • Change from Baseline in Diastolic Blood Pressure Over Time [ Time Frame: Baseline, Weeks 1, 25, and 49, and at study completion (up to approximately 42 months) ]
  • Number of Participants with Anti-Emicizumab Antibodies [ Time Frame: 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 42 months) ]
  • Plasma Trough Concentration (Ctrough) of Emicizumab [ Time Frame: 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 42 months) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 17, 2017)
  • Reduction from Baseline in Number of All Bleeds (Whether Treated or Not Treated With Coagulation Factors) Over 24 Weeks [ Time Frame: From Baseline up to 24 weeks ]
  • Reduction From Pre-Study in Number of Treated Bleeds Over 24 Weeks [ Time Frame: Up to 24 weeks before study entry (will be assessed retrospectively at baseline), 24 weeks ]
  • Reduction From Pre-Study in Number of All Bleeds (Whether Treated or not Treated by Coagulation Factors) Over 24 Weeks [ Time Frame: Up to 24 weeks before study entry (will be assessed retrospectively at baseline), 24 weeks ]
  • Reduction From Baseline in Number of Spontaneous Bleeds Over 24 Weeks [ Time Frame: From Baseline up to 24 weeks ]
  • Reduction from Baseline in Number of Joint Bleeds Over 24 Weeks [ Time Frame: From Baseline up to 24 weeks ]
  • Reduction from Baseline in Number of Target Joint Bleeds Over 24 Weeks [ Time Frame: From Baseline up to 24 weeks ]
  • Change from Baseline in Hemophilia A Quality of Life (Haemo-A-QoL) Questionnaire Score in Participants Greater Than or Equal to (>/=) 18 Years of Age at Week 24 [ Time Frame: Baseline, Week 24 ]
  • Change from Baseline in Hemophilia-Specific Quality of Life Short Form (Haemo-QoL-SF) Questionnaire Score in Participants 12 to 17 Years of Age at Week 24 [ Time Frame: Baseline, Week 24 ]
  • Change from Baseline in European Quality of Life 5-Dimensions-5 Levels Questionnaire (EQ-5D-5L) Score at Week 24 [ Time Frame: Baseline, Week 24 ]
  • Percentage of Participants with Adverse Events (AEs) [ Time Frame: From Baseline up to end of study (overall approximately 22 months) ]
  • Percentage of Participants with Anti-Emicizumab Antibodies [ Time Frame: From Baseline up to end of study (overall approximately 22 months) ]
  • Plasma Trough Concentration (Ctrough) of Emicizumab [ Time Frame: QW: predose (0 hours) on Weeks (Wk) 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 33, 41, 49, every 12 Wk until end of study (EOS); Q4W: 0 hours on Wk 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, every 12 Wk until EOS (EOS: approximately 22 months) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy, Safety, and Pharmacokinetic Study of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Participants
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Hemophilia A
Intervention  ICMJE Drug: Emicizumab
Emicizumab will be administered via subcutaneous (SC) injection, as described for each treatment arm.
Other Names:
  • Hemlibra
  • RO5534262
  • RG6013
  • ACE910
Study Arms  ICMJE
  • Experimental: 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 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.
    Intervention: Drug: Emicizumab
  • Experimental: 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.
    Intervention: Drug: Emicizumab
  • Arm C: No Prophylaxis (Control Arm)
    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.
    Intervention: Drug: Emicizumab
  • Experimental: 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.
    Intervention: Drug: Emicizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: September 10, 2019)
85
Original Estimated Enrollment  ICMJE
 (submitted: October 17, 2017)
70
Estimated Study Completion Date  ICMJE September 22, 2021
Estimated Primary Completion Date December 17, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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

Exclusion Criteria:

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China,   Hong Kong,   Malaysia,   Thailand
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03315455
Other Study ID Numbers  ICMJE YO39309
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP