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

Brief Title

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

Official Title

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.

Study Phase

Phase 3

Study Type

Interventional

Primary Outcome

Model-Based Annualized Bleeding Rate for Treated Bleeds

Secondary Outcome

 Model-Based Annualized Bleeding Rate for All Bleeds (Whether Treated or Not Treated With Coagulation Factors)

Condition

Hemophilia A

Intervention

Emicizumab

Study Arms / Comparison Groups

 Arm A: Emicizumab Prophylaxis at 1.5 mg/kg QW

Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status

Drug

Estimated Enrollment

Start Date

April 26, 2018

Completion Date

May 31, 2025

Primary Completion Date

August 3, 2022

Eligibility Criteria

        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

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Clinical Trials, ,

Location Countries

China

Location Countries

China

Administrative Informations

NCT ID

NCT03315455

Organization ID

YO39309

Responsible Party

Sponsor

Study Sponsor

Hoffmann-La Roche

Study Sponsor

Clinical Trials, Study Director, Hoffmann-La Roche

Verification Date

August 2022