Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270-301)
Condition: Hemophilia A
MeSH terms: Hemophilia A
Intervention: valoctocogene roxaparvovec
Intervention description: Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 144.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Gene Therapy; Clotting Disorders; Blood Disorder; Blood Coagulation Disorders; Inherited Blood Coagulation disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases; Inborn; Factor VIII; Coagulants

Summary:

      This Phase III clinical study will assess the impact of BMN 270 (compared to FVIII
      prophylaxis) on the number of bleeding episodes irrespective of exogenous FVIII replacement
      treatment in the efficacy evaluation period (EEP) (from Week 5 post-BMN 270 infusion (Study
      Day 33) or the end of FVIII prophylaxis plus the washout period (3 days for products of
      standard half-life or plasma-derived and 5 days for products of extended half-life),
      whichever is later, to last visit by the data cut-off for the 2-year analysis, hereafter
      referred to as "Post FVIII Prophylaxis to Last Visit"). The study will also assess the impact
      of BMN 270 (compared to FVIII prophylaxis) on: the number of bleeding episodes requiring
      exogenous FVIII treatment in "Post FVIII Prophylaxis to Last Visit", FVIII activity as
      measured by chromogenic sustrate assay at Week 104 following intravenous infusion of BMN 270,
      usage of exogenous FVIII replacement therapy in "Post FVIII Prophylaxis to Last Visit",
      health-related quality of life patient-reported outcomes at week 104 following intravenous
      infusion of BMN 270. The study will also evaluate the safety of the BMN 270.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as
             evidenced by medical history, at the time of signing the informed consent.

          2. Must have been on prophylactic FVIII replacement therapy for at least 12 months prior
             to study entry.

          3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure
             days (EDs).

          4. No previous documented history of a detectable FVIII inhibitor, and results from a
             Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda
             Units (BU) on 2 consecutive occasions at least one week apart within the past 12
             months.

        Exclusion Criteria:

          1. Detectable pre-existing antibodies to the adeno-associated virus 5 (AAV5) capsid.

          2. Any evidence of active infection or any immunosuppressive disorder, except for HIV
             infection

          3. Any evidence of active infection or any immunosuppressive disorder, including HIV
             infection (effective as of Protocol Amendment 3)

          4. Significant liver dysfunction.

          5. Prior liver biopsy showing significant fibrosis.

          6. Evidence of any bleeding disorder not related to hemophilia A.

          7. Platelet count of < 100 x 10^9/L.

          8. Creatinine ≥ 1.5 mg/dL.

          9. Liver cirrhosis of any etiology as assessed by liver ultrasound.

         10. Chronic or active hepatitis B.

         11. Active Hepatitis C.

         12. Active malignancy, except non-melanoma skin cancer.

         13. History of hepatic malignancy.

         14. History of arterial or venous thromboembolic events.

         15. Known inherited or acquired thrombophilia, including conditions associated with
             increased thromboembolic risk, such as atrial fibrillation.