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Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270-301)

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ClinicalTrials.gov Identifier: NCT03370913
Recruitment Status : Recruiting
First Posted : December 13, 2017
Last Update Posted : November 15, 2018
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Brief Summary:
This clinical trial is being conducted to learn more about a potential treatment (valoctocogene roxaparvovec) for people with severe hemophilia A. This research study will test and confirm the safety and effectiveness of the 6E13 vg/kg dose of the study drug (valoctocogene roxaparvovec) that contains the correct gene to make Factor VIII so that the body can make its own Factor VIII that functions properly. Only one dose of valoctocogene roxaparvovec is being given in this study, and this dose has been previously studied in another clinical trial in patients with hemophilia A. This is a phase 3 study which is meant to show that the study drug is safe and works to help treat hemophilia A. The study will see if liver cells are able to make Factor VIII that functions properly after receiving this study drug. The study will also examine the effects that the study drug has on how much Factor VIII concentrates patients have to inject into their veins and on their bleeding episodes after the study drug has been administered. Finally, the study will see if and how the body responds to the study drug - for example, whether liver cells become inflamed or whether the body makes antibodies (something the immune system makes to protect itself against things like bacteria and viruses) against the vector or the new Factor VIII gene.

Condition or disease Intervention/treatment Phase
Hemophilia A Biological: valoctocogene roxaparvovec Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3 Open-Label, Single-Arm Study To Evaluate The Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients With Residual FVIII Levels ≤ 1 IU/dL Receiving Prophylactic FVIII Infusions
Actual Study Start Date : December 19, 2017
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : September 2023


Arm Intervention/treatment
Experimental: valoctocogene roxaparvovec Open Label
Single administration of valoctocogene roxaparvovec at a dose of 6E13 vg/kg
Biological: valoctocogene roxaparvovec
Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A
Other Name: BMN 270




Primary Outcome Measures :
  1. Change of the median FVIII activity [ Time Frame: 52 weeks ]

Secondary Outcome Measures :
  1. Change in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy [ Time Frame: 52 weeks ]
  2. Change in the annualized number of bleeding episodes requiring exogenous FVIII replacement treatment [ Time Frame: 52 weeks ]

Other Outcome Measures:
  1. Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemo-QoL-A. [ Time Frame: 52 weeks ]
    Haemo-QoL-A is a hemophilia-specific, health-related quality of life questionnaire for adults

  2. Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) EQ-5D-5L [ Time Frame: 52 weeks ]
    EQ-5D-5L is a general questionnaire designed to measure health status

  3. Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemophilia Activities List (HAL) [ Time Frame: 52 weeks ]
    HAL is a questionnaire that measures the impact of hemophilia on functional abilities in adults

  4. Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Work Productivity and Activity Impairment plus Classroom Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) [ Time Frame: 52 weeks ]
    WPAI+CIQ:HS is a questionnaire that is designed to measure the effect of symptom severity due to hemophilia on work productivity and activity/classroom impairment

  5. Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcomes, Burdens, and Experiences (PROBE) Questionnaire [ Time Frame: 52 weeks ]
    PROBE is a questionnaire that is designed to investigate and directly probe patient perspectives on outcomes they deem relevant to their life and care

  6. Percentage of participants with treatment-related adverse events, as assessed by CTCAE v4.03 in the first 52 weeks following valoctocogene roxaparvovec infusion [ Time Frame: 52 weeks ]
  7. Percentage of participants with treatment-related adverse events, as assessed by de novo development of FVIII inhibitors in the first 52 weeks following valoctocogene roxaparvovec infusion [ Time Frame: 52 weeks ]
  8. Percentage of participants with treatment-related adverse events, as assessed by CTCAE v4.03 during years 2-5 following valoctocogene roxaparvovec infusion. [ Time Frame: 5 years ]
  9. Percentage of participants with treatment-related adverse events, as assessed by de novo development of FVIII inhibitors during years 2-5 following valoctocogene roxaparvovec infusion. [ Time Frame: 5 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Biological male genders to only be included
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.
  • Must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry. High-quality, well-documented historical data concerning bleeding episodes and FVIII usage over the previous 12 months must be available.
  • Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs).
  • 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) (or less than 1.0 BU for laboratories with a historical lower sensitivity cutoff for inhibitor detection of 1.0 BU) on 2 consecutive occasions at least one week apart within the past 12 months (at least one of which should be tested at the central laboratory).

Exclusion Criteria:

  • Detectable pre-existing antibodies to the AAV5 capsid.
  • Any evidence of active infection or any immunosuppressive disorder, including HIV infection.
  • Significant liver dysfunction with any of the following abnormal laboratory results:

    • ALT (alanine aminotransferase) > 1.25x ULN;
    • AST (aspartate aminotransferase) > 1.25x ULN;
    • GGT (gamma-glutamyltransferase) > 1.25x ULN;
    • Total bilirubin > 1.25x ULN;
    • Alkaline phosphatase > 1.25x ULN
    • INR (international normalized ratio) ≥ 1.4.

Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat testing of the entire liver test panel within the same Screening window and, if eligibility criteria are met on retest, may be enrolled after confirmation by the Medical Monitor.

  • Prior liver biopsy showing significant fibrosis of 3 or 4 as rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is used.
  • Evidence of any bleeding disorder not related to hemophilia A.
  • Platelet count of < 100 x 10^9/L.
  • Creatinine ≥ 1.5 mg/dL.
  • Liver cirrhosis of any etiology as assessed by liver ultrasound.
  • Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody [HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control (CDC) table for the interpretation of serological test results.
  • Active Hepatitis C as evidenced by detectable HCV RNA or currently on antiviral therapy.
  • Active malignancy, except non-melanoma skin cancer.
  • History of hepatic malignancy.
  • History of arterial or venous thromboembolic events (eg, deep vein thrombosis, nonhemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing.
  • Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03370913


Contacts
Contact: Trial Specialist medinfo@bmrn.com

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Sponsors and Collaborators
BioMarin Pharmaceutical
Investigators
Study Director: Medical Monitor, MD BioMarin Pharmaceutical

Responsible Party: BioMarin Pharmaceutical
ClinicalTrials.gov Identifier: NCT03370913     History of Changes
Other Study ID Numbers: BMN 270-301
2017-003215-19 ( EudraCT Number )
First Posted: December 13, 2017    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by BioMarin Pharmaceutical:
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

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants