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Gene Therapy Study in Severe Hemophilia A Patients With Antibodies Against AAV5 (270-203)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03520712
Recruitment Status : Enrolling by invitation
First Posted : May 11, 2018
Last Update Posted : November 16, 2020
Sponsor:
Information provided by (Responsible Party):
BioMarin Pharmaceutical

Tracking Information
First Submitted Date  ICMJE April 10, 2018
First Posted Date  ICMJE May 11, 2018
Last Update Posted Date November 16, 2020
Actual Study Start Date  ICMJE April 3, 2018
Estimated Primary Completion Date November 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 12, 2020)
Safety of a single intravenous administration of BMN 270 in severe HA subjects with pre-existing antibody to AAV5 vector capsid, including development of FVIII neutralizing antibody. [ Time Frame: 61 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: April 27, 2018)
Assess the safety of a single intravenous administration of valoctocogene roxaparvovec in severe Hemophilia A (HA) subjects with pre-existing antibody to AAV5 vector capsid, including development of FVIII neutralizing antibody [ Time Frame: 61 months ]
Percentage of participants with treatment-related adverse events, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for 5 years following valoctocogene roxaparvovec infusion.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2020)
  • Efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26. [ Time Frame: 26 weeks ]
  • Impact of BMN 270 on usage of exogenous FVIII replacement therapy. [ Time Frame: 61 months ]
  • Impact of BMN 270 on the number of bleeding episodes requiring exogenous FVIII therapy. [ Time Frame: 61 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 27, 2018)
  • Assess the efficacy of valoctocogene roxaparvovec defined as FVIII activity at or above 5 IU/dL at Week 26 [ Time Frame: 26 weeks ]
  • Change in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy [ Time Frame: 61 months ]
  • Assess the impact of valoctocogene roxaparvovec on the number of bleeding episodes requiring exogenous FVIII therapy [ Time Frame: 61 months ]
  • Evaluate the FVIII antigen and activity level following IV infusion of valoctocogene roxaparvovec [ Time Frame: 61 months ]
  • Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemophilia Quality of Life for Adults (Haemo-QoL-A). [ Time Frame: 61 months ]
    Haemo-QoL-A is a hemophilia-specific, health-related quality of life questionnaire for adults on a scale of 0-5 with a higher value representing a better outcome
  • Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) EQ-5D-5L. [ Time Frame: 61 months ]
    EQ-5D-5L is a general questionnaire designed to measure health status on a scale of 0-100 with the higher value representing a better outcome
  • Assess the impact of valoctocogene roxaparvovec following Patient Reported Outcome (PRO) Haemophilia Activities List (HAL) [ Time Frame: 61 months ]
    HAL is a questionnaire that has several activities listed that could be difficult for people with hemophilia. Subjects are asked to rate their level of difficulty with activities of daily living on a 6-point scale from 1 (Impossible) to 6 (Never)
  • 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: 61 months ]
    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. WPAI+CIQ:HS outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Gene Therapy Study in Severe Hemophilia A Patients With Antibodies Against AAV5
Official Title  ICMJE A Phase 1/2 Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients With Residual FVIII Levels ≤ 1 IU/dL and Pre-existing Antibodies Against AAV5
Brief Summary This study is being conducted by Biomarin Pharmaceutical Inc. as an open label, single dose study to determine the safety of valoctocogene roxaparvovec (an Adenovirus-Associated Virus (AAV) based gene therapy vector) in severe Hemophilia A patients with pre-existing antibodies against AAV5.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hemophilia A
  • Gene Therapy
  • Clotting Disorders
  • Blood Disorder
Intervention  ICMJE Biological: Valoctocogene Roxaparvovec
Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A
Other Name: BMN 270
Study Arms  ICMJE Experimental: valoctocogene roxaparvovec Open Label
Single administration of BMN270 at a dose of 6E13 vg/kg
Intervention: Biological: Valoctocogene Roxaparvovec
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: April 27, 2018)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2026
Estimated Primary Completion Date November 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total antibody ELISA.
  3. Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry.
  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) (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).
  5. Sexually active participants must agree to use an acceptable method of effective contraception, either double barrier contraception (ie, condom + diaphragm; or condom or diaphragm + spermicidal gel or foam) or their female partner either using hormonal contraceptives or having an intrauterine device. Participants must agree to contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples with viral vector DNA below the limit of detection.
  6. Willing to abstain from consumption of alcohol for at least the first 52 weeks following BMN 270 infusion.

Exclusion Criteria:

  1. Any evidence of active infection including COVID-19, or any immunosuppressive disorder, including HIV infection.
  2. Evidence of liver dysfunction as assessed by liver tests and most recent, prior FibroScan or 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.
  3. Chronic or active hepatitis B or C as evidenced by testing at screening.
  4. Active malignancy, except non-melanoma skin cancer, or history of hepatic malignancy.
  5. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the requirements of the study (including corticosteroid treatment and/or use of alternative immunosuppressive agents outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy result.
  6. Prior treatment with any vector or gene transfer agent.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (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 France,   South Africa,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03520712
Other Study ID Numbers  ICMJE BMN 270-203
2017-000662-29 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party BioMarin Pharmaceutical
Study Sponsor  ICMJE BioMarin Pharmaceutical
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director, MD BioMarin Pharmaceutical
PRS Account BioMarin Pharmaceutical
Verification Date November 2020

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