A Phase 3 study to evaluate the efficacy and safety of BMN 270 gene transfer in patients with severe hemophilia A

Phase 1

• Conditions: Haemophilia A; MedDRA version: 20.0Level: LLTClassification code 10060612Term: Hemophilia ASystem Organ Class: 100000004850; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2017-003215-19-FR
• Lead Sponsor: BioMarin Pharmaceutical Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2018-09-27
• Last Update Posted: 10 October 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Male
• Target Recruitment: 130

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. High-quality, well-documented historical data concerning bleeding episodes and FVIII usage over the previous 12 months must be available.
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs).
4. Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study-related procedures.
5. 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).
6. 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 no detectable viral vector DNA.
7. Willing to abstain from alcohol consumption for at least the first 52 weeks following BMN 270 infusion.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 115
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 15

Exclusion Criteria

1. Detectable pre-existing antibodies to the AAV5 capsid.
2. Any evidence of active infection or any immunosuppressive disorder, including HIV infection.
3. 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; or
• 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
4. 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.
5. Evidence of any bleeding disorder not related to hemophilia A.
6. Platelet count of < 100 x 10^9/L.
7. Creatinine = 1.5 mg/dL.
8. Liver cirrhosis of any etiology as assessed by liver ultrasound.
9. Chronic or active hepatitis B as evidenced by positive serology testing (HBsAg, HBsAb, and HBcAb) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control (CDC) table for the interpretation of serological test results in the Laboratory Manual.
10. Active Hepatitis C as evidenced by detectable HCV RNA or currently on antiviral therapy.
11. Active malignancy, except non-melanoma skin cancer.
12. History of hepatic malignancy.
13. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), with the exception of catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing.
14. Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation.
15. Treatment with any investigational product within 30 days or 5 half-lives of the investigational product prior to the screening period. For subjects who have received a prior investigational product, all ongoing adverse events (AEs) experienced while receiving that investigational product must have resolved prior to screening for this study.
16. 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 possible corticosteroid treatment outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy result.
17. Prior treatment with any vector or gene transfer agent.
18. Major surgery planned in the 52-week period following the infusion with BMN 270.
19. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines within 30 days before the BMN 270 infusion.
20. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study that does not interfere with the requirements of the current protocol or have the potential to impact the evaluation of efficacy and safety of BMN 270 and with prior consultation with the Medical Monitor.
21. Known allergy or hypersensitivity to BMN 270 investigational product formulation.
22. Unwilling to receive blood or blood products

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified