Haemophilia A
Conditions
Interventions
Product Code: BMN 270
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: valoctocogene roxaparvovec
CAS Number: 1819334-78-5
Sponsors
BioMarin Pharmaceutical Inc.
Eligibility
Sex/Gender
Male
Inclusion 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. 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. 8. HIV positive patients may be enrolled, only if the patient has a CD4 count > 200/mm^3 and an undetectable viral load (unquantifiable viral load defined as less than the limit of quantification by the testing laboratory’s assay is permitted). 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 50 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. Detectable pre-existing antibodies to the AAV5 capsid. 2. Any evidence of active infection or any immunosuppressive disorder, except for HIV infection as described in the inclusion criterion above. 3. Significant liver dysfunction with any of the following abnormal laboratory results: • ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >2X ULN; • Total bilirubin >2X ULN; • Alkaline phosphatase >2X ULN; or • INR (international normalized ratio) = 1.4. Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat testing and, if eligibility criteria are met on retest, may be enrolled after confirmation by the Medical Monitor. In addition, subjects with abnormal laboratory results related to confirmed benign liver conditions are considered eligible for the study notwithstanding their abnormal laboratory results and may be enrolled after discussion with the Medical Monitor. •Benign liver conditions are those conditions (eg, Gilbert’s syndrome) where physiologic hepatic findings can be considered non-serious in nature and do not confer illness or in most instances require treatment. Individuals with such conditions that do not impact laboratory values such as serum transaminases or conjugated bilirubin (eg, Gilbert’s syndrome) and enable assessment of potential liver toxicity following BMN 270 infusion may be included in the study following a review 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 (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 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. 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. 14. 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. 15. Prior treatment with any vector or gene transfe
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - Assess the efficacy of BMN 270 defined as FVIII activity, as measured by one-stage clotting assay, during Weeks 49-52 following intravenous infusion of BMN 270 ; Secondary Objective: - Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy from Week 5 to Week 52 - Assess the impact of BMN 270 on the number of bleeding episodes requiring exogenous FVIII replacement therapy from Week 5 to Week 52 ;Primary end point(s): - Change of the hFVIII activity, as measured by one-stage clotting assay, during Weeks 49-52 post-BMN 270 infusion from baseline. Each subject’s hFVIII activity during Weeks 49-52 is defined as the median of the values obtained during this 4-week window. Values for hFVIII activity will be excluded if obtained within 72 hours since the last infusion of exogenous FVIII protein concentrates.;Timepoint(s) of evaluation of this end point: During Weeks 49-52 post-BMN 270 infusion | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Change in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy during Week 5 to Week 52 post-BMN 270 infusion from the baseline utilization of exogenous FVIII replacement therapy. - Change in the annualized number of bleeding episodes requiring exogenous FVIII replacement treatment (annualized bleeding rate, ABR) during Week 5 to Week 52 of the study post-BMN 270 infusion from the baseline ABR. ; Timepoint(s) of evaluation of this end point: - Utilization (IU/kg) of exogenous FVIII replacement therapy will be evaluated during Week 5 to Week 52 post-BMN 270 infusion from the baseline utilization of exogenous FVIII replacement therapy - The number of bleeding episodes requiring exogenous FVIII replacement treatment will be evaluated during Week 5 to Week 52 post-BMN 270 infusion from the baseline ABR | — |
Countries
Brazil, France, Germany, Israel, Italy, Japan, South Africa, Spain, United Kingdom, United States
Contacts
Public ContactClinical Trials Information
BioMarin Pharmaceutical Inc.
Outcome results
None listed