Haemophilia A MedDRA version: 20.0 Level: LLT Classification code 10060612 Term: Hemophilia A System Organ Class: 100000004850
Conditions
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. Detectable pre-existing antibodies against the AAV5 vector capsid as measured by AAV5 total antibody ELISA 3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs) 4. Subject must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry. 5. 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. 6. 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) 7. 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. 8. Willing to abstain from consumption of alcohol 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 10 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, including HIV infection. 2. Significant liver dysfunction with any of the following abnormal laboratory results: o ALT (alanine aminotransferase) > 1.25x ULN; o AST (aspartate aminotransferase) > 1.25x ULN; o GGT (gamma-glutamyltransferase) > 1.25x ULN; o Total bilirubin > 1.25x ULN; o Alkaline phosphatase > 1.25x ULN; or o 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. 3. 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 4. Evidence of any bleeding disorder not related to hemophilia A 5. Platelet count of < 100 x 10^9/L 6. Creatinine = 1.5 mg/dL 7. Liver cirrhosis of any etiology as assessed by liver ultrasound/FibroScan. 8. 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 . 9. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy 10. Active malignancy, except non-melanoma skin cancer 11. History of hepatic malignancy 12. 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. 13. Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation. 14. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, vasculitis). 15. Treatment with any Investigational Product within 30 days or 5 half-lives of the investigational product (whichever is longer) 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 corticosteroid treatment and/or the 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. 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 saf
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - Assess the safety of a single intravenous administration of BMN 270 in severe Haemophilia A subjects with pre-existing antibody to AAV5 vector capsid, including development of FVIII neutralizing antibody ;Secondary Objective: - Assess the efficacy of BMN 270 defined as FVIII activity at or above 5 IU/dL at Week 26 - Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy - Assess the impact of BMN 270 on the number of bleeding episodes requiring exogenous FVIII therapy - Evaluate the pharmacodynamics of FVIII expression following intravenous infusion of BMN 270 - Assess the impact of BMN 270 on patient-reported outcomes (PROs) ;Primary end point(s): - The following safety outcome measurements will be assessed: • Incidence of adverse events (AEs), including serious AEs (SAEs) • Change in clinical laboratory tests (serum chemistry and hematology) • Change in vital signs • Change in physical examination • Vector shedding (blood, urine, semen, feces, saliva) • Liver tests (LTs, including ALT, AST, GGT, LDH, total bilirubin, and alkaline phosphatase) • Immune response to FVIII transgene product and AAV5 vector capsid;Timepoint(s) of evaluation of this end point: Week 26 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - The efficacy goal is to achieve FVIII activity = 5 IU/dL at 26 weeks post-BMN 270 administration. Other efficacy measures: - assessment of the impact of BMN 270 on the use of FVIII replacement therapy and on the number of bleeding episodes during the study. Subjects will be asked to keep a subject diary, provided by the sponsor, to record the relevant details. - Change from baseline in the total score of HAEMO-QoL-A at Week 26 of the study post-BMN 270 infusion - Change from baseline in the EQ-5D-5L score at Week 26 of the study post-BMN 270 infusion. - Change from baseline in the Haemophilia Activities List (HAL) score at Week 26 of the study post-BMN 270 infusion. - Change from baseline in the Work Productivity and Activity Impairment plus Classroom Impairment Questions: Hemophilia Specific (WPAI+CIQ:HS) score at Week 26 of the study post-BMN 270 infusion. ;Timepoint(s) of evaluation of this end point: Week 26 | — |
Countries
France, South Africa, United Kingdom
Contacts
Public ContactClinical Trials Information
BioMarin Pharmaceutical Inc.
Outcome results
None listed