E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To assess the safety of a single intravenous administration of a recombinant AAV5 encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector. - To determine the dose of AAV5-hFVIII-SQ required to achieve FVIII at or above 5% of normal activity (≥5 IU/dL) at 16 weeks after infusion. The kinetics, duration and magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be determined and correlated to an appropriate BMN 270 dose. |
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E.2.2 | Secondary objectives of the trial |
- To describe the immune response to the FVIII transgene and AAV capsid proteins following systemic administration of AAV5-hFVIII-SQ - To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during the study - To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment during the study |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Liver Biopsy Substudy The exploratory objectives of the liver biopsy substudy are: • To examine the histopathology of the liver following BMN 270 therapy, including assessing for possible safety findings (eg, fibrosis, fatty liver disease, lymphocytic invasion) • To quantify FVIII DNA, RNA, and protein expression within hepatocytes • To determine which forms of rAAV vector DNA are present at the time of biopsy. • To determine the transduction pattern of BMN 270 in humans (ie, peri-portal hepatocytes, central vein hepatocytes)
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E.3 | Principal inclusion criteria |
1. Males that are 18 years or older with established severe haemophilia A as evidenced by their medical history. Patients will be considered as severe if their base FVIII level is 1 IU/dL or less 2. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs) 3. Greater or equal to 12 bleeding episodes only if receiving on-demand therapy over the previous 12 months. Does not apply to patients on prophylaxis 4. Able to sign informed consent and comply with requirements of the trial 5. No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 12 months 6. Sexually active patients must be willing to use an acceptable method of contraception such as double barrier, including hormonal contraception for at least 6 months post-treatment. After 6 months, subjects may stop contraception use only if they have had 3 consecutive semen samples below the limit of detection of the test. |
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E.4 | Principal exclusion criteria |
1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction inhibition or AAV5 total antibodies 2. Any evidence of active infection or any immunosuppressive disorder. 3. HIV positive 4. Significant liver dysfunction as defined by abnormal elevation of: ALT (alanine transaminase) to 3 times the upper limit of normal; Bilirubin above 3 times the upper limit of normal; Alkaline phosphatase above 3 times the upper limit of normal; or INR (international normalized ratio) ≥ 1.4. 5. Potential participants who have had a liver biopsy in the past 3 years are excluded if they had significant fibrosis of 3 or 4 as rated on a scale of 0-4 6. Evidence of any bleeding disorder not related to Haemophilia A 7. Platelet count of < 100 x 10^9/L 8. Creatinine ≥ 1.5 mg/dL 9. Liver cirrhosis of any etiology as assessed by liver ultrasound 10. Hepatitis B if surface antigen is positive 11. Hepatitis C if RNA is positive 12. Treatment with any IP within 30 days prior to the end of the screening period 13. Any disease or condition at the physician’s discretion that would prevent the patient from fully complying with the requirements of the study including possible corticosteroid treatment outlined in the protocol. The physician may exclude patients unwilling or unable to agree on not using alcohol for the 16-week period following the viral infusion. 14. Prior treatment with any vector or gene transfer agent 15. Major surgery planned in the 16-week period following the viral infusion 16. Use of systemic immunosuppressive agents or live vaccines within 30 days before the viral infusion |
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E.5 End points |
E.5.1 | Primary end point(s) |
- To assess the safety of a single intravenous administration of a recombinant AAV5 encoding human coagulation FVIII (AAV5-hFVIII-SQ) vector. - To determine the dose of AAV5-hFVIII-SQ required to achieve FVIII at or above 5% of normal activity (≥5 IU/dL) at 16 weeks after infusion. The kinetics, duration and magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be determined and correlated to an appropriate BMN 270 dose. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety will be closely monitored during dosing and for 24 hours after dosing. Safety follow-up evaluations will be conducted at least once a week after the infusion for 36 weeks, once every 2 weeks until the end of the first year and then once every three months until the end of the study (in year 7). Dose determination will be evaluated using FVIII activity assays and will be assessed weekly during the first 36 weeks after the infusion, once every 2 weeks until the end of the first year and then once every three months until the end of year 5. |
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E.5.2 | Secondary end point(s) |
- To describe the immune response to the FVIII transgene and AAV capsid proteins following systemic administration of AAV5-hFVIII-SQ - To assess the impact of BMN 270 on the frequency of FVIII replacement therapy during the study - To assess the impact of BMN 270 on the number of bleeding episodes requiring treatment during the study
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Immune responses will be assessed every week through Week 20, then every other week through Week 36, then once every 2 months until the end of the first year and then once every three months until the end of year 5 and then every 26 weeks until the end of the study (in year 7). The impact of BMN 270 on the frequency of FVIII replacement therapy and number of bleeding episodes will be assessed at each visit by providing diaries to participants to record these events.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 5 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 5 |