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 |
- 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
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E.2.2 | Secondary objectives of the trial |
- 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)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal exclusion criteria |
1. Any evidence of active infection 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. 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
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
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 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 safety and efficacy of BMN 270 and with prior consultation with the Medical Monitor
21. Known allergy or hypersensitivity to investigational product formulation
22. Unwilling to receive blood or blood products for treatment of an adverse event and/or a bleed
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E.5 End points |
E.5.1 | 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, total bilirubin, and alkaline phosphatase)
• Immune response to FVIII transgene product and AAV5 vector capsid |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | 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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
safety, tolerability, efficacy of BMN 270 in haemophilia A patients w/ pre-existing AAV5 antibodies |
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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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
South Africa |
United Kingdom |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 1 |