E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
|
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 efficacy of BMN 270 defined as FVIII activity, as measured by chromogenic substrate assay, during Weeks 49-52 following intravenous infusion of BMN 270
|
|
E.2.2 | Secondary objectives of the trial |
- Assess the impact of BMN 270 on usage of exogenous FVIII replacement therapy in the efficacy evaluation period (from Week 5 to last visit by the data cutoff for the 1-year analysis, hereafter referred to as “Week 5 to Last Visit”) - Assess the impact of BMN 270 on the number of bleeding episodes requiring exogenous FVIII replacement therapy in the efficacy evaluation period (“Week 5 to Last Visit”)
|
|
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 |
An optional liver biopsy will be performed as part of the liver biopsy substudy (in subjects who consent to do so) during Year 1 post-infusion, at or around Week 52, and/or during Years 2-5 following BMN 270 infusion. Subjects who consent to the liver biopsy will have additional assessments, including a liver ultrasound and FibroScan, and will receive prophylactic FVIII prior to the procedure if indicated in the judgment of the Investigator, to minimize the risk of bleeding. Additional liver biopsies may be performed as part of the substudy during Years 2-5 as clinically indicated.
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) |
|
E.3 | Principal inclusion criteria |
- 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. - Must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry. - Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs). - 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) on 2 consecutive occasions at least one week apart within the past 12 months. |
|
E.4 | Principal exclusion criteria |
- Detectable pre-existing antibodies to the AAV5 capsid. - Any evidence of active infection or any immunosuppressive disorder, including HIV infection. - Significant liver dysfunction. - Prior liver biopsy showing significant fibrosis. - Evidence of any bleeding disorder not related to hemophilia A. - Platelet count of < 100 x 10^9/L. - Creatinine ≥ 1.5 mg/dL. - Liver cirrhosis of any etiology as assessed by liver ultrasound. - Chronic or active hepatitis B. - Active Hepatitis C. - Active malignancy, except non-melanoma skin cancer. - History of hepatic malignancy. - History of arterial or venous thromboembolic events. - Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change of the hFVIII activity, as measured by chromogenic substrate 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.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
During Weeks 49-52 post-BMN 270 infusion |
|
E.5.2 | Secondary end point(s) |
- Change in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy in the efficacy evaluation period (“ Week 5 to Last Visit”) from the baseline utilization of exogenous FVIII replacement therapy. - Change in the annualized number of bleeding episodes requiring exogenous FVIII replacement treatment (ABR) therapy in the efficacy evaluation period (“Week 5 to Last Visit”) from the baseline ABR.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Utilization (IU/kg) of exogenous FVIII replacement therapy will be evaluated during Week 5 to Last Visit post-BMN 270 infusion from the baseline utilization of exogenous FVIII replacement therapy - The annualized number of bleeding episodes requiring exogenous FVIII replacement treatment will be evaluated during Week 5 to Last Visit post-BMN 270 infusion from the baseline ABR |
|
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) | No |
E.7.1.1 | First administration to humans | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
subjects' historical annualized bleeding rate and annualized FVIII utilization |
|
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
Australia |
Brazil |
Israel |
Japan |
Korea, Republic of |
South Africa |
Taiwan |
United States |
Belgium |
France |
Germany |
Italy |
Spain |
United Kingdom |
|
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
|
|
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 |