E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe hemophilia A (<1% FVIII:C) |
|
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 | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060613 |
E.1.2 | Term | Hemophilia A (Factor VIII) |
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 |
The primary objective of this study is to determine the efficacy of Wilate in the prophylactic treatment of previously treated patients (PTP) with severe hemophilia A. |
|
E.2.2 | Secondary objectives of the trial |
• Determine the efficacy of Wilate in the treatment of breakthrough bleeding episodes (BEs)
• Calculate the FVIII:C pharmacokinetics (PK) for Wilate at baseline and after 6 months of prophylactic treatment
• Calculate the FVIII:C incremental IVR of Wilate over time (at baseline, and at 3 and 6 months of treatment)
• Assess the association between AB0 blood type and the FVIII:C halflife of Wilate
• Assess the association between the VWF:Ag concentration and the FVIII:C half-life of Wilate
• Assess the safety and tolerability of Wilate
• Assess the immunogenicity of Wilate
Additional Objective: descriptive efficacy of Wilate in surgical prophylaxis. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Severe hemophilia A (<1% FVIII:C) according to medical history 2. Male patients aged ≥12 years
3. Previous treatment with a FVIII concentrate for at least 150 exposure days (EDs)
4. Immunocompetence (CD4+ count >200/μL)
5. Good documentation of the historical bleeding rate (at least for the 6 months pre-ceding study start)
6. Voluntarily given, fully informed written and signed consent obtained by the pa-tient (or parent/legal guardian in case of adolescents) before any study-related pro-cedures are conducted
Whenever possible, the interval between the Screening Visit and the PK or Non-PK Visit should not exceed 30 days. If the 30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be >200/μL for patients to be enrolled (i.e., inclusion criterion no. 4). |
|
E.4 | Principal exclusion criteria |
1. Any coagulation disorders other than hemophilia A
2. History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory anti-bodies (≥0.6 BU using the Nijmegen modification of the Bethesda assay) at screening, as determined by the central laboratory
3. Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate transaminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 μmol/L)
4. Patients receiving or scheduled to receive immunomodulating drugs (other than anti-retroviral chemotherapy) such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs
5. Treatment with any investigational medicinal product in another interventional clinical study currently or within 4 weeks before enrollment |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is a 50% reduction of the total annualized bleeding rate (TABR) observed in the GENA-01 study, with a total of 58.1 BEs per patient per year.
TABR will be calculated as the total number of BEs in the time period between first dose of IMP and the Study Completion Visit, divided by the duration (in years) between first dose of IMP and the Study Completion Visit. Surgery periods, and BEs occurring within these peri-ods, will be excluded from the calculation of TABR. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
After the end of the study |
|
E.5.2 | Secondary end point(s) |
1. Spontaneous annualized bleeding rate (SABR)
2. Efficacy of Wilate in the treatment of breakthrough BEs based on the proportion of BEs successfully treated with Wilate
3. Wilate consumption data (FVIII IU/kg per week per patient) for prophylaxis
4. Baseline PK parameters for FVIII:C using both the chromogenic (CHR) and one-stage (OS) assays and actual IMP potencies
5. Incremental IVR of Wilate over time (at baseline, and at 3 and 6 months of treatment)
6. Association between AB0 blood type and the FVIII:C half-life of Wilate
7. Association between VWF:Ag concentration and the FVIII:C half-life of Wilate
8. Safety and tolerability of Wilate by monitoring adverse events (AEs) throughout the study
9. Immunogenicity of Wilate by testing for FVIII inhibitors
10. Virus safety in terms of parvovirus B19
Exploratory Endpoint: the descriptive efficacy of Wilate in surgical
prophylaxis. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
After the end of the study |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Russian Federation |
Serbia |
Ukraine |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 20 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 20 |