E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Younger Male Haemophilia A patients < 6 years of age with moderately severe to severe hemophilia A (FVIII activity =< 2%), with previous FVIII replacement therapy experience (>=50 exposure days).
Niños menores de 6 años con hemofilia A de grado moderadamente grave a grave (actividad de FVIII =< 2%), con experiencia previa en tratamiento sustitutivo de FVIII (días de exposición >=50). |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate that ReFacto AF prophylaxis reduces annualized bleeding rates (ABRs) relative to on-demand therapy. |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of a high- versus low-frequency dosing schedule on the efficacy of ReFacto AF prophylaxis. To characterize the PK of ReFacto AF in children younger than 6 years of age. To describe Refacto AF efficacy and safety in children, including characterization of the incidence of "less than expected therapeutic effect". |
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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 |
A subset of subjects will participate in assessments for PK characterization. |
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E.3 | Principal inclusion criteria |
1. Male subjects with moderately severe to severe hemophilia A (FVIII:C ≤ 2%) by both the local laboratory and the central laboratory at screening. 2. A negative FVIII inhibitor by both the local laboratory and the central laboratory at screening (for local laboratory, a Bethesda inhibitor titer less than the upper limit of normal [ULN] for the laboratory performing the assay and is not reported to be ≥ 0.6 Bethesda Units [BU]/mL; for central laboratory, Bethesda inhibitor titer < 0.6 BU/mL by Nijmegen assay). 3. A medical history negative for a past FVIII inhibitor (see Protocol Definitions). 4. Age < 6 years at time of screening visit (study visit 1). 5. Previous experience of FVIII therapy (≥ 50 exposure days to any FVIII replacement product). 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 × ULN, and bilirubin ≤ 2 mg/dL (< 35 μmol/L). 7. Serum albumin ≥ the lower limit of normal (LLN). 8. Serum creatinine ≤ 1.25 × ULN. 9. Platelet count ≥ 100,000/μL. 10. Absolute CD4 count > 400/μL. 11. Prothrombin time (PT) ≤ 1.25 × ULN, or international normalized ratio (INR) ≤ 1.5 12. The subject is not receiving treatment for HIV or hepatitis infection, or the subject is on a stable antiviral regimen at the time of signing the consent/assent form (ie, stable dosing for at least 3 months before signing the consent/assent form). 13. The subject is able to comply with the mandatory 72-hour FVIII washout preceding each FVIII:C and FVIII inhibitor assessment during the study
Additionnal Criteria for subjects participating in the PK and recvery assessments: 1. Male subjects as described immediately above except they must have a FVIII:C of =< 1% confirmed by the central laboratory screening test 2. Age < 6 years at time of PK assessment (study visit 2). 3. The subject's size is sufficient to permit PK-related phlebotomy. 4. The subject is able to comply with the procedures conducted during the PK and recovery assessment, including a mandatory 72-hour washout period preceding the PK and Recovery assessments. |
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E.4 | Principal exclusion criteria |
1. A history of FVIII inhibitor (clinical or laboratory-based assessment). For laboratory assessments, any measured Bethesda inhibitor titer ≥ 0.6 BU/mL, regardless of the laboratory normal range, or any measured Bethesda inhibitor titer greater than the ULN for the laboratory performing the assay. 2. Presence of a bleeding disorder in addition to hemophilia A. 3. Treatment with any investigational drug or device within 30 days before the time of signing the consent/assent form. 4. Surgery planned to occur within a 26-month period following the signing of the consent/assent form (ie, during the course of the study). 5. Regular (eg, daily, every other day) use of antifibrinolytic agents or medications known to influence platelet function such as aspirin or certain nonsteroidal anti-inflammatory drugs (NSAIDs). 6. Regular, concomitant therapy with immunomodulating drugs (eg, intravenous immunoglobulin [IVIG], routine systemic corticosteroids). 7. Known hypersensitivity to hamster protein. 8. Any condition(s) that compromises the subject’s ability to comply with and/or perform study-related activities or that poses a clinical contraindication to study participation (these conditions include, but are not limited to, inadequate medical history to assure study eligibility; inability to properly store study drug; expectation of poor compliance in study related documentation). 9. Unwilling or unable to follow the terms of the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end point for the primary objective of this study, to demonstrate that ReFacto AF prophylaxis reduces annualized bleeding rates relative to on-demand therapy, is the annualized bleed rate (ABR).
The primary efficacy endpoint for the secondary objective, to assess the effect of a high- versus low-frequency dosing schedule on the efficacy of ReFacto AF prophylaxis, is the annualized bleed rate (ABR).
The primary endpoints for the secondary objective, to characterize the pharmacokinetics (PK) of ReFacto AF in children younger than 6 years of age with hemophilia A, is terminal phase half-life (t1/2) and incremental recovery (K-value).
The primary endpoints for the secondary objective, to describe ReFacto AF efficacy and safety in children, including characterization of the incidence of “less than expected therapeutic effect; for efficacy are: the 4-point response (efficacy rating) for study drug-treated bleeds and the number of study drug infusions used to treat a bleed; for safety are: the number (%) of subjects experiencing any adverse event and the number (%) of subjects who develop a confirmed FVIII inhibitor. |
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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 | 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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.6 | Cross over | Yes |
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 |
Comparison of two prophylaxis Regimen and Comparison of On-Demand to Prophylaxis |
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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 | Information not present in EudraCT |
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 | 20 |
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 | Information not present in EudraCT |
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 |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 42 |