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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053753 |
E.1.2 | Term | Hemophilia A without inhibitors |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
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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 the study is to characterize the PK of rFVIIIFc administered at vial strengths of 1000 and 3000 IU in subjects with severe hemophilia A. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of the study is to evaluate the safety of rFVIIIFc beyond the PK assessment for up to 6 months. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of randomization, on Day 1:
1.Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations. Parental or guardian consent is required for subjects who are less than 18 years of age or unable to give consent, or as applicable per local laws. Subjects who are less than 18 years of age may provide assent in addition to the parental/guardian consent, if appropriate.
2.Male, age ≥12 years at the time of informed consent, and weighing at least 40 kg.
3.Have severe hemophilia A, defined as <1 IU/dL (<1%) endogenous FVIII as determined by one-stage clotting assay from the central laboratory at screening. If the screening result is ≥1%, then the severity of hemophilia A may be confirmed by documented historical evidence from a certified clinical laboratory demonstrating <1% FVIII:C as determined by the one-stage clotting assay from the medical record.
4.Previously treated subject, defined as having at least 150 documented prior EDs to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products (other than any use of rFVIIIFc – study drug or commercial product) at Day 1. Fresh frozen plasma treatment must not be considered in the count for documented EDs.
5.No history of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors will not exclude the subject.
6.No measurable inhibitor activity using the Nijmegen-modified Bethesda assay (≥0.6 BU/mL is considered positive) at Screening.
7.Willingness and ability of the subject or a surrogate (a caregiver or a family member ≥18 years of age) to complete training in the use of the study electronic diary (eDiary) and to complete the eDiary in a timely manner throughout the study.
8.Platelet count ≥100,000 platelets/μL at screening (test performed by the central laboratory and reviewed prior to randomization on Day 1).
The following inclusion criteria refer to tests performed within 6 months prior to screening. If not available, the test should be conducted by the central laboratory, sampled at screening and reviewed prior to randomization on Day 1.
9.CD4 lymphocytes >200 mm3 if known as HIV antibody positive at screening.
10.Viral load of <400 copies/mL if known HIV antibody positive at screening.
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E.4 | Principal exclusion criteria |
Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of randomization, on Day 1.
1.Subject is at high risk of bleeding during the 5-day period between the first and second injections for PK analyses, as per Investigator discretion.
2.Previous treatment with rFVIIIFc as study drug or commercial product.
3.Other coagulation disorder(s) in addition to hemophilia A.
4.History of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration.
5.Currently taking (or likely to require during the study) acetylsalicylic acid (ASA), except for low-dose ASA as prophylaxis (other non steroidal anti-inflammatory drugs are permitted).
6.Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to Day 1. Exceptions to this include: ribavirin for treatment of hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days at a dose of ≤1 mg/kg within 12 weeks prior to Day 1) and/or inhaled steroids.
7.Major surgery within the previous 8 weeks.
8.Current enrollment, or enrollment within the past 30 days, in any other clinical trial involving investigational drugs.
9.Any concurrent clinically significant major disease or other unspecified reasons that, in the opinion of the Investigator, makes the subject unsuitable for participation in the study.
10.Abnormal renal function (serum creatinine >2.0 mg/dL) [test performed by the central laboratory and reviewed prior to randomization on Day 1].
11.Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of normal (ULN) [test performed by the central laboratory and reviewed prior to randomization on Day 1].
12.Serum total bilirubin >3 × ULN (test performed by the central laboratory and reviewed prior to randomization on Day 1).
13.Inability to comply with study requirements in the opinion of the Investigator.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoints include the following PK parameters of rFVIIIFc: area under the concentration-time curve from time zero to infinity (AUCinf) and incremental recovery (IR, K value) as estimated from the FVIII activity data measured by aPTT clotting assay. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Blood samples for PK analysis will be collected at 0.5 hour (±5 minutes); 1 hour and 6 hours (±10 minutes); and 24, 48, 72, and 96 hours (±60 minutes) after each injection. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints are as follows:
•Secondary PK parameters will include, but are not limited to, the following:
-Cmax, t½, CL, volume of distribution at steady state (Vss), and mean residence time (MRT) measured by aPTT clotting assay.
-The same PK parameters as stated in the primary and secondary endpoints above measured by two stage chromogenic clotting assay.
•Development of inhibitor as measured by the Nijmegen-modified Bethesda assay.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood samples for PK analysis will be collected at 0.5 hour (±5 minutes); 1 hour and 6 hours (±10 minutes); and 24, 48, 72, and 96 hours (±60 minutes) after each injection.
Inhibitor Development will be measured at screening, pre dose, month 3 and month 6 or final study visit by Nijmegen-modified Bethesda assay. |
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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 | No |
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) | 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 |
PK assessment of two vial strengths |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
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 | 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 | No |
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 | 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 | 6 |
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 | 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 |
South Africa |
United Kingdom |
United States |
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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
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
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 | 10 |