| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe hemophilia A - defined as <1 IU/dL (<1%) endogenous FVIII |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10056493 |
| E.1.2 | Term | Haemophilia A without inhibitors |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10018937 |
| E.1.2 | Term | Haemophilia A |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060612 |
| E.1.2 | Term | Hemophilia A |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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 |
• To evaluate the safety and tolerability of rFVIIIFc administered as a prophylaxis, weekly, on-demand, and surgical treatment regimen
• To evaluate the efficacy of the rFVIIIFc tailored prophylaxis regimen (Arm 1)
• To evaluate the efficacy of rFVIIIFc administered as an on demand (Arm 3) and surgical treatment regimen
|
|
| E.2.2 | Secondary objectives of the trial |
• To characterize the PK profile of rFVIIIFc and compare the PK of rFVIIIFc with the currently marketed product, Advate
• To characterize the range of dose and schedules required to adequately prevent bleeding in a prophylaxis regimen; maintain hemostasis in a surgical setting; or to treat bleeding episodes in an on-demand, weekly treatment, or prophylaxis setting |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide written informed consent and any authorizations required by local law (e.g., Protected Health Information [PHI]). Parental or guardian consent is required for subjects who are less than 18 years of age (or as per local regulations). Subjects less than 18 years of age (or as per local regulations) should consent to the study providing a signed assent form if required by local regulations.
2. Male, ≥12 years of age 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 the time of 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 or from a documented genotype known to produce severe hemophilia A.
4. Previously treated subject, defined as having at least 150 documented prior exposure days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products at Day 0 (Advate or rFVIIIFc). Fresh frozen plasma treatment must not be considered in the count for the documented exposure days.
5. No measurable inhibitor activity in 2 consecutive samples and absence of clinical signs or
symptoms of decreased response to FVIII administration. (First negative sample can be
historical if obtained within 12 weeks prior to screening. The second confirmatory
sample must in all cases be performed by the central laboratory using the
Nijmegen-modified Bethesda assay. If no recent sample is available, then 2 negative
samples at least 1 week apart and analyzed by the central laboratory using the
Nijmegen-modified Bethesda assay should be obtained during screening.)
6. History of bleeding events and/or treatment with FVIII during the prior 12 weeks, as documented in the subjects’ medical records
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 EPD and to use the EPD throughout the study
8. For subjects entering Arm 1: Currently on a prophylaxis regimen at least 2 times per week with a FVIII product or on an on-demand regimen with ≥12 bleeding episodes in the 12 months prior to Day 0 (Advate or rFVIIIFc)
9. For subjects entering Arm 2 or 3: Currently on an on-demand regimen with ≥12 bleeding \episodes in the 12 months prior to Day 0 (rFVIIIFc)
The following inclusion criterion refers to tests by the central laboratory sampled at screening and reviewed prior to Day 0 (Advate or FVIIIFc):
10. Platelet count ≥100,000 cells/μL
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 Day 0 (Advate or rFVIIIFc):
11. CD4 lymphocytes >200 mm3, if known as human immunodeficiency virus (HIV) antibody positive
12. Viral load of <400 copies/ml, if known as HIV antibody positive |
|
| E.4 | Principal exclusion criteria |
1. History of, or currently detectable inhibitor. A positive inhibitor value is ≥0.6 BU/mL (or any value greater than or equal to the lower sensitivity cut-off for laboratories with cut offs for inhibitor detection between 0.7 and 1.0 BU/mL). In addition, the following documentation should be provided:
- at least 2 negative inhibitor tests prior to the screening test AND
- within the past 5 years (or since the start of treatment with FVIII or cryoprecipitate, if available) absence of clinical suspicion of inhibitors (from medical records and patient history- no evidence of decreased therapeutic response due to inhibitor and normal FVIII recovery, as available).
Family history of inhibitors will not exclude the subject.
2. Other coagulation disorder(s) in addition to hemophilia A
3. History of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration
4. For the PK subgroup only: known hypersensitivity to mouse or hamster proteins
5. Currently taking (or likely to require during the study) acetylsalicylic acid (ASA) or ibuprofen (other non-steroidal anti-inflammatory drugs are permitted)
6. Concurrent systemic treatment with immunosuppressive drugs 12 weeks prior to Day 0 (Advate or rFVIIIFc). (Exceptions: ribavirin, treatment of hepatitis C virus [HCV] and HIV and/or systemic steroids [a total of 2 courses of pulse treatments within 7 days ≤1 mg/kg] and/or inhaled steroids)
7. Major surgery within the previous 8 weeks
8. Unable to enter accurate and timely information regarding injections and bleeding episodes into an EPD and without adequate parental/caregiver support to manage this (per the Investigator’s judgment)
9. Unable or unwilling to refrain from taking additional prophylactic doses of rFVIII prior to sports activities or an increase in physical activity
10. Current enrollment or enrollment within the past 30 days in any other clinical trial involving investigational drugs.
11. 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
The following exclusion criteria refer to tests by the central laboratory sampled at screening and reviewed prior to Day 0 (Advate or rFVIIIFc):
12. Abnormal renal function (serum creatinine >2.0 mg/dL)
13. Serum alanine transaminase (ALT) or aspartate aminotransferase (AST) >5x upper limit of normal (ULN)
14. Serum bilirubin >3x ULN
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
For Safety and Tolerability:
• Clinically notable changes from baseline in physical examinations and vital signs
• Incidence of AEs, including clinically significant abnormal laboratory values
• Incidence of inhibitor development using the Nijmegen-modified Bethesda assay
For Efficacy:
• Annualized number of bleeding episodes (spontaneous and traumatic)
• Primary PK parameters are the following assessments of FVIII activity: dose-corrected area under the curve (AUC/dose), half-life, MRT, clearance (CL), and incremental recovery based on the one-stage clotting assay. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Through-out treatment period. |
|
| E.5.2 | Secondary end point(s) |
• Total annualized rFVIIIFc consumption per subject
• Subjects’ individual assessments of response to treatment with rFVIIIFc for bleeding episodes, using a bleeding response scale
• Investigators’ assessment of subjects’ response to treatment with rFVIIIFc for bleeding episodes treated in the clinic, using a bleeding response scale
• Annualized number of spontaneous bleeding episodes (joint, soft tissue, and muscle) per subject
• Annualized number of joint bleeding episodes (spontaneous and traumatic) per subject
• Time from last injection of rFVIIIFc to a bleeding episode
• Number of injections and dose per injection of rFVIIIFc required to resolve a bleeding episode (joint, soft tissue, and muscle)
• Additional parameters for PK/pharmacodynamic (PD) assessments will include but not be limited to: AUC/dose, half-life, MRT, CL, and incremental recovery based on
the two-stage chromogenic assay; volume of distribution (Vd), time at maximum activity (Tmax); and percent recovery for FVIII activity based on both the one-stage clotting assay and the two-stage chromogenic assay.
• QoL via hemophilia-specific HRQoL questionnaire for children and parents (Haemo QoL; ages 13 to 16 years) or hemophilia-specific HRQoL questionnaire for adults (Haem-A-QoL; ages 17 years and above)
For the Surgery Subgroup:
• Investigators’/Surgeons’ assessments of subjects’ response to surgery with rFVIIIFc, using a bleeding response scale
• Number of injections and dose per injection required to maintain hemostasis during the surgical period
• Estimated blood loss during surgery
• Number and type of blood component transfusions required during surgery |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Through-out treatment period.
End-points for surgery sub-group are all collected at the time of surgery. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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) | Yes |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| The Cross over element refers only to the PK subgroup, wherein PK of rFVIIIFc is compared to Advate. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Denmark |
| France |
| Germany |
| Hong Kong |
| India |
| Israel |
| Italy |
| Japan |
| New Zealand |
| Poland |
| Portugal |
| Russian Federation |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
| This is defined in section 7.5 of the protocol |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
