| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hemophilia B (congenital coagulation factor IX [FIX] deficiency; Christmas disease) is an X-linked bleeding disorder that occurs predominantly in males, characterized by a deficiency of functional FIX. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hemophilia B is a genetic disorder that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken. |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053754 |
| E.1.2 | Term | Hemophilia B without inhibitors |
| 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 the study is to evaluate the safety of rFIXFc in previously untreated subjects with severe hemophilia B. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of rFIXFc in the prevention and treatment of bleeding episodes in previoulsy untreated patients (PUPs).
- To evaluate rFIXFc consumption for prevention and treatment of bleeding episodes in PUPs. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability of the subject or their parent or legal guardian to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) or equivalent, and/or to provide assent in accordance with national and local regulations.
2. Male, age <18 years at the time of informed consent.
3. Weight ≥3.5 kg at the time of informed consent.
4. Severe hemophilia B defined as ≤2 IU/dL (≤2%) endogenous FIX documented in the medical record or as tested during the Screening Period. Any subject who is enrolled based on results of the local laboratory must be withdrawn if the central laboratory screening results indicate a baseline FIX activity level >2% of normal. |
|
| E.4 | Principal exclusion criteria |
1. History of positive inhibitor testing. A prior history of inhibitors is defined based on a patient's historical positive inhibitor test using the local laboratory Bethesda value for a positive inhibitor test (i.e. equal to or above lower limit of detection).
2. History of hypersensitivity reactions associated with any rFIXFc administration.
3. Exposure to blood components or injection with a FIX concentrate (including plasma derived) other than rFIXFc.
4. Injection with commercially available rFIXFc more than 28 days prior to Screening.
5. More than 3 injections of commercially available rFIXFc prior to confirmation of eligibility.
6. Other coagulation disorder(s) in addition to hemophilia B.
7. Any concurrent clinically significant major disease that, in the opinion of the Investigator, would make the subject unsuitable for enrollment (e.g., HIV infection with CD4 lymphocyte count <200 cells/µL or a viral load > 200 particles/µL, or any other known congenital or acquired immunodeficiency).
8. Current systemic treatment with chemotherapy and/or other immunosuppressant drugs. Use of steroids for treatment of asthma or management of acute allergic episodes or otherwise life-threatening episodes is allowed. Treatment in these circumstances should not exceed a 14-day duration.
9. Participation within the past 30 days in any other clinical study involvoing investigational treatment.
10. Current enrollment in any other clinical study involving investigational treatment.
11. Inability to comply with study requirements.
12. Other unspecified reasons that, in the opinion of the Investigator or Bioverativ, make the subject unsuitable for enrollment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is the occurrence of inhibitor development. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Subjects will be tested for inhibitor formation:
- at each clinic visit.
- at 5 (±1), 10 (±1), 15 (±1), 20 (±1), 50, and 100 EDs
- 2 to 4 weeks prior to elective major surgery, preoperatively, postoperatively, and at the Last Postoperative Visit (see Section 4.2.2). For minor surgeries, testing for inhibitors will only be performed if indicated by the nature of the procedure, according to local standard of care.
- if inhibitor development is suspected at any time during the study
Additional unscheduled testing for inhibitors may be performed, if required by local standards of care |
|
| E.5.2 | Secondary end point(s) |
- the annualized number of bleeding episodes (spontaneous and traumatic) per subject
- the annualized number of spontaneous joint bleeding episodes per subject
- assessments of response to treatment with rFIXFc for bleeding episodes, using the 4-point bleeding response scale (Investigator assessment for bleeding episodes treated in the clinic; parent or caregiver assessment for all other bleeding episodes)
- the total number of EDs per subject per year
- total annualized rFIXFc consumption per subject for the prevention and treatment of bleeding episodes
- the number of injections and dose per injection of rFIXFc required to resolve a bleeding episode
- rFIXFc incremental recovery |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Incidence of bleeding episodes, dose and number of injections, and response to treatment will be monitored by the physician on an ongoing basis and will be obtained from electronic patient diaries (EPDs), electronic case report forms (eCRFs), and medical records. During clinic visits when rFIXFc is injected, blood samples will be taken to assess incremental recovery. |
|
| 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
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Belgium |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| New Zealand |
| Poland |
| 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
|
| The end of the study will occur when at least 40 subjects have reached at least 100 EDs with rFIXFc. Once this milestone has been achieved, any additional study subjects who have not reached 100 EDs will be required to attend the study center for the Early Termination/End of Study Visit assessments. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 16 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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