| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The medical condition to be investigated is Hemophilia B, or Christmas disease. Hemophilia B is a deficiency in the clotting FIX and is a recessively inherited coagulation disorder due to an X-chromosome mutation carried by females and expressed mainly by males, affecting approximately 80,000 people worldwide. |
|
| 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 | 14.1 |
| 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 treated pediatric subjects with hemophilia B. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of rFIXFc for prevention and treatment of bleeding episodes.
- To evaluate and assess the PK of rFIXFc.
- To evaluate rFIXFc consumption for prevention and treatment of bleeding episodes.
- To evaluate the effect of rFIXFc based on patient-reported outcomes and health outcomes. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability of 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) in accordance with national and local subject privacy regulations. Subjects may provide assent in addition to the parental/guardian consent, if appropriate.
2. Male, <12 years of age at time of informed consent, and weight ≥13 kg.
3. Severe hemophilia B defined as ≤2 IU/dL (≤2%) endogenous FIX as documented in medical records from a local clinical laboratory demonstrating ≤2% Factor IX coagulant activity (FIX:C) or a documented genotype known to produce severe hemophilia B.
4. Previously treated subject, defined as having at least 50 documented EDs to any recombinant or plasma-derived FIX product including prothrombin complex concentrate (blood products including fresh frozen plasma treatment must not be considered in the count of the documented EDs).
5. If known to be HIV positive, the following laboratory values are required, based on results within last 6 months:
a. platelet count ≥100,000 plts/μL
b. CD4 count ≥200 cells/μL
c. viral load of <400 copies/mL
6. No history of, or currently detectable, inhibitor. This includes the following:
a. at least 2 negative inhibitor tests from the reporting laboratory AND/OR normal recovery tests within the first 50 EDs to FIX products AND
b. absence of clinical signs of decreased response to FIX administrations
Historical positive inhibitor test is defined as per local laboratory Bethesda value for positive inhibitor test (i.e., equal to or above lower level of detection). Family history of inhibitors will not exclude the subject.
7. No measurable inhibitor activity using the Nijmegen-modified Bethesda assay (≥0.6 BU/mL is considered positive) at screening.
8. Willingness and ability of the subject’s parent or legal guardian to complete training in the use of the study EPD and to use the EPD throughout the study. |
|
| E.4 | Principal exclusion criteria |
1. Other coagulation disorder(s) in addition to hemophilia B.
2. History of anaphylaxis associated with any FIX or IV immunoglobulin administration.
3. Active renal disease (per the discretion of the Investigator and medical records).
4. Active hepatic disease (per the discretion of the Investigator and medical records).
5. Any concurrent clinically significant major disease that, in the opinion of the Investigator, would make the subject unsuitable for enrollment.
6. Current systemic treatment with chemotherapy and/or other immunosuppressant drugs, with the following exceptions: use of steroids for treatment of asthma or management of acute allergic episodes, and routine immunizations.
7. Participation within the past 30 days in any other clinical study involving investigational drugs.
8. Surgery within 30 days prior to the screening visit (visit can be re-scheduled and subject screened). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Frequency of inhibitor development. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| On every scheduled clinic visit by Nijmegen-modified Bethesda Assay. |
|
| E.5.2 | Secondary end point(s) |
- the number of annualized bleeding episodes (spontaneous and traumatic) per subject.
- the number of annualized spontaneous joint bleeding episodes per subject.
- assessments of response to treatment with rFIXFc for bleeding episodes, using the 4-point bleeding response scale.
- total annualized rFIXFc consumption per subject for prevention of bleeding episodes.
- total annualized rFIXFc consumption per subject for treatment of bleeding episodes.
- time from last injection of rFIXFc to the bleeding episode.
- number of injections and dose per injection of rFIXFc required to resolve a bleeding episode (joint, soft tissue, and muscle).
- number of adverse events (AEs) and serious adverse events (SAEs).
- Pharmacokinetics end-points relating to standard PK parameters and assessment of rFIXFc as a surrogate marker of efficacy.
- Patient-reported outcomes as recorded by the subject throughout the course of the study. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The bleeding episodes, the number of treatment days and the dose of rFVIIIFc per kg per subject will be monitored by the physician on an ongoing basis, by reviewing the patient eDiary information. The physician and subject assessment of response will be taken at every visit. AE and SAE information will be collected on an ongoing basis. |
|
| 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 | 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) | 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 | 6 |
| 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 |
| Hong Kong |
| India |
| Ireland |
| Netherlands |
| South Africa |
| Turkey |
| 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
|
End of study will occur when:
• At least 20 subjects (10 subjects <6 yr and 10 subjects 6 to <12 yr) have adequate PK data (per Protocol Section 16.5.1)
• At least 10 subjects from each cohort have valid Central Lab inhibitor test results for samples collected ≥50 EDs
Once the above 2 criteria have been met, any additional study subjects will be required to come for Week 50 Visit assessments at the time of their next scheduled dose, and will be eligible to transfer to Study 9HB01EXT. |
|
| 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 | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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