| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hereditary blood disorder characterised by spontaneous bleeding episodes |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10060614 |
| E.1.2 | Term | Hemophilia B (Factor IX) |
| 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 |
| To evaluate the safety, pharmacokinetics (PK) and efficacy with respect to breakthrough bleeding during prophylaxis and with respect to control of haemorrhaging in both the prophylaxis and on demand groups of IB1001 in subjects with haemophilia B |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate markers of thrombogenicity including D-dimer, fragment 1 +2 (F1+2), and thrombin-antithrombin III complex (TAT)
2. To obtain information on subject response to an intravenously delivered recombinant factor IX (rFIX) product in terms of tolerance and compliance
3. To estimate the frequency of spontaneous bleeding in subjects with haemophilia B treated on demand
4. To evaluate the ability of IB1001 to provide coverage against bleeding under surgical circumstances, as well as to manage breakthrough bleeding during prophylaxis
5. To evaluate the long-term safety and efficacy of IB1001 |
|
| 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 |
| Surgical sub-study, included in protocol Amendment 08.1: A minimum of 10 surgical cases (in at least 5 subjects) will be evaluated for efficacy of IB1001 to provide coverage in surgical circumstances. The surgical cases must be considered major surgeries. Subjects in the surgical sub-study must meet all acceptance criteria; however they will not necessarily have participated in other phases of the IB1001-01 trial. |
|
| E.3 | Principal inclusion criteria |
1. Patient must be willing to give written Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)-approved informed consent, make the required study visits, and follow instructions while enrolled in the study.
2. Severe (factor IX activity ≤2 U/dL) hemophilia B subjects on-demand therapy with a minimum of 3 bleeding episodes over the preceding 6 months or 6 bleeding episodes over the preceding 12 months; subjects on prophylaxis with a bleeding pattern as above demonstrated prior to starting prophylaxis
3. Immunocompetent (CD4 count >400/mm3) and not receiving immune modulating or chemotherapeutic agents
4. Previously treated patients with a minimum of 150 exposure days to a factor IX preparation
5. Platelet count at least 150,000/mm3
6. Liver function: alanine transaminase [ALT] and aspartate transaminase [AST] ≤2 times the upper limit of the normal range
7. Total bilirubin ≤1.5 times the upper limit of the normal range
8. Renal function: serum creatinine ≤1.25 times the upper limit of the normal range
9. Willingness to participate in the trial for up to 12-15 months
10. European Union (EU), Israel, and India: Age of at least 12 years and body weight of ≥40 kilograms to participate in any PK Study or the Surgical Sub-study; age of at least 12 years for the prophylaxis and on-demand components of the Treatment Phase and Continuation Study. Subjects in France less than 18 years of age will not be included in any PK study.
United States (US): Age of at least 12 years and body weight of ≥40 kilograms to participate in any PK Study or the Surgical Sub-study; age of at least 5 years for the prophylaxis and on-demand components of the Treatment Phase and Continuation Study
11. Hemoglobin ≥7 g/dL at the time of the blood draw |
|
| E.4 | Principal exclusion criteria |
1. History of factor IX inhibitor ≥0.6 Bethesda units (BU)
2. Existence of another coagulation disorder
3. Evidence of thrombotic disease, fibrinolysis, or disseminated intravascular coagulation (DIC)
4. Use of an investigational drug within 30 days prior to study entry
5. On medications that could impact hemostasis, such as aspirin
6. Hypersensitivity to the active substance or to any of the excipients in the investigational products
7. Known allergic reaction to hamster proteins
8. History of poor compliance, a serious medical or social condition, or any other circumstance that, in the opinion of the investigator, would interfere with participation or compliance with the study protocol
9. History of adverse reaction to either plasma-derived factor IX or recombinant factor IX that interfered with the subject’s ability to treat bleeding episodes with a factor IX product |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety: acute effects associate with infusion, and inhibitor development
PK: Cmax, AUC, t1/2, clearance, recovery, Vd
Efficacy: breakthrough bleeding during prophylaxis and on demand groups for IB1001 in subjects with haemophilia B |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety:
- Acute effects are defined as adverse events (AEs) which occur within the first 72 hours after administration of a study product
- Inhibitor development: prior to the first infusion of IB1001, after the first 5 infusions (for subjects on prophylaxis), and every 3 months (+/- 2 weeks) thereafter
PK: parameters determined for each separate PK assessment period during 72 hours after single infusion
Efficacy: diaries maintained by all subjects throughout treatment document breakthrough bleeding and the subjects assessment efficacy of IB1001 to treat breakthrough (prophylaxis) or other bleeds (on demand); investigators assess efficacy of treatment at each 3 month visit. |
|
| E.5.2 | Secondary end point(s) |
1. Plasma levels of D-dimer, F1+2, TAT
2. Tolerance: defined as the ability to use IB1001 without AE + compliance
3. Frequency of spontaneous bleeding in subjects treated on demand
4. Surgeon estimation of blood loss at the time of surgery + post-surgery haemostasis
5. Evaluate long term safety and efficacy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. During the BeneFix/IB1001 PK study within the first 24 hours after PK infusion dose
2 and 3. Diaries maintained by all subjects during treatment with IB1001 and evaluated during follow-up visits
4, At the time of the surgery and post-surgery (12 and 24 hours)
5. Subjects are seen every 3 months during continuation phase |
|
| 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 | Yes |
| 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 | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| India |
| Israel |
| 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 trial is defined by the last visit of the last subject undergoing the trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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