E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital Hemophilia A with factor VIII inhibitors |
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E.1.1.1 | Medical condition in easily understood language |
Haemophilia bleeding disorder present at birth, characterized by spontaneous bleeding episodes, as well as prolonged bleeding after trauma or surgery |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018938 |
E.1.2 | Term | Haemophilia A (Factor VIII) |
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 |
To evaluate the efficacy of OBI-1 for the treatment of serious bleeding episodes in subjects with congenital hemophilia A with inhibitors to human factor VIII and with a history of inadequate response to bypassing agents. |
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E.2.2 | Secondary objectives of the trial |
1) To determine the proportion of serious bleeding episodes controlled with OBI-1 therapy
2) To assess the efficacy of OBI-1 at designated time points after the initiation of therapy
3) To determine the frequency, total dose and total number of infusions of OBI-1 required to control serious bleeding episodes
4) To assess the correlations between response to OBI-1 therapy at specified assessment time points and eventual control of serious bleeding episodes.
5) To assess the correlations between the pre-infusion anti-OBI-1 inhibitor titer, the total dose of OBI-1, the outcome at 24 hours and the eventual control of the bleeding disorder
6) To assess the anti-OBI-1 inhibitor level pre-infusion, at specified time points during treatment and at the end of the follow-up period at 90 days post final infusion
7) To evaluate the safety of OBI-1
8) To assess the simple recovery and elimination rate parameters of OBI-1 in subjects with inhibitors treated with OBI-1 therapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Males or females ≥ 6 years of age.
2) Written informed consent from subject or subject’s legal representative.
3) Subjects with congenital hemophilia A with a human factor VIII inhibitor ≤30 BU assessed within 30 days prior to study entry and no documented human factor VIII inhibitor >30 BU within the prior 90 days..
4) Has previously or is currently demonstrating suboptimal hemostatic response to bypassing agents for treatment of bleeding episodes; suboptimal response is determined by the investigator, but minimally includes no or minimal evidence of response after at least two doses of bypassing agents, either for the current or a historic bleeding episode.
5) Has an anti-OBI-1 titer ≤10 BU.
6) Has any serious or life-threatening bleeding episode; or requires a major or minor surgical procedure that could lead to a serious bleeding episode if not well controlled.
7) Is willing and able to follow all instructions and attend all study visits.
8) Has no other significant hemostatic abnormality and:
a) Platelets >100,000/mm^3
b) Prothrombin time <15 seconds
c) INR ≤1.3
9) Subjects taking anti-thrombotics (such as clopidogrel, heparin or heparin analogue) may be included provided three half-lives of the agent have elapsed since the last dose of the agent. |
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E.4 | Principal exclusion criteria |
1) Hemodynamically unstable after blood transfusion, fluid resuscitation and pharmacologic or volume replacement pressor therapy. This hemodynamic instability is characterized by symptomatic hypotension resulting in vital organ dysfunction, such as cardiac ischemia, oliguria (urine volume <0.5 mL/kg in the previous six hours), central nervous system hypoperfusion manifested by mental status change such as confusion (unless head injury or intracranial hemorrhage is present), pulmonary compromise, and/or acidosis (manifested by pH and lactate levels).
2) Bleeding episode assessed likely to resolve on its own if left untreated.
3) Prior history of bleeding disorder other than congenital hemophilia A.
4) Known major sensitivity (anaphylactoid reactions) to therapeutic products of porcine or hamster origin; examples include therapeutics of porcine origin (e.g. previously marketed porcine factor VIII, Hyate-C®) and recombinant therapeutics prepared from hamster cells (e.g. Humira®, Advate® and Enbrel®).
5) Received any other investigational treatment within 30 days of the first OBI-1 treatment.
6) Anticipated need for treatment or device during the study that may interfere with the evaluation of the safety or efficacy of OBI-1, whose safety or efficacy may be affected by OBI-1.
7) Is planning to father a child during the study.
8) Has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might jeopardize the subject’s safety or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study.
9) Inability or unwillingness to comply with the study design, protocol requirements, or the follow-up procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of serious bleeding episodes responsive to OBI-1 therapy at 24 hours after the initiation of treatment. Response to OBI-1 therapy will be based on assessment of effectiveness and factor VIII blood levels. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 hours after initiation of treatment |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
1. The overall proportion of serious bleeding episodes successfully controlled with OBI-1 therapy, as assessed by the investigator.
2. The proportion of bleeding episodes responsive to OBI-1 therapy at designated assessment time points after the initiation of therapy, as assessed by the investigator.
3. Frequency, total dose, and total number of infusions of OBI-1 required to successfully control qualifying bleeding episodes.
4. Correlation between response to OBI-1 therapy at specified time points and eventual control of serious bleeding episodes.
5. Correlation between the pre-infusion anti-OBI-1 antibody titers, the total dose of OBI-1, the outcome at 24 hours and the eventual control of the bleeding episode.
6. Correlation between the pre-infusion anti-OBI-1 antibody titers and the recovery of OBI-1.
Safety endpoints:
7. TEAEs and serious adverse events (SAEs) throughout the study.
8. Biochemistry, hematology, urinalyses and vital signs.
9. Anti-human factor VIII antibody titer.
10. Anti-OBI-1 antibody titer.
11. Anti-host cell protein (BHK) antibody titer. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
1,3,4,5,6. Ongoing basis throughout study
2. 24h after end of first dose;each dose or q8h to 24h, q12h from 24-120h and q24h thereafter until last OBI-1 dose or withdrawal;all f-up visits
Safety:
7. 0, 10-20min and 24h after end of first dose;at each dose or q8h to 24h, q12h from 24-120h and q24h thereafter until last OBI-1 dose or withdrawal;all f-up visits;termination
8. Biochemistry, hematology and urinalyses: screening;24h after end of first dose;f-up visits 2-5;
Vital signs: screening;10-20min and 24h after end of first dose;at each dose or q8h to 24h, q12h from 24-120h and q24h thereafter until last OBI-1 dose or withdrawal;all f-up visits
9-10: Screening;q5 days during treatment and healing;all f-up visits;termination
11: Screening;f-up visit 5;termination |
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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 | No |
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 | No |
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.8.3 |
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 | 4 |
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 |
Canada |
South Africa |
United States |
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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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |