E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Male paediatric subjects with Haemophilia A who develped high titre antibodies to human coagulation Factor VIII |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of patients with hereditary deficiency of blood coagulation factor VIII that developed neutralizing antibodies against Factor VIII is investigated |
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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 | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018941 |
E.1.2 | Term | Haemophilia NOS |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the proportion of subjects who achieve a complete response (success) following ITI treatment with Biostate. |
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E.2.2 | Secondary objectives of the trial |
Secondary Objective: To assess the safety of Biostate when administered to subjects with haemophilia A and inhibitors to FVIII in an ITI treatment regimen.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male subjects diagnosed with haemophilia A (≤2% FVIII level in the absence of factor replacement, according to their medical history). 2. Age 28 days to <12 years. 3. ITI treatment can be initiated if: a. An inhibitor level of >5 and <200 BU/mL was confirmed in 2 repeated tests by the central laboratory during the screening period and no waiting period is required as judged by the investigator. b. An inhibitor level of >5 and <200 BU/mL was confirmed in 2 repeated tests by the central laboratory during the screening period and the inhibitor titre decreased from the peak titre during a waiting period (maximum 11 months) added at the discretion of the investigator. c. A subject has pre-existing inhibitors, determined no more than 11 months prior to the Screening visit, which decreased from the peak titre, and an inhibitor level of >5 and <200 BU/mL was confirmed in 2 repeated tests by the central laboratory during the screening period. A waiting period could still be added if the total duration from inhibitor diagnosis until start of ITI treatment (ie, including the screening period) does not exceed 12 months. 4. The subject and/or his legally acceptable representative understand the nature of the study and have given written informed consent to participate in the study. 5. Sufficient peripheral venous access or central venous line.
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E.4 | Principal exclusion criteria |
Exclusion Criteria: 1. The subject has received ITI previously. 2. Subjects with a historical peak inhibitor titre of ≥200 BU/mL. 3. Concomitant treatment with drugs with immunosuppressive side effects (eg, systemic corticosteroids), azathioprine, cyclophosphamide, high dose immunoglobulin or the use of a protein A column or plasmapheresis and interferons. 4. High risk of cardiovascular, cerebrovascular, or other thromboembolic events (excluding catheter thrombosis) as judged by the investigator. 5. Subjects who are human immunodeficiency virus (HIV)-1 or HIV-2 positive (as reported in the medical records or determined at screening). 6. The subject has evidence or a history (within the previous 12 months) of abuse of any drug substance, licit or illicit. 7. The subject has a known or suspected hypersensitivity or has previous evidence of severe side effects to von Willebrand factor (VWF)/FVIII or FVIII concentrates or human albumin. 8. The subject has participated in a clinical study or used an investigational compound (eg, a new chemical entity not approved for clinical use) in the past 3 months, unless the study was for haemophilia A and the subject developed an inhibitor (then, a wash-out period of at least 4 weeks must be applied), or is planning to enter such a study during the study period. 9. Subjects or legal guardians/ representatives with suspected inability (eg, language problems) or unwillingness to comply with study procedures. 10. The subject has an acute or chronic medical condition other than haemophilia A, which may, in the opinion of the investigator, affect the conduct of the study. 11. Mental condition rendering the subject (or the subject’s legally acceptable representative) unable to understand the nature, scope and possible consequences of the study). 12. Any condition that is likely to interfere with evaluation of the investigational medicinal product (IMP) or satisfactory conduct of the study. 13. Employee at the study site, or spouse/partner or relative of the investigator or subinvestigators. Study Product, Dose, and Mode of Administration: The IMP Biostate will be intravenously (i.v.) administered at a daily dose of 200 international units (IU)/kg body weight (b.w.), preferably split into 2 doses of 100 IU/kg b.w. per day. For subjects with an undetectable inhibitor titre (<0.6 BU/mL) at 2 consecutive assessments, tested at intervals of 2 weeks (±3 days), and normal recovery (≥66% of predicted) for 6-8 weeks, the daily Biostate dose will be reduced by 20 IU/kg b.w. (ie, by 10% of the initial daily ITI dose), if possible, every 2-4 weeks down to a dose of 100 IU/kg b.w., provided the recovery remains normal during that time (assessed weekly). After further gradual reduction of the dose and extension of the administration interval (at the discretion of the investigator), Biostate will be administered as prophylaxis at a daily dose of 50 IU/kg b.w. on 3 days per week (about every second day). Any daily dose >100 IU/kg b.w. should preferably be evenly split into 2 doses per day. Daily doses of 100 IU/kg b.w. or lower will be administered once daily. Bleeding complications during the tolerization period should be treated according to centre’s standard of care. Study treatment should not be interrupted for surgical procedures.
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E.5 End points |
E.5.1 | Primary end point(s) |
Study endpoints: Efficacy endpoints: • Response to ITI treatment: complete response (success), partial response (partial success), or ITI failure. • FVIII inhibitor titre. • Time to complete response (success). • Time to inhibitor <0.6 BU/mL for the first time. Safety endpoints: • Adverse events (AEs). • Clinical laboratory testing (haematology, biochemistry). • Thrombogenic risk assessment: markers of activation of coagulation (eg, fibrin fragments, thrombin-antithrombin complex [TAT]). • Frequency and nature of bleeding events. • Catheter-related complications (eg, line infections). • Physical examination. • Vital signs (blood pressure, heart rate, and body temperature).
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 5 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |