E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Haemophilia A with or without inhibitors
Haemophilia B with our without inhibitors |
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E.1.1.1 | Medical condition in easily understood language |
Bleeding disorder, inherited deficiency in clotting factor VIII or IX with or without antibodies to replacement therapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053752 |
E.1.2 | Term | Hemophilia B with anti factor IX |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053751 |
E.1.2 | Term | Hemophilia A with anti factor VIII |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053753 |
E.1.2 | Term | Hemophilia A without inhibitors |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
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 | 10010331 - Congenital, familial and genetic disorders |
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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 establish superiority of concizumab prophylaxis in concizumab-naïve children less than 12 years with haemophilia A or B with inhibitors compared to their previous on demand treatment on the number of treated spontaneous and traumatic bleeding episodes. |
|
E.2.2 | Secondary objectives of the trial |
- To establish non-inferiority of concizumab prophylaxis in concizumab-naïve children less than 12 years with haemophilia A or B without inhibitors compared to their previous PPX treatment on the number of treated spontaneous and traumatic bleeding episodes
- To evaluate the safety of concizumab administered once-daily in concizumab-naïve children less than 12 years with haemophilia A or B with or without inhibitors
- To evaluate the safety of concizumab administered once-daily in patients previously treated with concizumab via compassionate use
- To evaluate pharmacokinetics and pharmacodynamics of concizumab administered once-daily in concizumab-naïve children less than 12 years with haemophilia A or B with or without inhibitors |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Informed consent/assent obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study.
- Diagnosis of congenital severe haemophilia A (FVIII less than 1%) or moderate/severe congenital haemophilia B (FIX equal to or less than 2%), or congenital haemophilia with inhibitors.
• For arm 1 only: Male aged <12 years of age at the time of signing informed consent.
- For arm 1 only: Patients with inhibitors (HAwI or HBwI): a) Patients with HAwI with historical medical records of a total of at least 26 weeks of on-demand treatment within the last 52 weeks prior to enrolment b) Patients with HBwI with historical medical records of a total of at least 26 weeks of on-demand treatment within the last 52 weeks prior to enrolment c) Patients with HBwI regardless of the regimen and duration of previous haemophilia treatment
- For arm 1 only: Patients without inhibitors (HA or HB): a) Patients with historical medical records of at least 52 weeks of on-demand treatment during the last year prior to enrolment and with at least 3 documented treated bleeds during this period b) Patients with historical medical records of a total of at least 26 weeks of PPX treatment within the last 52 weeks prior to enrolment
- For arm 2 only: Male patients (regardless of age) previously treated with concizumab via compassionate use. |
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E.4 | Principal exclusion criteria |
- Known or suspected hypersensitivity to study intervention or related products. - Known inherited or acquired coagulation disorder other than congenital haemophilia. - Ongoing or planned Immune Tolerance Induction treatment. - History of thromboembolic disease(a). Current clinical signs of or treatment for thromboembolic disease. Patients who in the judgement of the investigator are considered at high risk of thromboembolic events(b)
(a) Includes arterial and venous thrombosis including myocardial infarction, pulmonary embolism, cerebral infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events and peripheral artery occlusion. (b) Thromboembolic risk factors could include, but are not limited to, hypercholesterolemia, diabetes mellitus, hypertension, obesity, smoking, family history of thromboembolic events, arteriosclerosis, other conditions associated with increased risk of thromboembolic events. |
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E.5 End points |
E.5.1 | Primary end point(s) |
For inhibitor patients with at least 26 weeks on demand treatment during the last 52 weeks prior enrolment: Number of treated spontaneous and traumatic bleeding episodes
For non-inhibitor patients treated on demand during at least the last 52 weeks prior enrolment: Number of treated spontaneous and traumatic bleeding episodes |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From start of treatment (week 0) up until the primary analysis cut-off |
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E.5.2 | Secondary end point(s) |
For inhibitor patients with at least 26 weeks on-demand treatment during the last 52 weeks prior enrolment: 1. Number of all bleeding episodes (spontaneous and traumatic) 2. Number of treated spontaneous bleeding episodes 3. Number of treated joint bleeding episodes 4. Number of treated bleeding episodes in baseline target joints
For non-inhibitor patients treated on demand during at least the last 52 weeks prior enrolment: 5. Number of all bleeding episodes (spontaneous and traumatic) 6. Number of treated spontaneous bleeding episodes 7. Number of treated joint bleeding episodes 8. Number of treated bleeding episodes in baseline target joints
For non-inhibitor patients with at least 26 weeks PPX treatment during the last 52 weeks prior enrolment: 9. Number of treated spontaneous and traumatic bleeding episodes 10. Number of all bleeding episodes (spontaneous and traumatic) 11. Number of treated spontaneous bleeding episodes 12. Number of treated joint bleeding episodes 13. Number of treated bleeding episodes in baseline target joints . 14. Number of treatment emergent adverse events, reported both separately for inhibitor and non-inhibitor patients and combined 15. Number of thromboembolic events, reported both separately for inhibitor and non-inhibitor patients and combined 16. Number of hypersensitivity type reactions, reported both separately for inhibitor and non-inhibitor patients and combined 17. Number of injection site reactions, reported both separately for inhibitor and non-inhibitor patients and combined 18. Number of patients who develop antibodies to concizumab – yes/no, reported both separately for inhibitor and non-inhibitor patients and combined 19. Number of treatment emergent adverse events, reported both separately for inhibitor and non-inhibitor patients and combined 20. Concizumab plasma concentrations prior to dosing, reported both separately for inhibitor and non-inhibitor patients and combined 21. Peak thrombin generation prior to dosing, reported both separately for inhibitor and non-inhibitor patients and combined 22. Free TFPI concentration prior to dosing, reported both separately for inhibitor and non-inhibitor patients and combined
23. Pre-dose (trough) concizumab plasma concentration (Ctrough), reported both separately for inhibitor and non-inhibitor patients and combined 24. Maximum concizumab plasma concentration (Cmax), reported both separately for inhibitor and non-inhibitor patients and combined 25. Area under the concizumab plasma concentration-time curve (AUC), reported both separately for inhibitor and non-inhibitor patients and combined |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.-19. From start of treatment (week 0) up until the primary analysis cut-off 20.-22. Week 32 23. Prior to the concizumab administration at week 20 24.-25. From 0 to 24 hours where 0 is the time of the concizumab dose at week 20 |
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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 | No |
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 | Yes |
E.7.1.3.1 | Other trial type description |
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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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Malaysia |
Bosnia and Herzegovina |
North Macedonia |
Canada |
India |
Japan |
Lebanon |
Mexico |
South Africa |
Thailand |
United Kingdom |
United States |
European Union |
Norway |
Türkiye |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 7 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
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 | 7 |