E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Haemophilia A with inhibitors Haemophilia B with inhibitors |
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E.1.1.1 | Medical condition in easily understood language |
Bleeding disorders: - inherited deficiency in clotting factor VIII with antibodies to replacement therapy - inherited deficiency in clotting factor IX with 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 | 10053751 |
E.1.2 | Term | Hemophilia A with anti factor VIII |
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 | 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.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare effect of concizumab prophylaxis to no prophylaxis (on-demand treatment with bypassing agents) in reducing the number of bleeding episodes in adult and adolescent patients with haemophilia A or B with inhibitors |
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E.2.2 | Secondary objectives of the trial |
1. To compare the patient reported outcomes (PROs) after treatment with concizumab prophylaxis vs no prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors 2. To investigate the safety of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors 3. To investigate the PK and PD parameters of concizumab prophylaxis in adult and adolescent patients with haemophilia A or B with inhibitors |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial - Male aged 12 or older years at the time of signing informed consent - Congenital Haemophilia A or B of any severity with documented history of inhibitor (0.6 BU or more) - Patient has been prescribed, or in need of, treatment with bypassing agents in the last 24 weeks prior to screening (for patients not previously enrolled in NN7415-4310 (explorer 4)) |
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E.4 | Principal exclusion criteria |
- Known or suspected hypersensitivity to any constituent of the trial product or related products - Known inherited or acquired coagulation disorder other than congenital haemophilia - Ongoing or planned Immune Tolerance Induction treatment - History of thromboembolic disease (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). 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 (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) |
The number of treated spontaneous and traumatic bleeding episodes |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
On demand (arm 1): From randomisation (week 0) up until start of concizumab treatment (at least 24 weeks) Concizumab (arm 2): From start of the new concizumab dosing regimen (week 0) up until the primary analysis cut-off (at least 32 weeks) |
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E.5.2 | Secondary end point(s) |
1. Change in 36 Item short form health survey version 2 (SF36v2) bodily pain 2. Change in SF36v2 physical functioning 3. Number of treated spontaneous bleeding episodes 4. Number of treated spontaneous and traumatic joint bleeds 5. Number of treated spontaneous and traumatic target joint bleeds 6. Number of thromboembolic events 7. Number of thromboembolic events 8. Number of hypersensitivity type reactions 9. Number of hypersensitivity type reactions 10. Number of injection site reactions 11. Number of injection site reactions 12. Number of patients with antibodies to concizumab 13. Number of patients with antibodies to concizumab 14. Pre-dose (trough) concizumab plasma concentration (Ctrough) 15. Pre-dose thrombin peak 16. Pre-dose free tissue factor pathway inhibitor (TFPI) concentration 17. Maximum concizumab plasma concentration (Cmax) 18. Area under the concizumab plasma concentration-time curve (AUC) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2:treatment (Trt.) start (week (wk) 0), wk24 3-5:On demand (OD) (arm 1): Randomisation (wk0) to dose start (min. 24 wks) Concizumab (Conci.) (arm 2): new dosing start (wk0) to primary analysis cut-off (min. 32 wks) 6, 8 &10: OD (arm 1 main part): -Randomisation to OD Trt. to start of dose 6, 8, 10 & 12: Conci. (arms 2-4): -Before pause: Trt. start (wk0) to 7 wks after Trt. pause -After pause: dose start (wk0) to primary analysis cut-off (min. 32 wks) Conci. (arm 1 ext. part): new dosing start (wk25) to the primary analysis cut-off 7, 9, 11 & 13: Conci.: -Before pause: Trt. start (wk0) to 7 wks after Trt. pause -After pause: dose start to end of trial (up to 280 weeks) 14-16:Prior to dose at wk24 (after restart) 17-18:0-24 hrs (0: time of dose at wk24 (after restart)) |
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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 | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
2 randomised treatment arms (ppx/no ppx) and two non-randomised treatment arms |
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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 | Yes |
E.8.2.3.1 | Comparator description |
Treatment regimen before entering the trial will determine the assignment to the four treatment arms |
|
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 59 |
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 |
Algeria |
Malaysia |
Ukraine |
Australia |
India |
Japan |
Korea, Republic of |
Mexico |
Russian Federation |
Serbia |
South Africa |
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 | 6 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 11 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 11 |