E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Healthy volunteers (Haemophilia A with or without inhibitors) Haemophilia A Haemophilia A with inhibitors |
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E.1.1.1 | Medical condition in easily understood language |
Healthy volunteers Bleeding disorder inherited deficiency in clotting factor VIII Bleeding disorder inherited deficiency in clotting factor VIII with antibodies to clotting factor 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 | 10018938 |
E.1.2 | Term | Haemophilia A (Factor VIII) |
E.1.2 | System Organ Class | 100000004850 |
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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 | 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 investigate the safety and tolerability of subcutaneous Mim8 in healthy subjects and in subjects with severe haemophilia A with or without FVIII inhibitors |
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E.2.2 | Secondary objectives of the trial |
1. To investigate the pharmacokinetics of subcutaneous Mim8 in healthy subjects and in subjects with severe haemophilia A with or without FVIII inhibitors 2. To investigate the pharmacodynamics of subcutaneous Mim8 in healthy subjects and in subjects with severe haemophilia A with or without FVIII inhibitors |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Single ascending dose (SAD) part: - Male, aged 18−45 years (both inclusive) at the time of signing informed consent - Considered to be generally healthy based on the medical history, physical examination, and the results of vital signs, electrocardiogram and clinical laboratory tests performed during the screening visit, as judged by the investigator
Multiple ascending dose (MAD) part: - Male, aged 12−64 years (both inclusive) at the time of signing informed consent (Germany and Japan have local requirements) - Diagnosis of congenital haemophilia A with FVIII activity <1% based on medical records
Exploratory biomarker cohort: - Male, aged ≥12 years at the time of signing informed consent (Germany and Japan have local requirements) - Diagnosis of congenital haemophilia A with FVIII activity <1% based on medical records |
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E.4 | Principal exclusion criteria |
SAD part: - Factor VIII activity ≥150% at screening - Increased risk of thrombosis, e.g. known history of personal or first degree relative(s) with unprovoked deep vein thrombosis - Any clinical signs or established diagnosis of venous or arterial thromboembolic disease
MAD part: - Known congenital or acquired coagulation disorders other than haemophilia A - Increased risk of thrombosis as evaluated by the investigator. E.g. known history of personal or first degree relative(s) with unprovoked deep vein thrombosis with exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing - Any clinical signs or established diagnosis of venous or arterial thromboembolic disease with exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing - Advanced atherosclerotic disease (e.g. known history of ischemic heart disease, ischemic stroke) as evaluated by the investigator - Any autoimmune disease that may increase the risk of thrombosis - Receipt of emicizumab or drugs with similar modes of action within 5 half-lives before trial product administration - Ongoing or planned immune tolerance induction therapy
Exploratory biomarker cohort: - Known congenital or acquired coagulation disorders other than haemophilia A - Increased risk of thrombosis as evaluated by the investigator. E.g. known history of personal or first degree relative(s) with unprovoked deep vein thrombosis with exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing - Any clinical signs or established diagnosis of venous or arterial thromboembolic disease with exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing - Advanced atherosclerotic disease (e.g. known history of ischemic heart disease, ischemic stroke) as evaluated by the investigator - Any autoimmune disease that may increase the risk of thrombosis - Ongoing or planned immune tolerance induction therapy |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Single ascending dose (SAD) part: Number of treatment emergent adverse events 2. Multiple ascending dose (MAD) part: Number of treatment emergent adverse events 3. Extensíon to the MAD part: Number of treatment emergent adverse events |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From time of dosing (Day 1) to Week 16 2. From time of first dosing (Day 1) to Week 12 3. From Week 12 up to Week 176 (16 weeks after last dose) |
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E.5.2 | Secondary end point(s) |
SAD part: 1. Number of injection site reactions 2. Relative change in D-dimer 3. Relative change in prothrombin fragment 1 and 2 4. Relative change in fibrinogen 5. Relative change in platelets 6. Cmax, SD: the maximum concentration of Mim8 after a single dose 7. AUC0-inf, SD: the area under the Mim8 concentration-time curve from time 0 to infinity after a single dose 8. t1/2, SD: the terminal half-life of Mim8 after a single dose 9. tmax, SD: the time to maximum concentration of Mim8 after a single dose 10. Change in activated partial thromboplastin time MAD part (weekly and monthly dosing): 11. Number of injection site reactions 12. Occurrence of anti-Mim8 antibodies 13. Relative change in D-dimer 14. Relative change in prothrombin fragment 1 and 2 15. Relative change in fibrinogen 16. Relative change in platelets MAD part, PK session 2 (weekly dosing): 17. Cmax, MD: the maximum concentration of Mim8 after multiple doses 18. AUCτ, MD: the area under the Mim8 concentration-time curve in the dosing interval after multiple doses MAD part, PK session 2 (monthly dosing): 19. Cmax, MD: the maximum concentration of Mim8 after multiple doses 20. AUCτ, MD: the area under the Mim8 concentration-time curve in the dosing interval after multiple doses MAD part (weekly dosing): 21. Mean of maximum thrombin generation (peak height) MAD part (monthly dosing): 22. Mean of maximum thrombin generation (peak height) Extension to the MAD part: 23. Number of injection site reactions 24. Occurrence of anti-Mim8 antibodies |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From time of dosing (Day 1) to Week 16 2-10. From baseline (Day 1) to Week 16 11. From time of first dosing (Day 1) to Week 12 12-16. From baseline (Day 1) to Week 12 17-18. From Day 57 to Day 64 19-20. From Day 57 to Day 85 21. From Day 57 to Day 64 22. From Day 57 to Day 85 23-24. From Week 12 up to Week 176 (16 weeks after last dose) |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerability and exploratory efficacy |
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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) | No |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
1) SAD part (ph. 1): Double-blind in cohorts 2) MAD part (ph. 2) and Ext. to MAD part: Open-label |
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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 | Yes |
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
| 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 | 16 |
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 |
Japan |
South Africa |
United States |
European Union |
Switzerland |
Turkey |
United Kingdom |
Serbia |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 11 |