E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hemophilia A with inhibitors, Hemophilia B with inhibitors |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 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.1.2 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 | 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 |
Part 1 (PK part): To evaluate the single-dose PK of CSL689 (low dose, high dose) in subjects with hemophilia A or B and inhibitors and to compare with the single-dose PK of Eptacog alfa (low dose or high dose).
Part 2 (Dose-evaluation part): To determine the best dose ("population-based best dose") of the 2 CSL689 dose levels evaluated.
Part 3 (Repeated-dose part): To evaluate the clinical efficacy of the population-based best dose of CSL689 for on-demand therapy of bleeding events in subjects with hemophilia A or B and inhibitors. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of IV administration of CSL689. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male subjects with hemophilia A or B and inhibitors.
2. Age ≥ 12 and ≤ 65 years.
3. High responding inhibitor with documented historical inhibitor titer > 5 Bethesda Units/mL.
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E.4 | Principal exclusion criteria |
1. Congenital or acquired coagulation disorders other than hemophilia A or B.
2. Ongoing immune tolerance induction therapy or planned during study.
3. Known or suspected hypersensitivity to activated recombinant human FVII or to any excipient of CSL689.
4. Body mass index > 30 kg/m².
5. Major surgery within 28 days before screening or scheduled major and / or orthopedic surgery during the study.
6. Advanced atherosclerotic disease (ie, known history of ischemic heart disease, or ischemic stroke).
7. Any clinical signs or known history of thromboembolic events, including known deep vein thrombosis.
8. Human immunodeficiency virus (HIV)-positive subjects who have low cluster of differentiation 4 (CD4)+ lymphocyte count (200/μL or less) at screening.
9. Use of the following within the screening period and planned during study: a) plasma or coagulation factor concentrates other than rescue therapy or therapy during the Part 1, b) other platelet inhibitors, c) desmopressin, and d) fibrinolysis inhibitors (except if used as local treatment (eg, for oral bleeds).
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E.5 End points |
E.5.1 | Primary end point(s) |
PK of plasma factor VIIa activity (in Part 1 only): Area under the curve (AUC0-t); Incremental recovery; Elimination half-life; Total clearance.
Efficacy: Treatment success with first CSL689 injection (in Part 2 only); Treatment success with first CSL689 injection at the population best dose (in Part 3 only); Treatment success with first or second CSL689 injection at the population best dose (in Part 3 only).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK: Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until 120 hours after injection for CSL689.
Efficacy: Up to 16 hours after first CSL689 injection for each bleeding event |
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E.5.2 | Secondary end point(s) |
"Efficacy: Treatment success with first or second CSL689 injection ( in Part 2 only); Number of bleeding events requiring > 1 CSL689 injection (for Part 2 and for Part 3); Number of CSL689 injections per bleeding event (for Part 2 and for Part 3); Total dose of CSL689 per bleeding event (for Part 2 and for Part 3); Treatment success with first CSL689 injection at the population best dose in subjects participating in Parts 2 and 3; Percentage of first bleeding events successfully treated with first CSL689 injection at population best dose in Part 3; Treatment success at population best dose; Treatment success with CSL689 at the dose level that is not the population best dose; Percentage of bleeding events with only “definite” or “abrupt” subject-reported pain relief at the population best dose; Percentage of bleeding events with “good” or “excellent” investigator-reported assessment of treatment response at the population best dose of CSL689; Proportion of recurrences; Proportion of bleeding events with ultrarapid progression; Proportion of bleeding events requiring post-hemostatic maintenance dosing.
Safety: Number and percentage of subjects with treatment-emergent adverse events (TEAEs); Number and percentage of subjects with an antibody response.
PK: AUC(0-inf); Maximum observed plasma FVIIa activity; Time of occurrence of maximum observed plasma FVIIa activity; Volume of distribution at steady state; Mean residence time."
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: Up to 24 hours after the relevant CSL689 injection for the relevant bleeding event for the first eight endpoints; Up to 9 months for the last five endpoints.
Safety: Up to 16 months.
PK: Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 11 time points until 120 hours after injection for CSL689. |
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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 | Yes |
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 |
Health-related quality of life |
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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) | Yes |
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 | 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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 10 |
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 |
Australia |
Canada |
European Union |
Georgia |
Japan |
Korea, Republic of |
Malaysia |
Russian Federation |
Serbia |
South Africa |
Thailand |
Turkey |
Ukraine |
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 | 10 |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |