E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Haemophilia A without factor VIII inhibitors |
|
E.1.1.1 | Medical condition in easily understood language |
Haemophilia A is a genetic deficiency of blood clotting factor VIII (FVIII), which causes increased bleeding. It is treated with frequent, intravenous FVIII infusion |
|
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 | 10053753 |
E.1.2 | Term | Hemophilia A without inhibitors |
E.1.2 | System Organ Class | 100000004850 |
|
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 evaluate the efficacy of prophylactic emicizumab (1.5 mg/kg/week or 3 mg/kg/2weeks) compared with no prophylaxis in patients with haemophilia A without FVIII inhibitors on the basis of the number of bleeds over time (primary endpoint is based on treated bleeds) |
|
E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of prophylactic emicizumab on the basis of number of bleeds over time compared with the patient’s historical bleed rate (treated and all bleeds) • To evaluate the efficacy of prophylactic emicizumab (1.5 mg/kg/week or 3 mg/kg/2weeks) on the basis of: - All bleeds over time - Spontaneous bleeds over time (spontaneous bleed rate) - Joint bleeds over time - Target joint bleeds over time - Health-related quality of life (HRQoL) of patients according to Haem A QoL (aged >= 18) or Haemo-QoL-Short Form (aged 12-17) scores after 24 weeks - Health status of patients according to EuroQoL Five Dimension Five Levels Questionnaire (EQ-5D-5L) scores after 24 weeks • Maintaining adequate control of bleeding in patients previously treated with factor VIII prophylaxis by evaluation of the bleed rate (treated and all bleeds) • To evaluate overall safety of prophylactic emicizumab in patients with haem. A without inhibitors • To evaluate pharmacokinetic of emicizumab |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Aged 12 years or older at the time of informed consent - Body weight >= 40 kg at the time of screening - Diagnosis of severe congenital haemophilia A (intrinsic FVIII level < 1%) - A negative test for inhibitor (i.e., < 0.6 Bethesda units [BU]) within 8 weeks of enrollment - No documented inhibitor (i.e., < 0.6 BU), FVIII half-life < 6 hours, or FVIII recovery < 66% in the last 5 years - Patients who completed successful immune tolerance induction (ITI) at least 5 years before screening are eligible, provided they have had no evidence of inhibitor recurrence (permanent or temporary) as may be indicated by detection of an inhibitor, FVIII half-life < 6 hrs, or FVIII recovery < 66% since completing ITI - Documentation of the details of prophylactic or episodic FVIII treatment and of number of bleeding episodes for at least the last 24 weeks - For patients on no prophylaxis (episodic treatment) pre-study, >= 5 bleeds in the last 24 weeks prior to study entry - Patients who were on FVIII prophylaxis for at least the last 24 weeks, can be enrolled regardless of the number of bleeds during this period. Eligibility will be based on investigator’s attestation of adequate prophylaxis regimen. - At least 40 patients who were on FVIII prophylaxis pre-enrolment will have been enrolled for minimum of 24 weeks in Study BH29768 (non-interventional) - Adequate haematologic function, defined as platelet count >= 100,000/ microliter and haemoglobin >= 8 gram/decilitre (4.97 millimoles/liter) at the time of screening - Adequate hepatic and renal function - Agreement to remain abstinent or use contraceptive methods specified in the study |
|
E.4 | Principal exclusion criteria |
- Inherited or acquired bleeding disorder other than haemophilia A - Previous (in the past 12 months) or current treatment for thromboembolic disease (except previous catheter-associated thrombosis for which anti thrombotic treatment is not currently ongoing) or signs of thromboembolic disease - Other conditions (e.g., certain autoimmune diseases) that may increase risk of bleeding or thrombosis - Known human immunodeficiency virus infection with CD4 count < 200 cells/microlitre within 24 weeks prior to screening - Use of systemic immunomodulators at enrolment or planned use during the study (except anti-retroviral therapy) - Patients who are at high risk for thrombotic microangiopathy (e.g., have a previous medical or family history of TMA), in the investigator’s judgment - Receipt of emicizumab in a prior investigational study, an investigational drug to treat or reduce the risk of haemophilic bleeds within 5 half-lives of last drug administration, and a non-haemophilia-related investigational drug concurrently, within last 30 days or 5 half-lives, whichever is shorter - Pregnant or lactating, or intending to become pregnant during the study - Women who are not postmenopausal (>=48 weeks of non-therapy-induced amenorrhea) or surgically sterile must have a negative pregnancy test result within 7 days prior to initiation of study drug |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Number of bleeds over time (i.e., bleed rate) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Efficacy: 1. Change in the number of bleeds over time compared with the patient’s historical bleed rate over the last 24 weeks prior to study entry 2. All bleeds over time (treated and not treated) 3. Spontaneous bleeds over time (spontaneous bleed rate) 4. Joint bleeds over time 5. Target joint bleeds over time 6. HRQoL of patients according to Haem-A-QoL (aged >=18) or Haemo-QoL-Short Form (aged 12-17) scores 7. Health status of patients according to EQ-5D-5L scores 8. Maintaining adequate control of bleeding by evaluation of the bleed rate in patients previously on factor VIII prophylaxis
Safety: 9. Incidence of adverse events 10. Incidence of thromboembolic events 11. Incidence of new physical examination abnormalities 12. Incidence of new vital signs abnormalities 13. Incidence of laboratory abnormalities 14. Incidence injection-site reactions 15. Incidence of adverse events leading to drug discontinuation 16. Incidence of severe hypersensitivity, anaphylaxis, or anaphylactoid reactions 17. Incidence and severity of thrombotic microangiopathy 18. Incidence and clinical significance of anti-emicizumab antibodies 19. Incidence of de novo development of FVIII inhibitors in patients receiving emicizumab prophylaxis
Pharmacokinetic (PK): 20. Trough plasma concentrations of emicizumab |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
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 | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
armC: no prophylaxis (standard of care rescue medication); historical intrapatient control |
|
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
| 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 | 15 |
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 |
Costa Rica |
France |
Germany |
Ireland |
Italy |
Japan |
Korea, Republic of |
Poland |
South Africa |
Spain |
Taiwan |
United Kingdom |
United States |
|
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
|
The end of this study is defined as the date when the last patient completes the last safety follow-up visit 24 weeks after the last dose of emicizumab, enrolls in an emicizumab extension study, or is lost to follow-up. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |