E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hemophilia A with Inhibitors |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is a genetic deficiency in blood clotting factor VIII, which causes increased bleeding. Inhibitors, however, prevent replacement factor VIII concentrates from controlling bleeds. |
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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 | 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 evaluate clinical effect of prophylactic emicizumab on number of bleeds over time (bleed rate)* and efficacy in reducing bleed rate compared with the patient's historical bleed rate (cohort A only)*
•To characterize efficacy of up-titration on an intra-patient level, based on the basis of the no of bleeds over time*
•To evaluate Health-Related Quality of Life (HRQoL) of children 8-17 years of age according to Hemophilia-Specific Quality of Life Index (Haemo-QoL) Short Form
•To evaluate proxy-reported HRQoL and aspects of caregiver burden using the Adapted inhibitor-specific questionnaire for the assessment of health-related quality of life (InhibQoL) including aspects of caregiver burden questionnaire for all children (completed by caregivers)
•To assess number of days away from day care/preschool/school and days hospitalized
*Analyses will be performed for: all bleeds, and all treated bleeds including spontaneous, joint and target joint bleeds. |
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E.2.2 | Secondary objectives of the trial |
There is no formal hypothesis testing in the study.
Safety:
• To evaluate overall safety of emicizumab
Pharmacokinetic:
• To characterize the exposure [minimum observed analyte concentration (Ctrough)] of emicizumab in patients receiving 1.5 mg/kg QW (cohort A), 3 mg/kg Q2W (cohort B), and 6 mg/kg Q4W (cohort C) prior to drug administration
Pharmacodynamics:
• To assess potential pharmacodynamic (PD) biomarkers of emicizumab, including but not limited to activated partial thromboplastin time (aPTT) and FVIII activity |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Children < 12 years of age at time of informed consent with allowance for the following: for patients 12-17 years of age and who weigh < 40 kilograms (kg) at the time of informed consent (Cohort A only); and for patients < 2 years of age will be allowed to participate only after the protocol defined interim data review criteria are met (Cohort A only)
- Body weight > 3 kg at the time of informed consent
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
including the completion of applicable patient-reported outcome (PRO) questionnaires
- Caregivers must have the willingness and ability to comply with all study procedures including the completion of the bleed/medication questionnaire and applicable HRQoL questionnaires
- Diagnosis of congenital hemophilia A of any severity and documented history of high-titer inhibitor (i.e., >=5 BU)
- Requires treatment with bypassing agents
- For patients >= 2 years of age (Cohort A only): if on episodic bypassing agent regimen annualized bleeding rate (ABR) of >=6 ; or if on prophylactic bypassing agent regimen inadequately controlled or central venous access device (CVAD) placement medically not feasible or deemed unsafe
- For patients < 2 years of age determined by investigator to be in high unmet medical need
- Adequate hematologic, hepatic and renal functions
- Female patients of childbearing potential who have negative serum pregnancy test result and an agreement to remain abstinent or use contraceptive methods specified in the study |
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E.4 | Principal exclusion criteria |
- Inherited or acquired bleeding disorder other than hemophilia A
- Ongoing (or plan to receive during the study) immune tolerance induction (ITI) therapy or prophylaxis treatment with FVIII during the study. Patients awaiting initiation of ITI will be eligible and patients in whom ITI has failed will be eligible with a 72-hour washout period prior to the first emicizumab administration
- Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti thrombotic treatment is not currently ongoing) or signs of thromboembolic disease
- Other diseases (i.e., certain autoimmune diseases [e.g., systemic lupus erythematosus], cardiovascular disease) that may increase risk of bleeding or thrombosis
- Known infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus
- Patients who are at high risk for TMA (e.g., have a previous medical or family history of TMA), in the investigator's judgment
- Use of systemic immunomodulators (e.g., interferon or corticosteroids) at enrolment or planned use during the study period
- Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study
- Inability (or unwillingness by caregiver) to receive (allow receipt of) blood or blood products (or any standard-of care treatment for a life-threatening condition) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy:
1. Number of bleeds over time
2. An up-titration on both, an intra-patient and population level
3. Comparison between historical and on study treatment period for bleed over time (cohort A only)
4. HRQoL of children 8-17 years of age according to Haemo QoL short form (completed by patients)
5. Proxy-reported HRQoL and aspects of caregiver burden using the adapted InhibQoL Including aspects of caregiver burden questionnaire for all children (completed by caregivers)
6. Number of days away from day care/preschool/school and days hospitalized |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
1-3. Up to 52 weeks
4-6. Weeks 1, 13, 25, 37, 49, and every 24 weeks from Week 57 up to Week 152
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E.5.2 | Secondary end point(s) |
Safety:
1. Incidence and severity of adverse events
2. Incidence and severity of thromboembolic events
3. Changes in physical examination findings and vital signs
4. Incidence of laboratory abnormalities
5. Incidence and severity of injection-site reactions
6. Incidence of adverse events leading to drug discontinuation
7. Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events
8. Incidence and severity of thrombotic microangiopathy
9. Incidence and clinical significance of anti-emicizumab antibodies
Pharmacokinetic:
1. Ctrough of emicizumab in patients receiving 1.5 mg/kg QW (cohort A), 3 mg/kg Q2W (cohort B), and 6 mg/kg Q4W (cohort C)
Pharmacodynamics:
1. included but not limited to aPTT FVIII activity |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety:
1-8. Up to 152 weeks
9. Weeks 1, 5, 17, 33, 49, every 12 weeks starting from Week 57 up to Week 152
Pharmacokinetic:
1. Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 49, and every 12 weeks from Week 57 up to Week 152
Pharmacodynamics:
1. Weeks 1, 3, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 49, and every 12 weeks from Week 57 up to Week 152 |
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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 | 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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
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 |
Costa Rica |
France |
Germany |
Italy |
Japan |
South Africa |
Spain |
Turkey |
United Kingdom |
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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The end of this study is defined as the date when the last patient completes the last safety follow-up visit 24 weeks after discontinuing emicizumab, enrolls in a future separate emicizumab extension study, or is lost to follow-up. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |