E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is a bleeding disorder that slows the blood clotting process |
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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 | 10053753 |
E.1.2 | Term | Hemophilia A without inhibitors |
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 |
Main objectives: • To evaluate the efficacy of emicizumab • To evaluate the safety of emicizumab • To characterize the emicizumab pharmacokinetic (PK) profile • To investigate the effect of emicizumab on pharmacodynamics (PD) parameters • To evaluate the immune response to treatment
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria: • Age from birth to <= 12 months at time of informed consent • Body weight >= 3 kg at time of informed consent • Mandatory receipt of vitamin K prophylaxis according to local standard practice • Diagnosis of severe congenital hemophilia A (intrinsic FVIII level < 1%) • A negative test for FVIII inhibitor (i.e., < 0.6 Bethesda units [BU]/mL) locally assessed during the 2-week screening period for all patients • For PUPs or MTPs, up to 5 days of exposure with hemophilia-related treatments, such as plasma-derived FVIII, recombinant FVIII, fresh frozen plasma, cryoprecipitate, or whole blood products • Documentation of the details of the hemophilia-related treatments received since birth • Documentation of the details of the bleeding episodes since birth • For patients from birth to < 3 months of age at the time of study entry: no evidence of active ICH, as confirmed by a negative cranial ultrasound at screening irrespective of delivery mode • Adequate hematologic, hepatic, and renal function
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E.4 | Principal exclusion criteria |
Exclusion criteria • Inherited or acquired bleeding disorder other than severe hemophilia A • Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use during the study • Receipt of any of the following: – An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 drug-elimination half-lives of last drug administration – A non-hemophilia-related investigational drug within the last 30 days or 5 drug-elimination half-lives, whichever is shorter – An investigational drug concurrently • Current active severe bleed, such as ICH • Planned surgery during the study • History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection • Previous or current treatment for thromboembolic disease or signs of thromboembolic disease • Any hereditary or acquired maternal condition that may predispose the patient to thrombotic events • Other diseases (e.g., certain autoimmune diseases) that may increase risk of bleeding or thrombosis • Known infection with HIV, hepatitis B virus, or hepatitis C virus • Serious infection requiring antibiotics or antiviral treatments within 14 days prior to screening • Concurrent disease, treatment, abnormality in clinical laboratory tests, vital signs measurements, or physical examination findings that could interfere with the conduct of the study or that would, in the opinion of the investigator or Sponsor, preclude the patient’s safe participation in and completion of the study or interpretation of the study results • Unwillingness of the parent or caregiver to allow receipt of blood or blood products, or any standard-of-care treatment for a life-threatening condition • Any other medical, social, or other condition that may prevent adequate compliance with the study protocol in the opinion of the investigator
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints: 1. Number of treated bleeds over time 2. Number of all bleeds over time 3. Number of treated spontaneous bleeds over time 4. Number of treated joint bleeds over time 5. Joint health, as assessed through use of the Hemophilia Joint Health Score (HJHS) and magnetic resonance imaging (MRI) score of specific joints at specified timepoints only during the 7-year LTFU period 6. Incidence and severity of adverse events, with severity determined according to WHO Toxicity Grading Scale 7. Incidence of thromboembolic events 8. Incidence of thrombotic microangiopathy (TMA) 9. Change from baseline in physical examination findings 10. Change from baseline in vital signs 11. Incidence of laboratory abnormalities 12. Incidence and severity of injection-site reactions 13. Incidence of adverse events leading to drug discontinuation 14. Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events 15. Plasma trough concentrations (Ctrough) of emicizumab prior to study drug administration 16. aPTT levels prior to study drug administration 17. Thrombin generation (TG) prior to study drug administration 18. Reported FVIII activity prior to study drug administration 19. FIX antigen and FX antigen (emicizumab substrates) levels prior to study drug administration
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-8. Up to 8 years 9-10. Baseline (Day 1) to 8 years 11-14. Up to 8 years 15-19. Every 2 weeks during Weeks 1-9 and every 4 weeks during Weeks 13-53
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
Immunogenecity, Biomarkers, Health Status Utility |
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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) | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Brazil |
Canada |
Israel |
South Africa |
Turkey |
United States |
Austria |
Belgium |
France |
Germany |
Italy |
Netherlands |
Spain |
Switzerland |
United Kingdom |
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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 | 9 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 9 |
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 |