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 genetic deficiency of blood clotting factor VIII (FVIII), which causes increased bleeding. |
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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 |
There is no formal hypothesis testing in this study:
Expansion phase: Efficacy objectives •To evaluate the efficacy of prophylactic emicizumab in maintaining adequate control of bleeding •To evaluate the clinical effect of prophylactic emicizumab on the number of joint bleeds over time, target joint bleeds over time, all bleeds over time, spontaneous bleeds over time •To evaluate the health-related quality of life, health status and patient preference
Safety Objectives •To evaluate the overall safety of emicizumab given Q4W in patients with hemophilia A Pharmacokinetic Objective •To characterize the pharmacokinetics of multiple Q4W doses of 6mg/kg emicizumab |
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E.2.2 | Secondary objectives of the trial |
Please note, there is no formal hypothesis testing in this study
Run-in phase objectives: •To investigate the pharmacokinetics (PK) of emicizumab after single and multiple (every 4 weeks [Q4W]) subcutaneous (SC) administration of 6 milligram per Kilogram (mg/kg) •To assess the safety and tolerability of emicizumab after Q4W SC administration of 6 mg/kg •To explore the prophylactic effect of emicizumab in maintaining adequate control of bleeding •To investigate the effect of emicizumab on pharmacodynamic (PD) markers including (but not limited to) activated partial thromboplastin time, thrombin generation, and factor VIII (FVIII) activity |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Aged >=12 years •Body weight >= 40 kg at screening •Have severe congenital hemophilia A or hemophilia A with FVIII inhibitors •Patients using rFVIIa or willing to switch to rFVIIa as primary bypassing agent for the treatment of breakthrough bleeds •FVIII inhibitor test during screening with titer results available prior to first administration of study drug •Patients without FVIII inhibitors (< 0.6 Bethesda Units [BU]/milliliter [mL], < 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL) who completed successful immune tolerance induction (ITI) must have done so at least 5 years before screening and must have no evidence of inhibitor recurrence (permanent or temporary) indicated by detection of an inhibitor > 0.6 BU/mL (> 1.0 BU/mL only for laboratories with an historical sensitivity cutoff for inhibitor detection of 1.0 BU/mL) since ITI •For patients to be enrolled into PK run-in cohort: Current episodic treatment (FVIII or bypassing agents) at the time of entry into this study and documentation of details of episodic treatment for at least 24 weeks prior to entry into this study •For patients to be enrolled into the expansion cohort: Documentation of details of prophylactic or episodic treatment and the number of bleeding episodes for at least 24 weeks prior to entry into this study. For patients on an episodic regimen, >= 5 bleeds in the prior 24 weeks, regardless of inhibitor status •For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods that result in a failure rate of < 1percent per year during the treatment period and for at least 5 elimination half-lives (24 weeks) after the last dose of study drug •Adequate values of hematologic, hepatic, and renal function tests
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E.4 | Principal exclusion criteria |
•Inherited or acquired bleeding disorder other than hemophilia A •Ongoing or planned ITI therapy; patient in whom ITI has failed will be eligible with a 72-hour washout period prior to the first emicizumab administration •History of illicit drug or alcohol abuse within 48 weeks prior to screening •Patients who are at high risk for thrombotic microangiopathy (TMA) (e.g., have a previous medical or family history of TMA), in the investigator’s judgment •Previous (within the last 12 months) or current treatment for thromboembolic disease or signs of thromboembolic disease •Other conditions (e.g., certain autoimmune diseases) that may currently increase the risk of bleeding or thrombosis •History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection •Known HIV infection with cluster of differentiation 4 (CD4) counts < 200 cells/microliter (μL) (CD4 counts >= 200 cell/μL will be permitted) •Use of systemic immunomodulators (e.g., interferon) at enrollment or planned use during the study, with the exception of anti-retroviral therapy •Concomitant disease, condition, significant abnormality on screening evaluations or laboratory tests, or treatment that could interfere with the conduct of the study or pose an additional unacceptable risk in administering study drug to the patient •Women with a positive serum pregnancy test or pregnant/lactating women •Receipt of any of the following: emicizumab in a prior investigational study, an investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration, a non hemophilia related investigational drug within last 30 days or 5 half-lives, whichever is shorter, and any other investigational drug currently being administered or planned to be administered |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: (Expansion phase) 1.Number of bleeds over time 2.Number of joint bleeds over time 3.Number of target joint bleeds over time 4.Number of spontaneous bleeds over time 5.Number of all bleeds over time (treated and untreated) 6.HRQoL of patients according to Haem-A-QoL (>= 18years) or Haemo-QoL_SF (ages 12−17 years) scores after 24 weeks 7.EQ-5D-5L scores after 24 weeks 8.Patient preference (Preference Survey) 9.Number of bleeds over time compared with the patient’s historical bleed rate over the last 24 weeks prior to study entry 10.Number of days away from school/work 11.Number of days hospitalized
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-4. Day 1 to study completion (24 weeks after emicizumab stop OR transfer to other emicizumab trial OR withdrawal) 5-6. Week 1, 13, 25, then every 12 weeks until study completion (24 weeks after emicizumab stop OR transfer to other emicizumab trial OR withdrawal) 7-9. Day 1 to study completion (24 weeks after emicizumab stop OR transfer to other emicizumab trial OR withdrawal)
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E.5.2 | Secondary end point(s) |
PK endpoints: (Run-in and expansion phase) 1.Time to maximum observed plasma concentration 2.Area under the plasma concentration (AUC)-time curve over a dosing interval 3.Pre-dose (trough) plasma concentrations of emicizumab (Expansion phase)
Safety endpoints: (Run-in and expansion phase) 4.Incidence and severity of adverse events 5.Incidence and severity of thromboembolic events 6.Changes in physical examination findings and vital signs 7.Incidence of laboratory abnormalities 8.Incidence and severity of injection-site reactions 9.Incidence of adverse events leading to drug discontinuation 10.Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events 11.Incidence of thrombotic microangiopathy 12.Incidence of clinically significant levels of anti-emicizumab antibodies 13.Incidence of de novo development of FVIII inhibitors (non-inhibitor population)
Efficacy endpoint (Run-in phase): 14.Maintaining adequate control of bleeding
Pharmacodynamics (Run-in and expansion phase) 15.PD marker analyses
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Day 1 until study completion (24 weeks after emicizumab stop OR transfer to other emicizumab trial OR withdrawal) 4-14. Up to study completion (24 weeks after emicizumab stop OR transfer to other emicizumab trial OR withdrawal) 15. Day 1 until study completion (24 weeks after emicizumab stop OR transfer to other emicizumab trial OR withdrawal)
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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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Belgium |
Germany |
Japan |
Poland |
Russian Federation |
Spain |
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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 | 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 | 5 |
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 | 0 |