E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild or moderate hemophilia A |
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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] - 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 | 10010331 - Congenital, familial and genetic disorders |
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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. Safety: To evaluate safety profile of emicizumab in patients with non-severe hemophilia A without inhibitors Primary Efficacy: To evaluate the efficacy of emicizumab on the basis of number of treated bleeds over time
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E.2.2 | Secondary objectives of the trial |
Secondary Efficacy: 1. To evaluate the efficacy of emicizumab on basis of number of all bleeds, joint bleeds over time, target joint bleeds over time, spontaneous bleeds over time, joint health, health-related quality of life, preference for emicizumab compared with previous FVIII treatment and effect of emicizumab prophylaxis on physical activity compared with physical activity at baseline and menstruation heaviness and menstruation-related quality of life in female patients.
Pharmacokinetic: 2. To characterize emicizumab pharmacokinetic profile
Immunogenicity: 3. To evaluate immune response to emicizumab
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Diagnosis of mild (FVIII level between > 5% and < 40%) or moderate (FVIII level between >= 1% and <= 5%) congenital Hemophilia A without FVIII inhibitors - Weight >= 3 kg - Need for prophylaxis based on investigator assessment - A negative test for inhibitor (i.e., < 0.6 BU/mL) within 8 weeks prior to enrollment - No documented inhibitor (i.e., < 0.6 BU/mL), FVIII half-life < 6 hours, or FVIII recovery < 66% in the last 5 years - Documentation of the details of prophylactic or episodic FVIII treatment and of number of bleeding episodes for at least the last 24 weeks prior to enrollment - Adequate hematologic hepatic and renal function - For women of childbearing potential: agreement to remain abstinent or use contraception during the treatment period and for at least 24 weeks after the final dose of study drug
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E.4 | Principal exclusion criteria |
Inherited or acquired bleeding disorder other than mild (FVIII level between > 5% and < 40%) or moderate (FVIII level between >= 1% and <= 5%) congenital hemophilia A - History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the investigator’s judgment - Previous (within the last 12 months) or current treatment for thromboembolic disease or signs of thromboembolic disease - Other conditions 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 - Planned surgery during the emicizumab loading dose phase Surgeries in patients on emicizumab from Week 5 onwards are allowed - Known HIV infection with CD4 counts < 200 cells/micro L - Concomitant disease, condition, significant abnormality on screening evaluation or laboratory tests, or treatment that could interfere with the conduct of the study, or that would in the opinion of the investigator, pose an additional unacceptable risk in administering study drug to the patient - Receipt of any of the following: o An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration with the exception of prior emicizumab prophylaxis o A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter o Any other investigational drug currently being administered or planned to be administered - Inability to comply with the study protocol in the opinion of the investigator - Pregnant or breastfeeding, or intending to become pregnant during the study - Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study drug
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety: 1.Incidence and severity of adverse events, with severity determined according to WHO Toxicity Grading Scale 2.Incidence of thromboembolic events and thrombotic microangiopathy 3.Incidence of laboratory abnormalities, injection-site reactions, adverse events leading to drug discontinuation, severe hypersensitivity, anaphylaxis, and anaphylactoid events 4.Change from baseline in physical examination findings, vital signs and ECG parameters Primary Efficacy: 5.Number of treated bleeds over time |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-3. From Screening (Day -28 to -1) to 24 weeks after final dose of emicizumab or Study completion/discontinuation 4. From baseline (Day [D]-28 to -1) to 24 weeks after final dose of emicizumab or Study completion/discontinuation
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E.5.2 | Secondary end point(s) |
Secondary Efficacy: 1.Number of all bleeds (i.e., those treated and untreated with FVIII), joint bleeds, target joint bleeds and spontaneous bleeds over time 2.Joint health, as assessed through use of the Hemophilia Joint Health Score at specified timepoints 3.Health-related quality of life, as assessed through use of the Comprehensive Assessment Tool of Challenges in Hemophilia Questionnaire over time 4.Preference for emicizumab compared with previous FVIII regimen, as assessed through use of the Emicizumab Preference Survey 5.Effect of emicizumab prophylaxis treatment on physical activity compared with physical activity at baseline Pharmacokinetic: 6. Effect of emicizumab prophylaxis treatment on menstruation heaviness and menstruation-related quality of life in female patients, as assessed through the use of the Menstrual Bleeding Questionnaire (MBQ) and the Menstruation Diary (MD) with the Pictorial Blood Assessment Chart (PBAC) Immunogenicity: 7.Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during the study 8.Number and proportion of patients who develop anti-FVIII inhibitors (titer>= 0.6 BU/mL) at specified timepoints
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At least 52 weeks 2. D-7 to -1, Week 25, 49, at every 24 weeks till Study extension phase, Study completion/discontinuation 3. Week 1, 13, 25, 37 and 49; at every 12 weeks (Q12W) untill Study Extension or Study completion/discontinuation 4. Week 17 5. Up to week 49 6. Day 1 and monthly thereafter until Study Extension or Study Completion/Discontinuation 7. Week 1-5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45 and 49, every Q12W until Study Extension or Study completion/discontinuation 8. Week 1, 5, 13, 25, 33, 41 and 49, every Q12W until Study Extension or Study completion/discontinuation 9. D-28 to -1, Week 1, 13, 25, 37 and 49, every Q12W until Study Extension or Study completion/discontinuation |
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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 | 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 | 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 |
Canada |
South Africa |
United Kingdom |
United States |
Belgium |
France |
Germany |
Italy |
Netherlands |
Poland |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |