E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe or Moderate Hemophilia A |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is an inherited bleeding disorder in which blood does not clot normally. People with hemophilia A will bleed more than normal for example after an injury, surgery, or dental procedure. |
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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 |
• To evaluate the impact of emicizumab treatment on joint health and health-related quality of life (HRQoL) outcomes of participants with hemophilia A as well as their physical activity |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of emicizumab
• To evaluate the immune response to emicizumab
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age >=13 and <70 years at time of signing Informed Consent Form
• Diagnosis of severe congenital hemophilia A (intrinsic FVIII level <1%) or moderate congenital hemophilia A (intrinsic FVIII level <=5%) if previously prescribed prophylaxis
• A negative test for FVIII inhibitor (i.e., <0.6 BU) within 8 weeks of enrollment
• Participants 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 hours, or FVIII recovery < 66% since completing ITI
• Participants who were on standard FVIII prophylaxis, defined as the regular administration of FVIII to prevent bleeding, for at least the last 24 weeks, can be enrolled regardless of the number of bleeds during this period
• Adequate hematologic, hepatic and renal function
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for at least 24 weeks after the final dose of emicizumab
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E.4 | Principal exclusion criteria |
• Inherited or acquired bleeding disorder other than severe congenital hemophilia A (intrinsic FVIII level <1%) or moderate congenital hemophilia A (intrinsic FVIII level <=5%) without FVIII inhibitors who were previously prescribed prophylaxis for at least 24 weeks
• Participants who have previously received emicizumab prophylaxis
• Participants who had joint replacement, joint procedure, synovectomy or synoviorthesis less than 5 years ago, or participants who had joint replacement, joint procedure, synovectomy or synoviorthesis more than 5 years ago but are still experiencing pain in the joint (only the specific joint will be excluded from the study), or participants that plan to have joint replacement, joint procedure, synovectomy or synoviorthesis, or participants that are deemed suitable candidates for joint replacement, joint procedure, synovectomy or synoviorthesis at screening
• Participants who have conditions other than hemophilia A that can affect joint health and structure (e.g., osteoarthritis) or with severely impaired mobility due to conditions other than hemophilia A
• Participants with reduced bone mineral density defined as clinically relevant vitamin D deficiency
• Participants with pre-existing cardiovascular disease not receiving controlled and targeted medication or in a stable condition
• Participants not eligible for MRI
• History of illicit drug or alcohol abuse within 48 weeks prior to screening
• Participants who are at high risk for thrombotic microangiopathy (TMA)
• Previous (within the last 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 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
• Planned surgery during the emicizumab loading dose phase. Surgeries in participants on emicizumab from Week 5 onwards are allowed
• Known HIV infection not controlled by medication
• 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 participant
• 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 at screening
o A non-hemophilia-related investigational drug within last 30 days
or 5 half-lives at screening, whichever is shorter
o Any other investigational drug currently being administered or
planned to be administered
• Inability to comply with the study protocol
• Pregnant or breastfeeding, or intending to become pregnant during the study
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Joint status over time based on centrally reviewed Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) scores with a specific focus on the synovitis score in participants with synovitis
2. Clinical joint status over time based on the Hemophilia Joint Health Score (HJHS v2.1), excluding gait assessment
3. Joint status at screening and month 36 based on centrally reviewed International Prophylaxis Study Group (IPSG) score (with MRI)
4. Number of problem joints and proportion of problem joints, defined as joints having chronic joint pain and/or limited range of movement due to compromised joint integrity (i.e., chronic synovitis and/or hemophilic arthropathy) with or without persistent bleeding, over time
5. Number of target joint bleeds over time (target joints are defined as joints with >=3 bleeds occurring in the same joint during the last 24 weeks)
6. HRQoL, as assessed through use of the Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH) Questionnaire over time
7. Change in the level of physical activity during the study as measured with a wearable activity tracker (Fitbit)
8. Change in daily step count, active minutes metabolic equivalents of tasks (METs), moderate to vigorous physical activity (MVPA; as per activity tracker default categorization), and type of physical activities
9. Change in the time and intensity level of physical activity as measured by the International Physical Activity Questionnaire Short Format (IPAQ-SF)
10. Number of all bleeds (i.e., those treated and untreated with FVIII), treated bleeds, spontaneous bleeds, joint bleeds, treated joint bleeds, and target joint bleeds (i.e., bleed rate) over time (ABR) as assessed through use of the Bleed and Medication Questionnaire (BMQ)
11. Participant and/or caregiver preference for emicizumab compared with previous FVIII regimen, as assessed through use of the Emicizumab Preference Survey (EmiPref) at month 6
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-2. At Screening (Day -28 to Day -1), Months 6, 12, 24 and 36
3. At Screening (Day -28 to Day -1) and Month 36
4. At Months 6, 12, 24 and 36
5. Up to 36 months
6. At Baseline (Day 1), Months 3, 6, 12, 18, 24, and 36
7-8. Until Month 36
9. At Baseline (Day 1), Months 3, 6, 12, 18, 24, and 36
10. Until Month 36
11. At Month 6
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E.5.2 | Secondary end point(s) |
1. Incidence and severity of adverse events, with severity determined according to World Health Organization (WHO) toxicity scale
2. Incidence of thromboembolic events
3. Incidence of thrombotic microangiopathy
4. Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events
5. Incidence and severity of injection-site reactions
6. Prevalence of anti-drug antibodies (ADAs) against emicizumab at baseline and incidence of ADAs against emicizumab during the study
7. Number and proportion of participants 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 |
1-5. Until 24 weeks (Safety Follow-up) after the final dose of emicizumab
6. At Baseline (Day 1), Months 6, 12, 24 and 36
7. Up to 36 months
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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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | 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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 27 |
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 |
Brazil |
Canada |
Morocco |
Russian Federation |
Serbia |
Tunisia |
Turkey |
United States |
Germany |
Hungary |
Ireland |
Italy |
United Kingdom |
Spain |
Switzerland |
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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 | 3 |
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 | 3 |
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 |