A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Participants From Birth to 12 Months of Age With Hemophilia A Without Inhibitors

Study Overview
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Brief Summary
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This is a Phase IIIb, multicenter, open-label, single-arm study of prophylactic emicizumab in previously untreated and minimally treated patients at study enrollment from birth to ≤12 months of age with severe hemophilia A (intrinsic factor VIII [FVIII] level <1%) without FVIII inhibitors. The study is designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab administered at 3 milligrams per kilogram of body weight (mg/kg) once every 2 weeks (Q2W) for 52 weeks. After 1 year of treatment, participants will continue to receive emicizumab (1.5 mg/kg once every week [QW], 3 mg/kg Q2W or 6 mg/kg once every 4 weeks [Q4W]) over a 7-year long-term follow-up period under this study frame.

Official Title
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A Phase IIIb, Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Patients From Birth to 12 Months of Age With Hemophilia A Without Inhibitors

Conditions
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Severe Hemophilia A

Intervention / Treatment
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* Drug: Emicizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age from birth to ≤12 months at time of informed consent Body weight ≥3 kilograms (kg) at time of informed consent. Patients with a lower body weight can be enrolled after they have reached a body weight of 3 kg. Premature babies (gestational age <38 weeks) may be enrolled as long as they have reached a body weight of 3 kg. For premature babies, the corrected gestational age should be reported. 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 No history of documented FVIII inhibitor (i.e., <0.6 BU/mL), FVIII drug-elimination half-life <6 hours, or FVIII recovery <66% Previously untreated patients or minimally treated patients (i.e., 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 intracranial hemorrhage, as confirmed by a negative cranial ultrasound at screening irrespective of delivery mode Adequate hematologic, hepatic, and renal function, as defined in the protocol For parents/caregivers: willingness and ability to comply with the study protocol requirements, scheduled visits, treatment plans, laboratory tests, completion of applicable questionnaires, and other study procedures 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: Prior use of emicizumab prophylaxis including investigational or commercial emicizumab; 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 intracranial hemorrhage Planned surgery (excluding minor procedures, e.g., circumcision, CVAD placement) during the study History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection Patients who are at high risk for thrombotic microangiopathy (TMA) (e.g., have a previous medical or family history of TMA, such as thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome) in the investigator's judgment Previous or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis in patients for whom anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease Any hereditary or acquired maternal condition that may predispose the patient to thrombotic events (e.g., inherited thrombophilias antiphospholipid syndrome) 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

Ages Eligible for Study
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Minimum Age: 0 Months
Maximum Age: 12 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Emicizumab<br> | Drug: Emicizumab<br>* Initially, all participants will receive 4 loading doses of 3 milligrams per kilogram (mg/kg) emicizumab subcutaneously (SC) once every week (QW) for 4 weeks followed by the maintenance dosing regimen 3 mg/kg emicizumab SC once every 2 weeks (Q2W) for a total of 52 weeks. Starting from Week 17 of treatment, individual participants may have their dose up-titrated to 3 mg/kg SC QW if they experience suboptimal bleeding control. At the Week 53 clinic visit following consultation with the treating physician, parents/caregivers may elect for their child to continue with the maintenance 3-mg/kg SC Q2W dosing regimen or to switch to the maintenance 1.5-mg/kg SC QW or 6-mg/kg SC once every 4 weeks (Q4W) dosing regimen for the subsequent 7-year long-term follow-up period. During the study, participants will be treated with emicizumab until unacceptable toxicity, discontinuation from the study due to any cause, or other criteria specified in the protocol, whichever occurs first.<br>* Other names: ACE910;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Model-Based Annualized Bleeding Rate for Treated Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Median Calculated Annualized Bleeding Rate for Treated Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Mean Calculated Annualized Bleeding Rate for Treated Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Model-Based Annualized Bleeding Rate for All Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Median Calculated Annualized Bleeding Rate for All Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Mean Calculated Annualized Bleeding Rate for All Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Model-Based Annualized Bleeding Rate for Treated Spontaneous Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Median Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Mean Calculated Annualized Bleeding Rate for Treated Spontaneous Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Model-Based Annualized Bleeding Rate for Treated Joint Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Median Calculated Annualized Bleeding Rate for Treated Joint Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 
| Mean Calculated Annualized Bleeding Rate for Treated Joint Bleeds |  | From Baseline to 52 weeks, and during 7-year long-term follow-up period until study completion (up to 8 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemophilia Joint Health Score (HJHS) Total Score at Specified Timepoints During the Long-Term Follow-Up Period |  | At 4, 5, 6, 7, and 8 years | 
| Magnetic Resonance Imaging (MRI) Score of Specific Joints at Specified Timepoints During the Long-Term Follow-Up Period |  | At 5 and 8 years | 
| Incidence and Severity of Adverse Events, with Severity Determined According to World Health Organization (WHO) Toxicity Grading Scale |  | From Baseline until study completion (up to 8 years) | 
| Incidence of Thromboembolic Events |  | From Baseline until study completion (up to 8 years) | 
| Incidence of Thrombotic Microangiopathy |  | From Baseline until study completion (up to 8 years) | 
| Incidence and Severity of of Injection Site Reactions, with Severity Determined According to WHO Toxicity Grading Scale |  | From Baseline until study completion (up to 8 years) | 
| Incidence of Severe Hypersensitivity, Anaphylaxis, and Anaphylactoid Events |  | From Baseline until study completion (up to 8 years) | 
| Incidence of Adverse Events Leading to Study Drug Discontinuation |  | From Baseline until study completion (up to 8 years) | 
| Incidence of Laboratory Abnormalities in Serum Chemistry and Hematology Tests |  | Baseline, Weeks 4, 13, 21, 29, 37, 45, and 53 | 
| Change from Baseline in Pulse Rate Over Time |  | Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) | 
| Change from Baseline in Respiratory Rate Over Time |  | Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) | 
| Change from Baseline in Body Temperature Over Time |  | Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) | 
| Change from Baseline in Systolic Blood Pressure Over Time |  | Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) | 
| Change from Baseline in Diastolic Blood Pressure Over Time |  | Baseline, Weeks 1, 2, 3, 4, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53, and annually during the 7-year follow-up period until study completion (up to 8 years) | 
| Plasma Trough Concentrations (Ctrough) of Emicizumab |  | Predose at Weeks 1, 3, 5, 7, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, and 53 | 
| Incidence of Anti-Emicizumab Antibodies |  | Weeks 1, 5, 17, 29, 41, and 53, and thereafter as clinically indicated until study completion (up to 8 years) | 
| Incidence of De Novo Development of Factor VIII Inhibitors |  | As clinically indicated from baseline until study completion (up to 8 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe hemophilia A Without Factor VIII Inhibitors