A Study to Test a Medicine (Fitusiran) for Preventing Bleeds in People With Severe Hemophilia Who Previously Received Preventive Treatment With Emicizumab

Study Overview
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Brief Summary
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This is an exploratory, single group, Phase 1, 1-arm study to assess treatment with fitusiran prophylaxis after switching from emicizumab prophylaxis. This study aims to evaluate the safety and tolerability of switching to fitusiran after a transition period from the last dose of emicizumab. The study will be conducted in male participants with severe hemophilia A, with or without inhibitors, aged ≥18 years, who were previously receiving emicizumab prophylaxis. Study details include: The study duration will be up to approximately 28 months: There will be an approximately 2-month screening period. There will be a transition period before fitusiran treatment starts (pre-fitusiran treatment period) The fitusiran treatment duration will be up to 18-months (fitusiran treatment period) The antithrombin (AT) follow-up (FU) period will be up to 6 months after the last dose of fitusiran (during which the AT activity level will be monitored at approximately monthly intervals following the final fitusiran dose until AT activity levels return to at least 60%). The study site visits are scheduled at monthly/ every 2 months intervals of 28 days (4 weeks) / 56 days (8 weeks), respectively, during the fitusiran treatment period.

Official Title
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An Open-label, Single-arm Treatment Study to Investigate the Safety and Tolerability of Switching From Emicizumab to Fitusiran Prophylaxis in Male Participants Aged ≥18 Years of Age With Severe Hemophilia A, With or Without Inhibitors

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: Fitusiran (SAR439774)
* Biological: Clotting factor concentrates (CFC) or bypassing agents (BPA)
* Biological: Antithrombin concentrate (ATIIIC)
* Biological: Emicizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Male participants must be ≥18 years of age inclusive, at the time of signing the informed consent Diagnosis of severe congenital hemophilia A (FVIII < 1%) as evidenced by a central laboratory measurement at screening or documented medical record evidence. Inhibitor titer of ≥0.6 BU/mL at Screening, or Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 2 consecutive titers ≥0.6 BU/mL, or Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of anamnestic response. Participants who are currently on the full labeled dose of emicizumab prophylaxis, irrespective of inhibitor/non-inhibitor status. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF XE  ICF  \f Abbreviation \t informed consent form ) and in this protocol. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Known coexisting bleeding disorders History of antiphospholipid antibody syndrome. History of arterial or venous thromboembolism, atrial fibrillation, significant valvular disease, myocardial infarction, angina, transient ischemic attack, or stroke. Participants who have experienced thrombosis associated with indwelling venous access may be enrolled. Presence of clinically significant liver disease Current or prior participation in a fitusiran trial Current or prior participation in a gene therapy trial AT activity <60% at Screening, as determined by central laboratory measurement Coexisting thrombophilic disorder - Hepatitis C virus antibody positive, except participants who have negative Hepatitis C viral load and no evidence of cirrhosis Presence of acute hepatitis, ie, hepatitis A, hepatitis E. Presence of acute or chronic hepatitis B infection Known to be HIV positive with CD4 count <200 cells/μL. Reduced renal function The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: fitusiran<br>The pre-fitusiran treatment period is defined as the transition period up to the first fitusiran administration. Participants will receive on demand or prophylactic treatment with intravenous clotting factor concentrates (IV CFCs) or bypassing agents (BPAs) from Month-2 until Day 1. Fitusiran treatment period: Participants will receive subcutaneous (SC) fitusiran prophylaxis once every 2 months (Q2M) or once monthly (QM) from Day 1 until Month18. Participants may receive IV antithrombin concentrate (ATIIIC) upon investigator's judgement. AT FU period: Participants will be followed up until AT activity levels recover to at least 60% (per central laboratory). In case of bleeding events participants will receive IV CFCs or BPAs. Participants may receive IV ATIIIC upon investigator's judgement. | Drug: Fitusiran (SAR439774)<br>* Pharmaceutical form:Solution for injection-Route of administration:Subcutaneous (SC) injection<br>* Other names: SAR439774;Biological: Clotting factor concentrates (CFC) or bypassing agents (BPA)<br>* Pharmaceutical form: Solution for injection-Route of administration: Intravenous (IV) injection<br>Biological: Antithrombin concentrate (ATIIIC)<br>* Pharmaceutical form:Solution for injection-Route of administration:Intravenous (IV) injection<br>Biological: Emicizumab<br>* Pharmaceutical form:Solution for injection-Route of administration:SC injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse events (AEs) during the fitusiran treatment | Incidence, severity, and seriousness, of AEs occurred during fitusiran treatment period will be reported | From Day 1 up to Month 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The peak thrombin generation (TG) - pre fitusiran treatment | Central laboratory assessments (peak TG) will be reported for pre-fitusiran period | From Month -2 up to Day 1 | 
| The peak TG during fitusiran treatment | Central laboratory assessments (peak TG) will be reported for fitusiran treatment period | From Day 1 up to Month 4 | 
| The peak antithrombin (AT) levels during pre-fitusiran treatment | Central laboratory assessments (peak AT) will be reported for pre-fitusiran treatment period | From Month -2 up to Day 1 | 
| The peak AT levels during fitusiran prophylaxis | Central laboratory assessments (peak AT) will be reported for fitusiran treatment | From Day 1 up to Month 4 | 
| Emicizumab concentrations in plasma | Emicizumab concentrations in plasma will be reported | Up to Month 4 of fitusiran treatment | 
| Number of participants with AEs from Day 1 to Month 18 of fitusiran treatment | Incidence, severity, and seriousness of AEs will be reported | From Day 1 up to Month 18 | 
| Change in participants' overall treatment satisfaction during the fitusiran treatment period assessed via the Treatment Satisfaction Questionnaire for Medication (TSQM-9) domain scores | The three domains of effectiveness, convenience, and global satisfaction will be reported | From approximately Month -2 to Month 19 [end of study (EoS) visit] | 
| Participants' treatment preferences (via the Preference Questionnaire) | The Preference questionnaire Data will be reported | At Month 12 | 
| Change in participants' pain intensity during the fitusiran treatment period (via the PROMIS v2.0 Pain Intensity 3a questionnaire) over time | The data for participants' pain intensity via PROMIS v2.0 Pain Intensity 3a questionnaire will be reported | From approximately Month - 2 to Month 19 (EoS) visit | 
| Change in participants' physical functioning and physical activity during the fitusiran treatment period (via the International Physical Activity Questionnaire [IPAQ]) over time | Participants' physical functioning and physical activity data during the fitusiran treatment period will be collected via the International Physical Activity Questionnaire and reported | From approximately Month - 2 to Month 19 (EoS) visit | 
| Change in participants' joint health (via the Hemophilia Joint Health Score [HJHS]) during the fitusiran treatment period over time | HJHS during the fitusiran treatment period will be reported | From approximately Month - 2 to Month 19 (EoS) visit | 
| Annualized Bleeding Rate (ABR) while receiving fitusiran prophylaxis | The frequency of treated bleeding episodes will be reported | From Month 4 up to Month 18 (14-month extension period) |