Study of rFVIIIFc for Immune Tolerance Induction (ITI) in Haemophilia A Patients With Inhibitors Who Have Failed Previous ITI Therapies

Study Overview
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Brief Summary
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The primary purpose of this study is to describe the outcome of Immune Tolerance Induction (ITI) treatment performed with rFVIIIFc within a timeframe of 60 weeks in patients with haemophilia A who have failed previous attempts at tolerization.

Detailed Description
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This is an open-label, single-arm, interventional multi-center study designed to explore ITI performed with recombinant coagulation factor VIII Fc fusion protein (rFVIIIFc) within a timeframe of 60 weeks in patients with severe haemophilia A, who have failed previous attempts at tolerization including use of immunosuppressants.

Official Title
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A Non-Controlled, Open-Label, Multicenter, Study of Immune Tolerance Induction Performed With rFVIIIFc Within a Timeframe of 60 Weeks in Severe Haemophilia A Patients With Inhibitors Who Have Failed Previous Immune Tolerance Induction Therapies

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: Recombinant coagulation factor (rFVIIIFc)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent provided by the patient, or the patient's legally authorized representative for patients under the legal age. Assent should be obtained from pediatric patients according to local regulations Male patients of any age diagnosed with severe haemophilia A, as confirmed from the medical record Previously treated with any plasma-derived or recombinant conventional or extended half-life FVIII Diagnosed with high titer inhibitors (historical peak ≥5 Bethesda units (BU)/mL according to medical records) Inhibitor titer >0.6 BU at screening Failed previous ITI attempt(s) with any plasma-derived or recombinant conventional or extended half-life FVIII including the use of immunosuppressant The attempt should be documented in the medical records and have the following characteristics: A minimum FVIII dose equivalent to the low dose arm of the International ITI study (50 IU/kg, 3 times/week) A minimum ITI treatment period of 33 months or Shorter than 33 months if no downward trend of at least 20% in the inhibitor titer in a 6-month period after the initial 3 months of the ITI treatment All patients must practice effective contraception during the study and for 3 months after their last dose of study treatment Exclusion Criteria: Other coagulation disorder(s) in addition to haemophilia A History of hypersensitivity reactions associated with any rFVIIIFc administration High risk of cardiovascular, cerebrovascular, or other thromboembolic events, as judged by the investigator Planned major surgery to be deferred after study completion. Minor surgery such as tooth extraction or insertion/replacement of central venous access device is allowed. Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to screening. Exceptions to this include: ribavirin for treatment of Hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days within 12 weeks prior to Day 1) and/or inhaled steroids Abnormal renal function (serum creatinine >2.0 mg/dL) as assessed by local lab Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of normal (ULN) as assessed by local lab Serum total bilirubin >3 × ULN as assessed by local lab Cluster of differentiation 4 (CD4) lymphocytes ≤200 mm3 if known as HIV antibody positive at Screening Viral load of ≥400 copies/mL if known HIV antibody positive at Screening Patients with a documented history of alcohol or substance abuse within 12 months prior to randomization Previous inclusion in this study Participation in another concurrent clinical interventional study within 30 days of screening or intake of an investigational drug within five half-lives of that investigational drug has passed Foreseeable inability to cooperate with given instructions or study procedures Presence of any medical or psychological condition or laboratory result that in the opinion of the investigator can interfere with the patient's ability to comply with the protocol requirements or makes the patient not appropriate for inclusion to the study and treatment with rFVIIIFc
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: Recombinant coagulation factor VIII Fc (rFVIIIFc)<br>Participants will receive rFVIIIFc at a dose of 200 international units (IU)/kilogram (kg) as once daily injections or divided on several injections per day at the discretion of the Investigator, starting at baseline visit up to maximum of 60 Weeks during the ITI Period. Participants who meet the criteria for ITI success will enter a tapering period of 16 weeks where the dose will be tapered down until a prophylactic dose, as judged by the Investigator, is achieved and thereafter a follow-up period of 32 weeks where the patient will continue to receive prophylactic treatment with rFVIIIFc. | Biological: Recombinant coagulation factor (rFVIIIFc)<br>* rFVIIIFc 200 IU/kg/day during ITI Period and thereafter adjusted according to the Investigator's judgement administered intravenously.<br>* Other names: ELOCTATE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ITI Success | Number of patients who achieve ITI success where ITI success is defined as achieving all 3 of the following criteria: Negative titer for inhibitor (<0.6 Bethesda units/mL by the Nijmegen-modified Bethesda assay) at 2 consecutive visits FVIII incremental recovery (IR) >66% of the expected IR at 2 consecutive visits FVIII half-life (t½) ≥7 hours | up to 60 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to ITI Success | Time to the patient reaches ITI success according to the pre-defined criteria For the subset of patients who were classified as partial success at the end of the ITI period, the time to fulfillment of the criteria for partial success was also analyzed descriptively. | up to 60 weeks | 
| Occurrence of Relapse During a 48-week Period Following Successful ITI Treatment | Relapse was defined as a positive inhibitor (≥0.6 BU/mL) on 2 consecutive assessments and incremental recovery ≤66 % of the expected incremental recovery on 2 consecutive assessments | Up to 48 weeks | 
| Number of Bleedings During ITI Treatment | Only bleeds requiring treatment with rFVIIIFc or bypassing agents should be registered. A bleeding episode starts from the first sign of a bleed and ends no more than 72 hours after the last injection of bypassing agents or rFVIIIFc to treat the bleeding episode. | up to 60 weeks | 
| Bleeding Rate During a 48-week Period Following Successful ITI Treatment | Only bleeds requiring treatment with rFVIIIFc or bypassing agents should be registered. A bleeding episode starts from the first sign of a bleed and ends no more than 72 hours after the last injection of bypassing agents or rFVIIIFc to treat the bleeding episode. | up to 48 weeks | 
| Adverse Events (AEs) | All observed adverse events as a measure of tolerability. (AE=adverse event, SAE=serious adverse event, TEAE=treatment emergent adverse event) | SAEs - approx 166 weeks AEs - approx 110 weeks | 
| Consumption of rFVIIIFc | Consumption will be assessed based on amount of administered study treatment during the ITI period. | Up to 60 weeks | 
| Number of Days Missed School or Work During ITI Treatment | Days missed school or work will be registered by the patients in an electronic diary | up to 60 weeks | 
| Number of Days Missed School or Work During a 48-week Period Following Successful ITI Treatment | Days missed school or work will be registered by the patients in an electronic diary | up to 48 weeks | 
| Number of Hospitalizations During ITI Treatment | Days of hospitalization will be collected by the Investigator at the study visits | up to 60 weeks | 
| Number of Hospitalizations During a 48-week Period Following Successful ITI Treatment | Days of hospitalization will be collected by the Investigator at the study visits | Up to 48 weeks | 
| Adherence | Defined as percentage of administered doses versus planned doses | up to 108 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ITI, rFVIIIFc, Immune Tolerance Induction