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

Phase 4

Completed

Conditions: Hemophilia A

Interventions: Biological: Recombinant coagulation factor (rFVIIIFc)

Registration Number: NCT03103542

Lead Sponsor: Swedish Orphan Biovitrum

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 16

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Recombinant coagulation factor VIII Fc (rFVIIIFc)	Recombinant coagulation factor (rFVIIIFc)	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.

Primary Outcome Measures

Name	Time	Method
ITI Success	up to 60 weeks	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

Secondary Outcome Measures

Name	Time	Method
Time to ITI Success	up to 60 weeks	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.
Occurrence of Relapse During a 48-week Period Following Successful ITI Treatment	Up to 48 weeks	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
Number of Bleedings During ITI Treatment	up to 60 weeks	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.
Bleeding Rate During a 48-week Period Following Successful ITI Treatment	up to 48 weeks	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.
Adverse Events (AEs)	SAEs - approx 166 weeks AEs - approx 110 weeks	All observed adverse events as a measure of tolerability. (AE=adverse event, SAE=serious adverse event, TEAE=treatment emergent adverse event)
Consumption of rFVIIIFc	Up to 60 weeks	Consumption will be assessed based on amount of administered study treatment during the ITI period.
Number of Days Missed School or Work During ITI Treatment	up to 60 weeks	Days missed school or work will be registered by the patients in an electronic diary
Number of Days Missed School or Work During a 48-week Period Following Successful ITI Treatment	up to 48 weeks	Days missed school or work will be registered by the patients in an electronic diary
Number of Hospitalizations During ITI Treatment	up to 60 weeks	Days of hospitalization will be collected by the Investigator at the study visits
Number of Hospitalizations During a 48-week Period Following Successful ITI Treatment	Up to 48 weeks	Days of hospitalization will be collected by the Investigator at the study visits
Adherence	up to 108 weeks	Defined as percentage of administered doses versus planned doses