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

Hemophilia A Clinical Trial

— ReITIrate  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03103542
• Other study ID #: Sobi.Elocta-003
• Secondary ID: 2017-000065-73
• Status: Completed
• Phase: Phase 4
• Start date: August 29, 2017
• Est. completion date: August 31, 2020

Study information

• Verified date: February 2022
• Source: Swedish Orphan Biovitrum
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: August 31, 2020
• Est. primary completion date: September 4, 2019
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A and older

Eligibility

Inclusion Criteria:

1. 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

2. Male patients of any age diagnosed with severe haemophilia A, as confirmed from the medical record

3. Previously treated with any plasma-derived or recombinant conventional or extended half-life FVIII

4. Diagnosed with high titer inhibitors (historical peak =5 Bethesda units (BU)/mL according to medical records)

5. Inhibitor titer >0.6 BU at screening

6. 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

7. All patients must practice effective contraception during the study and for 3 months after their last dose of study treatment

Exclusion Criteria:

1. Other coagulation disorder(s) in addition to haemophilia A

2. History of hypersensitivity reactions associated with any rFVIIIFc administration

3. High risk of cardiovascular, cerebrovascular, or other thromboembolic events, as judged by the investigator

4. 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.

5. 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

6. Abnormal renal function (serum creatinine >2.0 mg/dL) as assessed by local lab

7. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of normal (ULN) as assessed by local lab

8. Serum total bilirubin >3 × ULN as assessed by local lab

9. Cluster of differentiation 4 (CD4) lymphocytes =200 mm3 if known as HIV antibody positive at Screening

10. Viral load of =400 copies/mL if known HIV antibody positive at Screening

11. Patients with a documented history of alcohol or substance abuse within 12 months prior to randomization

12. Previous inclusion in this study

13. 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

14. Foreseeable inability to cooperate with given instructions or study procedures

15. 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

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Biological:
• Recombinant coagulation factor (rFVIIIFc)
rFVIIIFc 200 IU/kg/day during ITI Period and thereafter adjusted according to the Investigator's judgement administered intravenously.

Locations

Country	Name	City	State
Canada	Swedish Orphan Biovitrum Research Site	Hamilton
Canada	Swedish Orphan Biovitrum Research Site	Vancouver
Germany	Swedish Orphan Biovitrum Research Site	Bonn
Germany	Swedish Orphan Biovitrum Research Site	Frankfurt am Main
Germany	Swedish Orphan Biovitrum Research Site	Mörfelden-Walldorf
Ireland	Swedish Orphan Biovitrum Research site	Dublin
Slovenia	Swedish Orphan Biovitrum Research Site	Ljubljana
Sweden	Swedish Orphan Biovitrum Research site	Gothenburg
United Kingdom	Swedish Orphan Biovitrum Research Site	Birmingham
United Kingdom	Swedish Orphan Biovitrum Research Site	Liverpool
United Kingdom	Swedish Orphan Biovitrum Research Site	London
United States	Swedish Orphan Biovitrum Research Site	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Swedish Orphan Biovitrum	Bioverativ Therapeutics Inc.

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Ireland,  Slovenia,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Consumption of rFVIIIFc	Consumption will be assessed based on amount of administered study treatment during the ITI period.	Up to 60 weeks
Secondary	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
Secondary	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
Secondary	Number of Hospitalizations During ITI Treatment	Days of hospitalization will be collected by the Investigator at the study visits	up to 60 weeks
Secondary	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
Secondary	Adherence	Defined as percentage of administered doses versus planned doses	up to 108 weeks