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

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ClinicalTrials.gov Identifier: NCT03103542
Recruitment Status : Completed
First Posted : April 6, 2017
Results First Posted : November 30, 2021
Last Update Posted : November 30, 2021
Sponsor:
Collaborator:
Bioverativ Therapeutics Inc.
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Hemophilia A Biological: Recombinant coagulation factor (rFVIIIFc) Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 29, 2017
Actual Primary Completion Date : September 4, 2019
Actual Study Completion Date : August 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: Recombinant coagulation factor VIII Fc (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.
Biological: Recombinant coagulation factor (rFVIIIFc)

rFVIIIFc 200 IU/kg/day during ITI Period and thereafter adjusted according to the Investigator's judgement

administered intravenously.

Other Names:
  • ELOCTA
  • ELOCTATE




Primary Outcome Measures :
  1. ITI Success [ Time Frame: 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 :
  1. Time to ITI Success [ Time Frame: 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.


  2. Occurrence of Relapse During a 48-week Period Following Successful ITI Treatment [ Time Frame: 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

  3. Number of Bleedings During ITI Treatment [ Time Frame: 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.

  4. Bleeding Rate During a 48-week Period Following Successful ITI Treatment [ Time Frame: 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.

  5. Adverse Events (AEs) [ Time Frame: 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)

  6. Consumption of rFVIIIFc [ Time Frame: Up to 60 weeks ]
    Consumption will be assessed based on amount of administered study treatment during the ITI period.

  7. Number of Days Missed School or Work During ITI Treatment [ Time Frame: up to 60 weeks ]
    Days missed school or work will be registered by the patients in an electronic diary

  8. Number of Days Missed School or Work During a 48-week Period Following Successful ITI Treatment [ Time Frame: up to 48 weeks ]
    Days missed school or work will be registered by the patients in an electronic diary

  9. Number of Hospitalizations During ITI Treatment [ Time Frame: up to 60 weeks ]
    Days of hospitalization will be collected by the Investigator at the study visits

  10. Number of Hospitalizations During a 48-week Period Following Successful ITI Treatment [ Time Frame: Up to 48 weeks ]
    Days of hospitalization will be collected by the Investigator at the study visits

  11. Adherence [ Time Frame: up to 108 weeks ]
    Defined as percentage of administered doses versus planned doses



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03103542


Locations
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United States, District of Columbia
Swedish Orphan Biovitrum Research Site
Washington, District of Columbia, United States, 20010-2970
Canada
Swedish Orphan Biovitrum Research Site
Hamilton, Canada
Swedish Orphan Biovitrum Research Site
Vancouver, Canada
Germany
Swedish Orphan Biovitrum Research Site
Bonn, Germany
Swedish Orphan Biovitrum Research Site
Frankfurt am Main, Germany
Swedish Orphan Biovitrum Research Site
Mörfelden-Walldorf, Germany
Ireland
Swedish Orphan Biovitrum Research site
Dublin, Ireland
Slovenia
Swedish Orphan Biovitrum Research Site
Ljubljana, Slovenia, 1000
Sweden
Swedish Orphan Biovitrum Research site
Gothenburg, Sweden, 41345
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 Kingdom, WC1N 3JH
Sponsors and Collaborators
Swedish Orphan Biovitrum
Bioverativ Therapeutics Inc.
Investigators
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Study Director: Stefan Lethagen, MD, PhD Study Medical Director
  Study Documents (Full-Text)

Documents provided by Swedish Orphan Biovitrum:
Study Protocol  [PDF] February 26, 2018
Statistical Analysis Plan  [PDF] October 22, 2020

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Responsible Party: Swedish Orphan Biovitrum
ClinicalTrials.gov Identifier: NCT03103542    
Other Study ID Numbers: Sobi.Elocta-003
2017-000065-73 ( EudraCT Number )
First Posted: April 6, 2017    Key Record Dates
Results First Posted: November 30, 2021
Last Update Posted: November 30, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: According to Sobi's data sharing policy Sobi may share anonymized clinical study data with qualified researchers. Sobi commits to sharing clinical study data on participant level and summary data for medicines and indications approved by EMA and/or FDA. Data access will be granted in response to qualified research requests. All requests are evaluated by a cross functional panel of experts within Sobi.
Time Frame: Evaluated on a case by case basis
Access Criteria:

A decision on data sharing will be based on the following:

  • The scientific merit of the proposal - i.e. the proposal should be scientifically sound, ethical, and have the potential to contribute to the advancement of public health.
  • The feasibility of the research proposal - i.e. the requesting research team must be scientifically qualified and have the resources to conduct the proposed project.
  • Maintenance of personal integrity - i.e. Sobi will not consider sharing individual data if there is a risk of re-identification of individuals despite a proper anonymisation. Moreover, the patients' informed consent will always be respected. Sobi reserves the right to reject the proposal if the anonymisation process will render unusable data.
  • Publication of results - the applicants should commit to submit their findings to a peer-reviewed scientific journal, alternatively to present the results at a congress (poster or similar), regardless of the research outcome
URL: https://www.sobi.com/en/policies

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Swedish Orphan Biovitrum:
ITI
rFVIIIFc
Immune Tolerance Induction
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn