Immune Tolerance Induction in Haemophilia A Patients Using Wilate or Nuwiq (PREVAIL)

Immune Tolerance Induction in Haemophilia A Patients Using Wilate or Nuwiq - A Canadian Study

Uncontrolled, multi-centre, non-interventional study with a prospective and a retrospective cohort, to evaluate the efficacy of Wilate or Nuwiq in achieving complete or partial immune tolerance induction (ITI) success in severe and moderate haemophilia A patients with inhibitors

Study Overview

• Status: Terminated
• Conditions: Hemophilia A
• Intervention / Treatment: Drug: Wilate or Nuwiq

• Study Type: Observational
• Enrollment (Actual): 80

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • Stollery Children's Hospital, University of Alberta
  • Ontario
    • Ottawa, Ontario, Canada
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada
      • Hamilton Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

A total of at least 80 patients, including at least 40 evaluable haemophilia A patients with an inhibitor against FVIII in the prospective cohort and a maximum of 40 evaluable haemophilia A patients with an inhibitor against FVIII in the retrospective cohort.

Description

Inclusion Criteria:

• Male patients of any age with moderate or severe haemophilia A.
• Patients with a first occurrence of inhibitors, inhibitors refractory to previous ITI attempt(s), or relapsed inhibitors to FVIII, with an inhibitor titre of ≥0.6 BU measured on 2 separate occasions at least 2 weeks apart.
• Informed written consent from the patient and/or the patient's parent(s) or legal guardian(s)

For patients in the prospective cohort:

• Patients who are currently on Wilate or Nuwiq ITI, have just initiated ITI, or are planned to initiate ITI treatment with Wilate or Nuwiq.

For patients in the retrospective cohort:

• Patients having received Wilate or Nuwiq ITI before entry into this study. Retrospective data will be collected for a maximum of 3 years before enrolment into the study. To be eligible, the following information is needed:
• Wilate or Nuwiq treatment details (start date, dose, treatment frequency, and dose change).
• Reliably documented bleeding frequency.
• FVIII inhibitor titres.
• FVIII half-life.
• FVIII IVR.

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible for the study:

• Congenital or acquired bleeding disorders other than haemophilia A.
• A history of hypersensitivity to blood products and/or plasma-derived FVIII concentrates.
• Inability to speak/read English or French well enough to provide consent and adhere to the study.
• People who are receiving other non-factor therapies, e.g. concizumab

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Wilate or Nuwiq prospective cohort; Evaluable haemophilia A patients with an inhibitor against FVIII enrolled prospectively	Drug: Wilate or Nuwiq; Wilate or Nuwiq administered via intravenous injection; Other Names: Wilate: Human von Willebrand factor / human coagulation factor VIII. Nuwiq: recombinant factor VIII (rhFVIII)
Wilate or Nuwiq retrospective cohort; Evaluable haemophilia A patients with an inhibitor against FVIII enrolled retrospectively	Drug: Wilate or Nuwiq; Wilate or Nuwiq administered via intravenous injection; Other Names: Wilate: Human von Willebrand factor / human coagulation factor VIII. Nuwiq: recombinant factor VIII (rhFVIII)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of Wilate or Nuwiq in achieving complete or partial immune tolerance induction (ITI) success in moderate and severe haemophilia A patients with inhibitors	ITI success will be determined using predefined success criteria to analyze the proportion of patients achieving complete or partial ITI success. Complete success is defined by achieving all of the following variables: 1) Inhibitor titre <0.6BU (at least 2 separate blood samplings) assessed using the modified Bethesda assay; 2) Incremental in vivo recovery (IVR) of FVIII in the normal range (≥66% of normal); 3) FVIII half-life ≥6 hours Wilate or Nuwiq infusion. Partial success is defined as two of the three criteria being met, whilst partial response is defined as one of the three criteria being met. Partial failure is defined as none of the three criteria are met, but the inhibitor titre has decreased to <5 BU; complete failure is defined as none of the three criteria are met, and the inhibitor titre is still ≥5 BU.	A maximum period of 5 years from ITI start

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time necessary to achieve complete or partial ITI success	Time to achieve complete or partial ITI success will be determined using predefined success criteria. Complete success is defined by achieving all of the following variables: 1) Inhibitor titre <0.6 BU (at least 2 separate blood samplings) assessed using the modified Bethesda assay; 2) Incremental IVR of FVIII in the normal range (≥66% of normal) ; 3) FVIII half-life ≥6 hours. Wilate or Nuwiq infusion. Partial success is defined as two of the three criteria being met, whilst partial response is defined as one of the three criteria being met. Partial failure is defined as none of the three criteria are met, but the inhibitor titre has decreased to <5 BU; complete failure is defined as none of the three criteria are met, and the inhibitor titre is still ≥5 BU.	A maximum period of 5 years from ITI start
In case of complete or partial ITI success, duration of immune tolerance	Time from start of ITI success to end of study period	A maximum period of 5 years from ITI start
Bleeding frequency while on Wilate or Nuwiq ITI treatment	Bleeding episodes occurring during the study period will be documented by the patient or their parents in a patient study diary.	A maximum period of 5 years from ITI start
Association of inhibitor titres with the probability of ITI success	Inhibitor titre will be assessed at the start of and throughout ITI treatment, including peak inhibitor titres, with the probability of ITI success. ITI success will be determined using predefined success criteria. Complete success is defined by achieving all of the following variables: 1) Inhibitor titre <0.6 BU (at least 2 separate blood samplings) assessed using the modified Bethesda assay; 2) Incremental IVR of FVIII in the normal range (≥66% of normal) ; 3) FVIII half-life ≥6 hours. Wilate or Nuwiq infusion. Partial success is defined as two of the three criteria being met, whilst partial response is defined as one of the three criteria being met. Partial failure is defined as none of the three criteria are met, but the inhibitor titre has decreased to <5 BU; complete failure is defined as none of the three criteria are met, and the inhibitor titre is still ≥5 BU.	A maximum period of 5 years from ITI start
Use of bypassing agents before and during ITI treatment with Wilate or Nuwiq	Use of bypassing agents is at the discretion of the Investigator, either to treat bleeding or to provide prophylactic therapy. As long as the patient's inhibitor level is ≥0.6 Bethesda units (BU), treatment of BEs may, in addition to FVIII treatment, require the administration of activated prothrombin complex concentrates (aPCC) or recombinant FVIIa.	12 months before the start of ITI with Wilate or Nuwiq to a maximum of 5 years from starting ITI with Wilate or Nuwiq
Use of emicizumab (Hemlibra) during ITI treatment with Wilate or Nuwiq	The dosing and frequency of emicizumab (Hemlibra) used is at the discretion of the Investigator. As a general guidance, the recommended dose is 3mg/kg once weekly for the first 4 weeks, followed by 1.5mg/kg once weekly, administered as a subcutaneous injection, as per the product monograph.	A maximum period of 5 years from ITI start
Relapse rate following complete or partial successful ITI using Wilate or Nuwiq	Reoccurrence of >0.6 BU in at least 2 consecutive blood samples after having reached the prophylactic treatment phase; a further ITI initiation (re-start) with Wilate or Nuwiq is at the discretion of the Investigator.	A maximum period of 5 years from ITI start
Time to relapse following complete or partial successful ITI using Wilate or Nuwiq	Time to reoccurrence of >0.6 BU in at least 2 consecutive blood samples after having reached the prophylactic treatment phase; a further ITI initiation (re-start) with Wilate or Nuwiq is at the discretion of the Investigator.	A maximum period of 5 years from ITI start
Adherence with the ITI regimen	During ITI, any injections of Wilate or Nuwiq will be recorded in the patient study diary. The treating physician will review and verify the information provided by the patient.	A maximum period of 5 years from ITI start
Safety: adverse drug reactions (ADRs)	ADRs will be documented.	A maximum period of 5 years from ITI start
Safety: infection-related adverse events (AEs)	Any infection-related AEs, including central-line infections and infections leading to hospitalisation, will be documented.	A maximum period of 5 years from ITI start

Collaborators and Investigators

• Sponsor: Octapharma
• Investigators: Study Director: Sri Adapa, Octapharma

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2018
• Primary Completion (Actual): November 20, 2020
• Study Completion (Actual): November 20, 2020

Study Registration Dates

• First Submitted: November 8, 2017
• First Submitted That Met QC Criteria: November 14, 2017
• First Posted (Actual): November 17, 2017

Study Record Updates

• Last Update Posted (Actual): February 23, 2021
• Last Update Submitted That Met QC Criteria: February 22, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: WIL-26

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No