Immune Tolerance Induction in Haemophilia A Patients Using Wilate or Nuwiq

Study Overview
=================
Brief Summary
-----------------
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

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

Conditions
-----------------
Hemophilia A

Intervention / Treatment
-----------------
* Drug: Wilate or Nuwiq


Participation Criteria
=================
Eligibility Criteria
-----------------
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
Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Wilate or Nuwiq prospective cohort<br>Evaluable haemophilia A patients with an inhibitor against FVIII enrolled prospectively | Drug: Wilate or Nuwiq<br>* Wilate or Nuwiq administered via intravenous injection<br>* Other names: Wilate: Human von Willebrand factor / human coagulation factor VIII. Nuwiq: recombinant factor VIII (rhFVIII);|
| Wilate or Nuwiq retrospective cohort<br>Evaluable haemophilia A patients with an inhibitor against FVIII enrolled retrospectively | Drug: Wilate or Nuwiq<br>* Wilate or Nuwiq administered via intravenous injection<br>* 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 |