Immune Tolerance Induction in Haemophilia A Patients Using Wilate or Nuwiq

• Wilate or Nuwiq (Drug), also known as Wilate: Human von Willebrand factor / human coagulation factor VIII. Nuwiq: recombinant factor VIII (rhFVIII): Wilate or Nuwiq administered via intravenous injection

Primary outcomes

• Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success [From ITI start until termination of study, a maximum of 2 years]: 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 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.

Secondary outcomes

• Time Necessary to Achieve Complete or Partial ITI Success [A maximum period of 5 years from ITI start]: 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 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. 0 participants analysed for this outcome due to termination of study.
• In Case of Complete or Partial ITI Success, Duration of Immune Tolerance [A maximum period of 5 years from ITI start]: Time from start of ITI success to end of study period
• Bleeding Frequency While on Wilate or Nuwiq ITI Treatment [A maximum period of 5 years from ITI start]: Bleeding episodes occurring during the study period will be documented by the patient or their parents in a patient study diary.
• Association of Inhibitor Titres With the Probability of ITI Success [A maximum period of 5 years from ITI start]: 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.
• Use of Bypassing Agents Before and During ITI Treatment With Wilate or Nuwiq [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 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.
• Use of Emicizumab (Hemlibra) During ITI Treatment With Wilate or Nuwiq [A maximum period of 5 years from ITI start]: 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.
• Relapse Rate Following Complete or Partial Successful ITI Using Wilate or Nuwiq [A maximum period of 5 years from ITI start]: 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.
• Time to Relapse Following Complete or Partial Successful ITI Using Wilate or Nuwiq [A maximum period of 5 years from ITI start]: 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.
• Adherence With the ITI Regimen [A maximum period of 5 years from ITI start]: 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.

Sex: Male

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

Participant flow

Outcome results

• Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success (Primary), Count of participants, Participants: Wilate® Respective Cohort 7; Wilate® Prospective Cohort 0
• Time Necessary to Achieve Complete or Partial ITI Success (Secondary)
• In Case of Complete or Partial ITI Success, Duration of Immune Tolerance (Secondary)
• Bleeding Frequency While on Wilate or Nuwiq ITI Treatment (Secondary)
• Association of Inhibitor Titres With the Probability of ITI Success (Secondary)
• Use of Bypassing Agents Before and During ITI Treatment With Wilate or Nuwiq (Secondary)
• Use of Emicizumab (Hemlibra) During ITI Treatment With Wilate or Nuwiq (Secondary)
• Relapse Rate Following Complete or Partial Successful ITI Using Wilate or Nuwiq (Secondary)
• Time to Relapse Following Complete or Partial Successful ITI Using Wilate or Nuwiq (Secondary)
• Adherence With the ITI Regimen (Secondary)

Adverse events

Time frame: Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2021-10-08)

• Sri Adapa, Study director, Octapharma