Hemophilia A
Conditions
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
Interventions
DRUGWilate or Nuwiq
Wilate or Nuwiq administered via intravenous injection
Sponsors
Octapharma
Study design
Observational model
COHORT
Time perspective
OTHER
Eligibility
Sex/Gender
MALE
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Wilate® Retrospective Cohort The population consists of all patients who had received Wilate immune tolerance induction (ITI) therapy within 3 years of enrolment. | 8 |
| Wilate® Prospective Cohort The population consists of all patients who were currently on Wilate ITI, had just initiated ITI, or were planned to initiate ITI treatment with Wilate. | 6 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Experienced a better response with recombinant activated factor VII (rFVIIa) | 1 | 0 |
| Overall Study | Switched to alternative treatment | 1 | 0 |
Baseline characteristics
| Characteristic | Wilate® Prospective Cohort | Total | Wilate® Retrospective Cohort |
|---|---|---|---|
| Age, Continuous | 14.8 years STANDARD_DEVIATION 7.3 | 12.4 years STANDARD_DEVIATION 6.1 | 10.6 years STANDARD_DEVIATION 5.2 |
| Blood type A | 2 Participants | 4 Participants | 2 Participants |
| Blood type AB | 2 Participants | 3 Participants | 1 Participants |
| Blood type B | 0 Participants | 1 Participants | 1 Participants |
| Blood type Missing | 0 Participants | 1 Participants | 1 Participants |
| Blood type O | 2 Participants | 5 Participants | 3 Participants |
| FVIII mutation Intron 1 Inversion | 0 Participants | 1 Participants | 1 Participants |
| FVIII mutation Intron 22 Inversion | 3 Participants | 6 Participants | 3 Participants |
| FVIII mutation Missense mutations | 1 Participants | 1 Participants | 0 Participants |
| FVIII mutation Missing | 0 Participants | 1 Participants | 1 Participants |
| FVIII mutation Unknown | 2 Participants | 5 Participants | 3 Participants |
| Previous inhibitor treatment No | 2 Participants | 4 Participants | 2 Participants |
| Previous inhibitor treatment Yes | 4 Participants | 10 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 9 Participants | 5 Participants |
| Severity of hemophilia A Mild | 2 Participants | 7 Participants | 5 Participants |
| Severity of hemophilia A Missing | 0 Participants | 1 Participants | 1 Participants |
| Severity of hemophilia A Moderate | 1 Participants | 2 Participants | 1 Participants |
| Severity of hemophilia A Severe | 3 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 14 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 6 |
| other Total, other adverse events | 0 / 8 | 1 / 6 |
| serious Total, serious adverse events | 1 / 8 | 1 / 6 |
Outcome results
Primary
Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success
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.
Time frame: From ITI start until termination of study, a maximum of 2 years
Population: Due to study termination, efficacy data was not collected for enrolled patients in the prospective cohort
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Wilate® Respective Cohort | Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success | Complete success | 7 Participants |
| Wilate® Respective Cohort | Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success | Partial success | 0 Participants |
| Wilate® Respective Cohort | Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success | Partial failure | 0 Participants |
| Wilate® Respective Cohort | Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success | Complete failure | 1 Participants |
| Wilate® Prospective Cohort | Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success | Complete failure | 0 Participants |
| Wilate® Prospective Cohort | Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success | Complete success | 0 Participants |
| Wilate® Prospective Cohort | Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success | Partial failure | 0 Participants |
| Wilate® Prospective Cohort | Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success | Partial success | 0 Participants |
Secondary
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.
Time frame: A maximum period of 5 years from ITI start
Population: Due to study termination, data was not collected for enrolled patients in either cohort. Therefore, 0 participants were analysed for this outcome
Secondary
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.
Time frame: A maximum period of 5 years from ITI start
Population: Due to study termination, data was not collected for enrolled patients in either cohort. Therefore, 0 participants were analysed for this outcome
Secondary
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.
Time frame: A maximum period of 5 years from ITI start
Population: Due to study termination, data was not collected for enrolled patients in either cohort. Therefore, 0 participants were analysed for this outcome
Secondary
In Case of Complete or Partial ITI Success, Duration of Immune Tolerance
Time from start of ITI success to end of study period
Time frame: A maximum period of 5 years from ITI start
Population: Due to study termination, data was not collected for enrolled patients in either cohort. Therefore, 0 participants were analysed for this outcome
Secondary
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.
Time frame: A maximum period of 5 years from ITI start
Population: Due to study termination, data was not collected for enrolled patients in either cohort. Therefore, 0 participants were analysed for this outcome
Secondary
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 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.
Time frame: A maximum period of 5 years from ITI start
Population: Due to study termination, data was not collected for enrolled patients in either cohort. Therefore, 0 participants were analysed for this outcome
Secondary
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.
Time frame: A maximum period of 5 years from ITI start
Population: Due to study termination, data was not collected for enrolled patients in either cohort. Therefore, 0 participants were analysed for this outcome
Secondary
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.
Time frame: 12 months before the start of ITI with Wilate or Nuwiq to a maximum of 5 years from starting ITI with Wilate or Nuwiq
Population: Due to study termination, data was not collected for enrolled patients in either cohort. Therefore, 0 participants were analysed for this outcome
Secondary
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.
Time frame: A maximum period of 5 years from ITI start
Population: Due to study termination, data was not collected for enrolled patients in either cohort. Therefore, 0 participants were analysed for this outcome