Trial Outcomes & Findings for Immune Tolerance Induction in Haemophilia A Patients Using Wilate or Nuwiq (NCT NCT03344003)

NCT ID: NCT03344003

Last Updated: 2024-08-09

Results Overview

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.

• Recruitment status: TERMINATED
• Target enrollment: 14 participants
• Primary outcome timeframe: From ITI start until termination of study, a maximum of 2 years
• Results posted on: 2024-08-09

Participant Flow

Participant milestones

Measure	Wilate® Retrospective Cohort The retrospective cohort was made up of 8 patients who had received Wilate immune tolerance induction (ITI) therapy within 3 years of enrolment. All patients had evaluable hemophilia A with an inhibitor against FVIII. The treatment regimen, doses, dosing intervals and dose adjustments were determined at the discretion of the treating physician. A usual dose for long-term prophylaxis against bleeding in patients with severe hemophilia A is 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. All enrolled patients were treated with Wilate. No patient discontinued the study before the study was terminated.	Wilate® Prospective Cohort The prospective cohort was made up of 6 patients who were currently receiving Wilate ITI, had just initiated ITI, or were planned to initiate ITI treatment with Wilate. All patients had evaluable hemophilia A with an inhibitor against FVIII. The treatment regimen, doses, dosing intervals and dose adjustments were determined at the discretion of the treating physician. A usual dose for long-term prophylaxis against bleeding in patients with severe hemophilia A is 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. All enrolled patients were treated with Wilate. No patient discontinued the study before the study was terminated.
Overall Study STARTED	8	6
Overall Study COMPLETED	6	6
Overall Study NOT COMPLETED	2	0

Reasons for withdrawal

Measure	Wilate® Retrospective Cohort The retrospective cohort was made up of 8 patients who had received Wilate immune tolerance induction (ITI) therapy within 3 years of enrolment. All patients had evaluable hemophilia A with an inhibitor against FVIII. The treatment regimen, doses, dosing intervals and dose adjustments were determined at the discretion of the treating physician. A usual dose for long-term prophylaxis against bleeding in patients with severe hemophilia A is 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. All enrolled patients were treated with Wilate. No patient discontinued the study before the study was terminated.	Wilate® Prospective Cohort The prospective cohort was made up of 6 patients who were currently receiving Wilate ITI, had just initiated ITI, or were planned to initiate ITI treatment with Wilate. All patients had evaluable hemophilia A with an inhibitor against FVIII. The treatment regimen, doses, dosing intervals and dose adjustments were determined at the discretion of the treating physician. A usual dose for long-term prophylaxis against bleeding in patients with severe hemophilia A is 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. All enrolled patients were treated with Wilate. No patient discontinued the study before the study was terminated.
Overall Study Switched to alternative treatment	1	0
Overall Study Experienced a better response with recombinant activated factor VII (rFVIIa)	1	0

Baseline Characteristics

Immune Tolerance Induction in Haemophilia A Patients Using Wilate or Nuwiq

Baseline characteristics by cohort

Measure	Wilate® Retrospective Cohort n=8 Participants The population consists of all patients who had received Wilate immune tolerance induction (ITI) therapy within 3 years of enrolment.	Wilate® Prospective Cohort n=6 Participants 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.	Total n=14 Participants Total of all reporting groups
Age, Continuous	10.6 years STANDARD_DEVIATION 5.2 • n=93 Participants	14.8 years STANDARD_DEVIATION 7.3 • n=4 Participants	12.4 years STANDARD_DEVIATION 6.1 • n=27 Participants
Sex: Female, Male Female	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Sex: Female, Male Male	8 Participants n=93 Participants	6 Participants n=4 Participants	14 Participants n=27 Participants
Race/Ethnicity, Customized Asian	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race/Ethnicity, Customized White	5 Participants n=93 Participants	4 Participants n=4 Participants	9 Participants n=27 Participants
Race/Ethnicity, Customized Other	1 Participants n=93 Participants	2 Participants n=4 Participants	3 Participants n=27 Participants
Race/Ethnicity, Customized Missing	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Blood type O	3 Participants n=93 Participants	2 Participants n=4 Participants	5 Participants n=27 Participants
Blood type A	2 Participants n=93 Participants	2 Participants n=4 Participants	4 Participants n=27 Participants
Blood type B	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Blood type AB	1 Participants n=93 Participants	2 Participants n=4 Participants	3 Participants n=27 Participants
Blood type Missing	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Severity of hemophilia A Mild	5 Participants n=93 Participants	2 Participants n=4 Participants	7 Participants n=27 Participants
Severity of hemophilia A Moderate	1 Participants n=93 Participants	1 Participants n=4 Participants	2 Participants n=27 Participants
Severity of hemophilia A Severe	1 Participants n=93 Participants	3 Participants n=4 Participants	4 Participants n=27 Participants
Severity of hemophilia A Missing	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
FVIII mutation Intron 22 Inversion	3 Participants n=93 Participants	3 Participants n=4 Participants	6 Participants n=27 Participants
FVIII mutation Intron 1 Inversion	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
FVIII mutation Missense mutations	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
FVIII mutation Unknown	3 Participants n=93 Participants	2 Participants n=4 Participants	5 Participants n=27 Participants
FVIII mutation Missing	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Previous inhibitor treatment Yes	6 Participants n=93 Participants	4 Participants n=4 Participants	10 Participants n=27 Participants
Previous inhibitor treatment No	2 Participants n=93 Participants	2 Participants n=4 Participants	4 Participants n=27 Participants

PRIMARY outcome

Timeframe: 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

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.

Outcome measures

Measure	Wilate® Respective Cohort n=8 Participants This cohort was made up of patients who had received Wilate immune tolerance induction (ITI) therapy within three years of enrolment	Wilate® Prospective Cohort This cohort consisted of patients who were currently on Wilate ITI, had just initiated ITI, or were planned to initiate ITI treatment with Wilate
Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success Complete success	7 Participants	0 Participants
Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success Partial success	0 Participants	0 Participants
Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success Partial failure	0 Participants	0 Participants
Number of Moderate and Severe Haemophilia A Patients With Inhibitors Achieving Complete or Partial Immune Tolerance Induction (ITI) Success Complete failure	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

Time from start of ITI success to end of study period

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

Bleeding episodes occurring during the study period will be documented by the patient or their parents in a patient study diary.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

Adverse Events

Wilate® Retrospective Cohort

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Wilate® Prospective Cohort

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Measure	Wilate® Retrospective Cohort n=8 participants at risk The population consists of all patients who had received Wilate immune tolerance induction (ITI) therapy within 3 years of enrolment.	Wilate® Prospective Cohort n=6 participants at risk 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.
Infections and infestations Device-related infection	12.5% 1/8 • Number of events 2 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study	0.00% 0/6 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study
Gastrointestinal disorders Gastroenteritis	12.5% 1/8 • Number of events 1 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study	0.00% 0/6 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study
Respiratory, thoracic and mediastinal disorders Bronchial hyperreactivity	12.5% 1/8 • Number of events 1 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study	0.00% 0/6 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/8 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study	16.7% 1/6 • Number of events 1 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study

Other adverse events

Measure	Wilate® Retrospective Cohort n=8 participants at risk The population consists of all patients who had received Wilate immune tolerance induction (ITI) therapy within 3 years of enrolment.	Wilate® Prospective Cohort n=6 participants at risk 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.
Infections and infestations Pyrexia	0.00% 0/8 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study	16.7% 1/6 • Number of events 1 • Adverse drug reactions were monitored throughout the study from first treatment through to study termination, a maximum of 2 years There were no treatment-related ADRs during the study

Additional Information

Dr. Sigurd Knaub, Senior VP CR&D Haematology

Octapharma AG

Phone: 01554512141

Email: Sigurd.Knaub@octapharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place