Treatment of Hemophilia A Patients With FVIII Inhibitors
ConditionHemophilia A
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexMale
AgeNot listed
SponsorEmory University
About this trial
This is a non-interventional, multicenter, observational, international study in male persons with haemophilia A who have developed inhibitors to any replacement coagulation factor VIII (FVIII) product. The purpose of the study is to capture different approaches in the management of persons with haemophilia A and FVIII inhibitors, document current immune tolerance induction approaches, and evaluate the efficacy and safety of immune tolerance induction, including the combination of FVIII and emicizumab. Patients will be assigned to 1 of 3 groups based on the treatments they receive, and may switch to another group if their treatment is changed. Participants will be followed after a maximum observational period of 5 years.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Male persons with haemophilia A, of any severity, who have a historical inhibitor titer ≥ 0.6 BU/mL, including those who have failed previous immune tolerance induction (ITI) attempt(s)
Persons undergoing ITI with Nuwiq, octanate, or wilateor undergoing ITI with Nuwiq®, octanate® or wilate® and receiving prophylactic therapy with emicizumab, activated prothrombin complex concentrate (aPCC), or activated recombinant factor VII (rFVIIa)
Participants or participants' parent(s)/legal guardian(s) must be capable of giving signed informed consent and be able to understand the trial documents
Disqualifiers
Participants are excluded from the trial if any coagulation disorder other than haemophilia A is diagnosed
Partly retrospective patients will be excluded if detailed documentation on treatment, all bleeding episodes, inhibitor titers, and FVIII levels is not available for the retrospective period
Trial population
The study population includes males with haemophilia A who have delveloped inhibitors to any FVIII product. Participants starting treatment after study inclusion will have all data recorded prospectively while those who have already started treatment can enter if detailed retrospective documentation is available. Participants will be observed for a maximum of 5 years.
Trial design
Design model
Cohort
Time perspective
Prospective
Treatments tested in this trial
Nuwiq
Biological/VaccineNuwiq is a recombinant FVIII concentrate from a human cell line. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Octanate
Biological/VaccineOctanate is a high-purity human Factor VIII / von Willebrand Factor (VWF) concentrate. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Wilate
Biological/VaccineWilate is a high-purity human von Willebrand Factor (VWF)/Factor VIII concentrate. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Emicizumab
Biological/VaccineEmicizumab is a therapeutic antibody which brings activated factor IX and factor X together It is administered via subcutaneous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Recombinant factor VIIa (rFVIIa)
Biological/VaccineRecombinant factor VIIa (rFVIIa) is a blood factor VII manufactured using recombinant technology. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Activated prothrombin complex concentrate (aPCC)
Biological/VaccineActivated prothrombin complex concentrate (aPCC) is an anti-inhibitor coagulant complex acting on multiple pathways to facilitate coagulation. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Treatment groups
120 Participants
are divided into 3 treatment groupsGroup A: Group 1: ITI with Nuwiq, octanate, or wilate5 interventions
Group B: Group 2: ITI with Nuwiq, octanate, or wilate with emicizumab6 interventions
Group C: Group 3: Prophylaxis with emicizumab, aPCC, or rFVIIa3 interventions
Trial outcomes
Primary outcomes
1
Proportion of participants achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements
The proportion of participants in Groups 1 and 2 achieving inhibitor titer \< 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements will be determined. FVIII inhibitor titer is measured at baseline and throughout the study, according to standard of care.
Time frame
Up to 5 years2
Proportion of participants achieving FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg body weight (Groups 1 and 2)
The proportion of participants in Groups 1 and 2 achieving FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg body weight will be determined. Once inhibitor has become negative (\< 0.6 BU/mL), FVIII plasma levels are measured prior to and approximately 15 to 30 minutes after FVIII to evaluate FVIII recovery.
Time frame
Up to 5 years3
Proportion of participants achieving FVIII half-life ≥ 6 h (Groups 1 and 2)
The proportion of participants in Groups 1 and 2 achieving FVIII half-life ≥ 6 h will be determined. Once inhibitor has become negative (\< 0.6 BU/mL), FVIII plasma levels are measured prior to and at 15-30 minutes and 2, 4, 8-12, and 24 hours after administration of the immune tolerance induction (or prophylactic FVIII) to evaluate half-life; when FVIII trough levels are \> 1% during regular prophylaxis, half-life can be evaluated from fewer samples or using a population pharmacokinetic model.
Time frame
Up to 5 years4
Annualized bleeding rate
Annualized rate of all bleeding episodes will be reported and compared between all 3 study groups.
Time frame
Up to 5 yearsSecondary outcomes
1
Time to achieve immune tolerance induction outcome
The time it takes to achieve immune tolerance induction will be assessed in Groups 1 and 2. Immune tolerance induction success is defined as inhibitor titer \< 0.6 BU/mL for at least 2 consecutive measurements, FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg body weight, and half-life of FVIII ≥ 6 h.
Time frame
Up to 5 years2
Frequency of emicizumab, aPCC, and rFVIIa use during immune tolerance induction
The number of times that participants in Groups 1 and 2 used emicizumab, aPCC, and rFVIIa during immune tolerance induction will be reported.
Time frame
Up to 5 years3
Rate of FVIII inhibitor relapse
Rate of FVIII inhibitor relapses for participants in Groups 1 and 2 during an observational follow-up period in participants who have achieved complete immune tolerance induction success. Relapse is defined as inhibitor titer ≥ 0.6 BU/mL on ≥ 2 consecutive occurrences during the observational follow-up period after having achieved complete success and a prophylactic dose of ≤ 50 IU FVIII/kg every other day.
Time frame
Up to 5 years4
Frequency of bleeding episodes
Frequency of all bleeding episodes (BEs), including all treated BEs, all spontaneous BEs, all joint BEs, and target joint BEs over time (≥ 3 bleeds in the same joint within 24 weeks) will be compared between study groups.
Time frame
Up to 5 yearsSponsors and contacts
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Emory University
Lead sponsor
Octapharma
Collaborator
Source ClinicalTrials.gov