Treatment of Hemophilia A Patients With FVIII Inhibitors

Recruiting

• Conditions: Hemophilia A
• Interventions: Biological: Nuwiq; Biological: Octanate; Biological: Wilate; Biological: Recombinant factor VIIa (rFVIIa); Biological: Emicizumab; Biological: Activated prothrombin complex concentrate (aPCC)

• Registration Number: NCT04023019
• Lead Sponsor: Emory University

Brief Summary

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.

Detailed Description

This study will capture different approaches in the management of persons with haemophilia A (HA) and inhibitors. HA is a serious blood coagulation disorder caused by a deficiency in FVIII that results in a failure to produce FVIII in sufficient quantities to achieve satisfactory haemostasis. Patients with HA are predisposed to recurrent bleeds into joints and soft tissues that culminate in debilitating arthropathy and long-term morbidity. HA can be effectively treated with replacement FVIII concentrates, obtained by fractionation of human plasma (pdFVIII) or using recombinant technology (rFVIII). In patients receiving FVIII replacement therapy, inhibitors can develop that neutralise the effect of treatment. Inhibitors develop in \~35% of patients who have not been previously exposed to FVIII treatment and \~1% of patients who have undergone previous FVIII treatment. Inhibitor development has major adverse implications on bleeding rates, morbidity, mortality and quality of life.

Immune tolerance induction (ITI), which involves prolonged treatment with plasma-derived (pdFVIII) or recombinant FVIII (rFVIII), is the only clinically proven strategy for eradication of inhibitors and is recommended as the primary treatment option in European and US guidelines. Bypassing agents (activated recombinant factor VII \[rFVIIa\] and activated prothrombin complex concentrate \[aPCC\]) are used to manage bleeding episodes (BEs) and for prophylaxis or in surgical settings in patients with FVIII inhibitors. The bispecific factor IX (FIX) and factor X (FX) monoclonal antibody emicizumab was approved in the US in November 2017, and in Europe in February 2018.

The overall objective of this study is to capture different approaches in the management of participants with HA and inhibitors, document current ITI approaches, and evaluate efficacy and safety of ITI, including the combination of FVIII and emicizumab. Patients will be assigned to 1 of 3 groups based on the treatments they receive:

* Group 1 receives ITI with Nuwiq, octanate, or wilate, with aPCC or rFVIIa administered as needed

* Group 2 receives ITI with Nuwiq, octanate, or wilate, in combination with emicizumab, with aPCC or rFVIIa administered as needed

* Group 3 receives routine prophylaxis with emicizumab, aPCC or rFVIIa without ITI

Basic Information
|
Recruitment & Eligibility
|
Study & Design
|
Trial Locations

Study Timeline

• Study First Submitted: 2019-07-12
• Study First Submitted QC: 2019-07-15
• Study First Posted: 2019-07-17
• Study Start: 2020-03-17
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-23
• Last Update Posted: 2024-08-26
• Primary Completion: 2028-12
• Study Completion: 2029-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 120

Inclusion Criteria

• 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

Read More

Exclusion Criteria

• 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

Read More

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Group 1: ITI with Nuwiq, octanate, or wilate	Octanate	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery and for prophylaxis.
Group 1: ITI with Nuwiq, octanate, or wilate	Wilate	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery and for prophylaxis.
Group 1: ITI with Nuwiq, octanate, or wilate	Recombinant factor VIIa (rFVIIa)	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery and for prophylaxis.
Group 2: ITI with Nuwiq, octanate, or wilate with emicizumab	Activated prothrombin complex concentrate (aPCC)	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate, in combination with emicizumab prophylaxis. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery.
Group 3: Prophylaxis with emicizumab, aPCC, or rFVIIa	Activated prothrombin complex concentrate (aPCC)	Participants receiving routine prophylaxis with emicizumab, aPCC, or rFVIIa without immune tolerance induction. On-demand aPCC/rFVIIa can be used as needed to treat bleeding episodes or during surgery.
Group 2: ITI with Nuwiq, octanate, or wilate with emicizumab	Emicizumab	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate, in combination with emicizumab prophylaxis. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery.
Group 1: ITI with Nuwiq, octanate, or wilate	Nuwiq	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery and for prophylaxis.
Group 2: ITI with Nuwiq, octanate, or wilate with emicizumab	Nuwiq	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate, in combination with emicizumab prophylaxis. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery.
Group 1: ITI with Nuwiq, octanate, or wilate	Activated prothrombin complex concentrate (aPCC)	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery and for prophylaxis.
Group 2: ITI with Nuwiq, octanate, or wilate with emicizumab	Octanate	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate, in combination with emicizumab prophylaxis. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery.
Group 2: ITI with Nuwiq, octanate, or wilate with emicizumab	Wilate	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate, in combination with emicizumab prophylaxis. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery.
Group 2: ITI with Nuwiq, octanate, or wilate with emicizumab	Recombinant factor VIIa (rFVIIa)	Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate, in combination with emicizumab prophylaxis. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery.
Group 3: Prophylaxis with emicizumab, aPCC, or rFVIIa	Emicizumab	Participants receiving routine prophylaxis with emicizumab, aPCC, or rFVIIa without immune tolerance induction. On-demand aPCC/rFVIIa can be used as needed to treat bleeding episodes or during surgery.
Group 3: Prophylaxis with emicizumab, aPCC, or rFVIIa	Recombinant factor VIIa (rFVIIa)	Participants receiving routine prophylaxis with emicizumab, aPCC, or rFVIIa without immune tolerance induction. On-demand aPCC/rFVIIa can be used as needed to treat bleeding episodes or during surgery.

Primary Outcome Measures

Name	Time	Method
Proportion of participants achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements	Up to 5 years	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.
Proportion of participants achieving FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg body weight (Groups 1 and 2)	Up to 5 years	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.
Proportion of participants achieving FVIII half-life ≥ 6 h (Groups 1 and 2)	Up to 5 years	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.
Annualized bleeding rate	Up to 5 years	Annualized rate of all bleeding episodes will be reported and compared between all 3 study groups.

Secondary Outcome Measures

Name	Time	Method
Number of infusions required to control bleeding episodes	Up to 5 years	The number of infusions required to control bleeding episodes will be compared between study groups.
Frequency of bleeding with surgical procedures	Up to 5 years	The frequency of bleeding during and after surgical procedures will be compared between study groups.
Proportion of participants experiencing adverse drug reactions	Up to 5 years	The proportion of participants experiencing adverse drug reactions will be compared between study groups.
Time to achieve immune tolerance induction outcome	Up to 5 years	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.
Rate of FVIII inhibitor relapse	Up to 5 years	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.
Frequency of bleeding episodes	Up to 5 years	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.
Severity of bleeding episodes	Up to 5 years	Severity 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. Assessment of BE severity will be defined as: * Minor BEs are superficial muscle or soft tissue and oral bleeds; * Moderate to major BEs are joint bleeds, bleeding into muscles, into oral cavity, known trauma; * Major to life threatening BEs are bleedings in the cranium, abdomen, digestive system or chest, central nervous system bleeds, bleeding in the area of the pharynx or bleeds of the pelvic muscles, eyes/retina, fractures or head trauma
Number of thrombotic events	Up to 5 years	The number of thrombotic events will be compared between study groups.
Frequency of emicizumab, aPCC, and rFVIIa use during immune tolerance induction	Up to 5 years	The number of times that participants in Groups 1 and 2 used emicizumab, aPCC, and rFVIIa during immune tolerance induction will be reported.
Severity of bleeding with surgical procedures	Up to 5 years	The severity of bleeding during and after surgical procedures will be compared between study groups. The severity of bleeding during surgery will be defined as: * Excellent - Intraoperative blood loss was lower than or equal to the average expected blood loss for the type of procedure performed in a patient with normal haemostasis and of the same sex, age, and stature; * Good - Intraoperative blood loss was higher than the average expected blood loss but lower or equal to the maximal expected blood loss for the type of procedure in a patient with normal haemostasis; * Moderate - Intraoperative blood loss was higher than the maximum expected blood loss for the type of procedure performed in a patient with normal haemostasis, but haemostasis was controlled; * None - Haemostasis was uncontrolled, necessitating a change in the treatment regimen
Treatment costs	Up to 5 years	The cost (in dollars) of treatment will be compared between study groups.

Trial Locations

Locations (2)

HZRM Hämophilie-Zentrum Rhein Main; 🇩🇪 Morfelden-Walldorf, Germany

Arthur M. Blank Hospital; 🇺🇸 Atlanta, Georgia, United States