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.
Brief Title
Treatment of Hemophilia A Patients With FVIII Inhibitors
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
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
Central Contacts
Central Contact Role
Contact
Central Contact Phone
404-785-1637
Central Contact Email
robert.sidonio.jr@emory.edu
Central Contact Role
Contact
Central Contact Phone
+4961059638909
Central Contact Email
carmen.escuriola@hzrm.de
Completion Date
Completion Date Type
Estimated
Conditions
Hemophilia A
Eligibility Criteria
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
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
* 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
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
Inclusion Criteria
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
* 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
Gender
Male
Gender Based
false
Keywords
Blood disorders
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
NCT Id
NCT04023019
Org Class
Other
Org Full Name
Emory University
Org Study Id
IRB00113316
Overall Status
Recruiting
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
MOdern Treatment of Inhibitor-PositiVe PATiEnts With Haemophilia A - An International Observational Study
Primary Outcomes
Outcome Description
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.
Outcome Measure
Proportion of participants achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements
Outcome Time Frame
Up to 5 years
Outcome Description
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.
Outcome Measure
Proportion of participants achieving FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg body weight (Groups 1 and 2)
Outcome Time Frame
Up to 5 years
Outcome Description
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.
Outcome Measure
Proportion of participants achieving FVIII half-life ≥ 6 h (Groups 1 and 2)
Outcome Time Frame
Up to 5 years
Outcome Description
Annualized rate of all bleeding episodes will be reported and compared between all 3 study groups.
Outcome Measure
Annualized bleeding rate
Outcome Time Frame
Up to 5 years
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Up to 5 years
Outcome Measure
Time to achieve immune tolerance induction outcome
Outcome Description
The number of times that participants in Groups 1 and 2 used emicizumab, aPCC, and rFVIIa during immune tolerance induction will be reported.
Outcome Time Frame
Up to 5 years
Outcome Measure
Frequency of emicizumab, aPCC, and rFVIIa use during immune tolerance induction
Outcome Description
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.
Outcome Time Frame
Up to 5 years
Outcome Measure
Rate of FVIII inhibitor relapse
Outcome Description
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.
Outcome Time Frame
Up to 5 years
Outcome Measure
Frequency of bleeding episodes
Outcome Description
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
* 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
Outcome Time Frame
Up to 5 years
Outcome Measure
Severity of bleeding episodes
Outcome Description
The number of infusions required to control bleeding episodes will be compared between study groups.
Outcome Time Frame
Up to 5 years
Outcome Measure
Number of infusions required to control bleeding episodes
Outcome Description
The frequency of bleeding during and after surgical procedures will be compared between study groups.
Outcome Time Frame
Up to 5 years
Outcome Measure
Frequency of bleeding with surgical procedures
Outcome Description
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
* 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
Outcome Time Frame
Up to 5 years
Outcome Measure
Severity of bleeding with surgical procedures
Outcome Description
The proportion of participants experiencing adverse drug reactions will be compared between study groups.
Outcome Time Frame
Up to 5 years
Outcome Measure
Proportion of participants experiencing adverse drug reactions
Outcome Description
The number of thrombotic events will be compared between study groups.
Outcome Time Frame
Up to 5 years
Outcome Measure
Number of thrombotic events
Outcome Description
The cost (in dollars) of treatment will be compared between study groups.
Outcome Time Frame
Up to 5 years
Outcome Measure
Treatment costs
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Study 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.
Std Ages
Child
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
0
Investigators
Investigator Type
Principal Investigator
Investigator Name
William Mitchell
Investigator Email
wimitchell@montefiore.org
Investigator Phone