Treatment of Hemophilia A Patients With FVIII Inhibitors

Official title

MOdern Treatment of Inhibitor-PositiVe PATiEnts With Haemophilia A - An International Observational Study

Overview

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

Interventions

• Biological Nuwiq
  Nuwiq 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.
• Biological Octanate
  Octanate 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.
• Biological Wilate
  Wilate 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.
• Biological Emicizumab
  Emicizumab 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.
• Biological Recombinant factor VIIa (rFVIIa)
  Recombinant 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.
• Biological Activated prothrombin complex concentrate (aPCC)
  Activated 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.

Primary outcome measures

• Proportion of participants achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements [Time frame: Up to 5 years]
• Proportion of participants achieving FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg body weight (Groups 1 and 2) [Time frame: Up to 5 years]
• Proportion of participants achieving FVIII half-life ≥ 6 h (Groups 1 and 2) [Time frame: Up to 5 years]
• Annualized bleeding rate [Time frame: Up to 5 years]

Secondary outcome measures (11)

• Time to achieve immune tolerance induction outcome [Time frame: Up to 5 years]
• Frequency of emicizumab, aPCC, and rFVIIa use during immune tolerance induction [Time frame: Up to 5 years]
• Rate of FVIII inhibitor relapse [Time frame: Up to 5 years]
• Frequency of bleeding episodes [Time frame: Up to 5 years]
• Severity of bleeding episodes [Time frame: Up to 5 years]
• Number of infusions required to control bleeding episodes [Time frame: Up to 5 years]
• Frequency of bleeding with surgical procedures [Time frame: Up to 5 years]
• Severity of bleeding with surgical procedures [Time frame: Up to 5 years]
• Proportion of participants experiencing adverse drug reactions [Time frame: Up to 5 years]
• Number of thrombotic events [Time frame: Up to 5 years]
• Treatment costs [Time frame: Up to 5 years]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 1 center

• Arthur M. Blank Hospital — Atlanta

Germany · 1 center

• HZRM Hämophilie-Zentrum Rhein Main — Mörfelden-Walldorf

Publications

• Escuriola Ettingshausen C, Sidonio RF Jr. Design of an international investigator-initiated study on MOdern Treatment of Inhibitor-positiVe pATiEnts with haemophilia A (MOTIVATE). Ther Adv Hematol. 2021 Sep 23;12:20406207211032452. doi: 10.1177/20406207211032452. eCollection 2021. PMID 34589194

Identifiers

NCT: NCT04023019 · IRB00113316

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗