Treatment of Hemophilia A Patients With FVIII Inhibitors

Официальное название

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

Обзор

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.

Подробное описание

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

Вмешательства

• Биопрепарат 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.
• Биопрепарат 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.
• Биопрепарат 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.
• Биопрепарат 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.
• Биопрепарат 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.
• Биопрепарат 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.

Первичные конечные точки

• Proportion of participants achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements [Срок оценки: 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) [Срок оценки: Up to 5 years]
• Proportion of participants achieving FVIII half-life ≥ 6 h (Groups 1 and 2) [Срок оценки: Up to 5 years]
• Annualized bleeding rate [Срок оценки: Up to 5 years]

Вторичные конечные точки (11)

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

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 1 центр

• Arthur M. Blank Hospital — Atlanta

Германия · 1 центр

• HZRM Hämophilie-Zentrum Rhein Main — Mörfelden-Walldorf

Публикации

• 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

Идентификаторы

NCT: NCT04023019 · IRB00113316

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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