Лечение пациентов с гемофилией А ингибиторами фактора VIII (MOTIVATE)
Современное лечение ингибитор-положительных пациентов с гемофилией А - международное обсервационное исследование
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.
Обзор исследования
Статус
Условия
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
Тип исследования
Регистрация (Оцененный)
Контакты и местонахождение
Контакты исследования
- Имя: Carmen Escuriola-Ettingshausen, MD
- Номер телефона: +4961059638909
- Электронная почта: carmen.escuriola@hzrm.de
Учебное резервное копирование контактов
- Имя: Robert Sidonio, MD, MSc
- Номер телефона: 404-785-1637
- Электронная почта: robert.sidonio.jr@emory.edu
Места учебы
-
-
-
Mörfelden-Walldorf, Германия, 64546
- Рекрутинг
- HZRM Hämophilie-Zentrum Rhein Main
-
Контакт:
- Carmen Escuriola-Ettingshausen, MD
- Номер телефона: +4961059638909
- Электронная почта: carmen.escuriola@hzrm.de
-
Главный следователь:
- Carmen Escuriola-Ettingshausen, MD
-
-
-
-
Georgia
-
Atlanta, Georgia, Соединенные Штаты, 30329
- Рекрутинг
- Arthur M. Blank Hospital
-
Главный следователь:
- Robert Sidonio, MD, MSc
-
Контакт:
- Robert Sidonio, MD, MSc
- Номер телефона: 404-785-1637
- Электронная почта: robert.sidonio.jr@emory.edu
-
-
Критерии участия
Критерии приемлемости
Возраст, подходящий для обучения
- Ребенок
- Взрослый
- Пожилой взрослый
Принимает здоровых добровольцев
Полы, имеющие право на обучение
Метод выборки
Исследуемая популяция
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.
Описание
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
Учебный план
Как устроено исследование?
Детали дизайна
- Наблюдательные модели: COHORT
- Временные перспективы: PROSPECTIVE
Когорты и вмешательства
Группа / когорта |
Вмешательство/лечение |
|---|---|
|
Group 1: ITI with Nuwiq, octanate, or 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. |
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. 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. 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. 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.
Другие имена:
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.
Другие имена:
|
|
Group 2: ITI with Nuwiq, octanate, or wilate with 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. |
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. 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. 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. 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.
Другие имена:
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.
Другие имена:
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.
Другие имена:
|
|
Group 3: Prophylaxis with emicizumab, aPCC, or 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. |
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.
Другие имена:
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.
Другие имена:
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.
Другие имена:
|
Что измеряет исследование?
Первичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
|
Proportion of participants achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements
Временное ограничение: 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. |
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)
Временное ограничение: 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. |
Up to 5 years
|
|
Proportion of participants achieving FVIII half-life ≥ 6 h (Groups 1 and 2)
Временное ограничение: 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. |
Up to 5 years
|
|
Annualized bleeding rate
Временное ограничение: Up to 5 years
|
Annualized rate of all bleeding episodes will be reported and compared between all 3 study groups. |
Up to 5 years
|
Вторичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
|
Time to achieve immune tolerance induction outcome
Временное ограничение: 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. |
Up to 5 years
|
|
Frequency of emicizumab, aPCC, and rFVIIa use during immune tolerance induction
Временное ограничение: 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. |
Up to 5 years
|
|
Rate of FVIII inhibitor relapse
Временное ограничение: 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. |
Up to 5 years
|
|
Frequency of bleeding episodes
Временное ограничение: 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. |
Up to 5 years
|
|
Severity of bleeding episodes
Временное ограничение: 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:
|
Up to 5 years
|
|
Number of infusions required to control bleeding episodes
Временное ограничение: Up to 5 years
|
The number of infusions required to control bleeding episodes will be compared between study groups. |
Up to 5 years
|
|
Frequency of bleeding with surgical procedures
Временное ограничение: Up to 5 years
|
The frequency of bleeding during and after surgical procedures will be compared between study groups. |
Up to 5 years
|
|
Severity of bleeding with surgical procedures
Временное ограничение: 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:
|
Up to 5 years
|
|
Proportion of participants experiencing adverse drug reactions
Временное ограничение: Up to 5 years
|
The proportion of participants experiencing adverse drug reactions will be compared between study groups. |
Up to 5 years
|
|
Number of thrombotic events
Временное ограничение: Up to 5 years
|
The number of thrombotic events will be compared between study groups. |
Up to 5 years
|
|
Treatment costs
Временное ограничение: Up to 5 years
|
The cost (in dollars) of treatment will be compared between study groups. |
Up to 5 years
|
Соавторы и исследователи
Спонсор
Соавторы
Следователи
- Главный следователь: Robert Sidonio, MD, MSc, Emory University
Публикации и полезные ссылки
Даты записи исследования
Изучение основных дат
Начало исследования (Действительный)
Первичное завершение (Оцененный)
Завершение исследования (Оцененный)
Даты регистрации исследования
Первый отправленный
Впервые представлено, что соответствует критериям контроля качества
Первый опубликованный (Действительный)
Обновления учебных записей
Последнее опубликованное обновление (Действительный)
Последнее отправленное обновление, отвечающее критериям контроля качества
Последняя проверка
Дополнительная информация
Термины, связанные с этим исследованием
Ключевые слова
Дополнительные соответствующие термины MeSH
- Генетические заболевания, врожденные
- Нарушения свертывания крови
- Геморрагические расстройства
- Нарушения свертывания крови, наследственные
- Нарушения белковой коагуляции
- Врожденные, наследственные и неонатальные заболевания и аномалии
- Гемики и лимфатические заболевания
- Гемофилия А
- Гематологические заболевания
- Аминокислоты, пептиды и белки
- Белки
- Биологические факторы
- Белки крови
- Факторы коагуляции крови
- Белковые предшественники
- Фактор VIII
- эмицизумаб
- Фон Виллебранд
- рекомбинантный FVIIA
- противодействие коагулянту
Другие идентификационные номера исследования
- IRB00113316
- 2025P011192 (Другой идентификатор: Emory IRB)
Планирование данных отдельных участников (IPD)
Планируете делиться данными об отдельных участниках (IPD)?
Информация о лекарствах и устройствах, исследовательские документы
Изучает лекарственный продукт, регулируемый FDA США.
Изучает продукт устройства, регулируемый Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов США.
Эта информация была получена непосредственно с веб-сайта clinicaltrials.gov без каких-либо изменений. Если у вас есть запросы на изменение, удаление или обновление сведений об исследовании, обращайтесь по адресу register@clinicaltrials.gov. Как только изменение будет реализовано на clinicaltrials.gov, оно будет автоматически обновлено и на нашем веб-сайте. .