MOdern Treatment of Inhibitor-PositiVe PATiEnts With Haemophilia A - An International Observational Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 2
- 主要终点
- Proportion of participants achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Nuwiq (Biological)
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.
干预措施: Octanate (Biological)
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.
干预措施: Wilate (Biological)
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.
干预措施: Recombinant factor VIIa (rFVIIa) (Biological)
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.
干预措施: Activated prothrombin complex concentrate (aPCC) (Biological)
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.
干预措施: Nuwiq (Biological)
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.
干预措施: Octanate (Biological)
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.
干预措施: Wilate (Biological)
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.
干预措施: Emicizumab (Biological)
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.
干预措施: Recombinant factor VIIa (rFVIIa) (Biological)
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.
干预措施: Activated prothrombin complex concentrate (aPCC) (Biological)
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.
干预措施: Emicizumab (Biological)
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.
干预措施: Recombinant factor VIIa (rFVIIa) (Biological)
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.
干预措施: Activated prothrombin complex concentrate (aPCC) (Biological)
结局指标
主要结局
Proportion of participants achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements
时间窗: 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)
时间窗: 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)
时间窗: 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
时间窗: Up to 5 years
Annualized rate of all bleeding episodes will be reported and compared between all 3 study groups.
次要结局
- Number of infusions required to control bleeding episodes(Up to 5 years)
- Frequency of bleeding with surgical procedures(Up to 5 years)
- Proportion of participants experiencing adverse drug reactions(Up to 5 years)
- Time to achieve immune tolerance induction outcome(Up to 5 years)
- Rate of FVIII inhibitor relapse(Up to 5 years)
- Frequency of bleeding episodes(Up to 5 years)
- Severity of bleeding episodes(Up to 5 years)
- Number of thrombotic events(Up to 5 years)
- Frequency of emicizumab, aPCC, and rFVIIa use during immune tolerance induction(Up to 5 years)
- Severity of bleeding with surgical procedures(Up to 5 years)
- Treatment costs(Up to 5 years)
研究者
Robert Sidonio
Associate Professor
Emory University