French Aspirin Study in Essential Thrombocythemia: an Open and Randomized Study
试验速览
- 阶段
- 3 期
- 入组人数
- 2,250
- 试验地点
- 1
- 主要终点
- Cumulative incidence of death from vascular origin and other thrombotic and hemorrhagic events (combined endpoint)
研究概览
简要总结
The hypothesis is that efficient prevention of thrombosis with aspirin at diagnosis becomes less useful once patients have achieved a hematologic response (HR) (modified by amendment 1/03/2017) and/or that this benefit is hampered by an increased hemorrhagic risk especially in elderly patients.
Hence, investigator propose a prospective randomized study to assess the benefit / risk ratio of aspirin maintenance in high risk Essential thrombocythemia (ET) patients, in hematological response (modified by amendment 1/03/2017) on Hydroxyurea.
详细描述
ET is a myeloproliferative neoplasm (MPN) characterized by a high platelet level. Increased occurrence of thrombosis and hemorrhages are the main complications in ET. In this regard, the key factors defining high risk ET include age over 60 years, past history of thrombosis, platelet > 1500 109/L and to a lesser degree cardiovascular risk factors. These criteria currently serve as therapeutic guidelines for the use of cytoreductive therapy, with hydroxyurea (HU) being the treatment of choice in the first line setting.
The use of antiplatelet agent i.e. low-dose aspirin is also generally recommended. However, the benefit of aspirin has never been formally demonstrated in ET. Only indirect evidence come from the ECLAP study that enrolled patients with polycythemia vera (PV). Of note in the ECLAP study, the efficacy of aspirin was assessed only at diagnosis but not correlated thereafter with the hematological response on cytoreductive therapy.
In general non-MPN population studies, primary prophylaxis with aspirin has been associated with a risk reduction of major vascular events, but an increased risk of hemorrhage, especially considering age and prior gastrointestinal history. In a recent retrospective study, the combination of aspirin and cytoreduction was reported to prevent thrombosis but concomitantly increase the bleeding risk when compared to HU alone , especially in patients older than 60 years, thus questioning the benefits of long term use of aspirin therapy. These data raise the question of the actual benefit of aspirin maintenance, once patients have been efficiently treated with cytoreductive therapy.
Hence, investigator propose a prospective randomized study to assess the benefit / risk ratio of aspirin maintenance in high risk ET patients, in hematological response (modified by amendment 1/03/2017) on Hydroxyurea. Patients for which Aspirin interruption will not be possible because of extra-ET indications will be enrolled in the control observational arm.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •> 18 years and older (modified by amendment 01/03/2017)
- •Contraception considered effective by the investigator: for women of childbearing and for men whose partner is likely to procreate (added by amendment 01/03/2017)
- •Diagnosis of ET performed within the last 10 years (modified by amendment 01/03/2017) : with or without Janus kinase 2V617F (JAK2V617F) mutation according to the WHO 2008 criteria (TEFFERI,2007)
- •ET patients currently treated with hydroxyurea in first line, who have achieved a complete or partial hematologic response according to the ELN 2009 (BAROSI, 2009) modified (at least three month apart and at inclusion) (modified by amendment 01/03/2017)
- •Signed Written Informed Consent
- •Health insurance coverage.
排除标准
- •Other myeloproliferative disorder than ET.
- •Contra-indication to hydroxyurea.
- •Other uncontrolled malignancies at the time of diagnosis or inclusion.
- •History of haemostasis perturbation not related to ET, associated with a significant risk of hemorrhage or thrombosis (modified by amendment 01/03/2017)
- •.• Pregnancy or breastfeeding (added by amendment 01/03/2017)
- •Inability to freely provide consent through judiciary or administrative condition.
研究组 & 干预措施
HU without aspirin
干预措施: Aspirin therapy interruption (Other)
HU without aspirin
干预措施: Hydroxyurea treatment (HU) (Drug)
HU + aspirin maintenance
干预措施: Usual treatment by aspirin 100 mg/d in the active comparator arm (Other)
HU + aspirin maintenance
干预措施: Hydroxyurea treatment (HU) (Drug)
HU + AAG
Observational arm
干预措施: No interruption of aspirin in the Observational arm (Other)
HU + AAG
Observational arm
干预措施: Hydroxyurea treatment (HU) (Drug)
结局指标
主要结局
Cumulative incidence of death from vascular origin and other thrombotic and hemorrhagic events (combined endpoint)
时间窗: at 2-years follow-up
Definition of vascular events: Thrombotic events: Myocardial infarction, unstable angina, stroke, transient ischemic attack, peripheral arterial thrombosis, splanchnic or limb deep vein thrombosis, pulmonary embolism, and erythromelalgia Hemorrhagic events: Intracranial or retroperitoneal bleed, overt hemorrhage associated with a decrease in hemoglobin ≥20 g/l or overt hemorrhage requiring a blood transfusion of two red blood cell (RBC) units or more, and hemorrhage of grade \>=2 according to the NCI Common Toxicity criteria (CTC) V.4.0 scale. Deaths will be included as a death from thrombosis or hemorrhage if they satisfied criteria for one of the above diagnoses immediately ANTE-MORTEM or if they had a POST-MORTEM examination confirming the diagnosis. Sudden death of presumed vascular origin without a POST-MORTEM examination will be included as a thrombotic death.
次要结局
- Cumulative incidence of progression to polyglobulia(at 5 years)
- Frequencies of mutations (JAK2V617F, MPLw515 and CALR) and JAK2V617F allele burden, MPLw515 allele burden and CALR mutation allele burden in patients presenting intolerance to treatment.(at 5 years)
- Rate of hematological response every 6 months(at 5 years)
- Short Form 36 (SF36) Health Survey(through study completion, an average of 1 year)
- Number of mortality cause.(at 5 years)
- Adverse event (AE) frequency and incidence, comparison in the two arms(at 5 years)
- Cumulative incidence and characteristics of vascular complications: thrombosis and hemorrhage, (grade, site, recurrence), assessed yearly over a 5-year follow-up period.(at 5 years)
- Number of HU-related nonhematologic toxicities(at 5 years)
- Cumulative incidence of progression to myelodysplastic syndrome (MDS)(at 5 years)
- Frequencies of mutations (JAK2V617F, MPLw515 and CALR) and JAK2V617F allele burden, MPLw515 allele burden and CALR mutation allele burden in patient who will lose their hematological response (modified by amendment 1/03/2017).(at 5 years)
- Cumulative incidence of thrombosis(at 5 years)
- Cumulative incidence of hemorrhagic complications(at 5 years)
- Estimation of the progression-free survival(at 5 years)
- Estimation of overall survival(at 5 years)
- Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)(through study completion, an average of 1 year)
- Cumulative incidence of progression to myelofibrosis (MF)(at 5 years)
- Cumulative incidence of progression AML(at 5 years)
- Frequencies of mutations (JAK2V617F, MPLw515 and CALR) and JAK2V617F allele burden, MPLw515 allele burden and CALR mutation allele burden (in blood DNA) in patients presenting thrombosis or not .(at 5 years)
- Frequencies of mutations (JAK2V617F, MPLw515 and CALR) and JAK2V617F allele burden, MPLw515 allele burden and CALR mutation allele burden in patients in persistent hematological response (modified by amendment 1/03/2017).(at 5 years)