Hydroxyurea Versus Aspirin and Hydroxyurea in Essential Thrombocythemia

Essential Thrombocythemia Clinical Trial

— FAST  

Official title:

French Aspirin Study in Essential Thrombocythemia: an Open and Randomized Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02611973
• Other study ID #: P140933
• Status: Recruiting
• Phase: Phase 3
• First received: October 13, 2015
• Last updated: July 24, 2017
• Start date: March 10, 2016
• Est. completion date: November 2022

Study information

• Verified date: July 2017
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Stéphane Giraudier, MD, PhD
• Phone: (0)149812880
• Email: stephane.giraudier[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2250
• Est. completion date: November 2022
• Est. primary completion date: November 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• > 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Essential Thrombocythemia
• MPN
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Other:
• Aspirin therapy interruption
Stop the treatment by aspirin 100mg/d in the experimental arm.
• Usual treatment by aspirin 100 mg/d in the active comparator arm
HU+ aspirin maintenance
• No interruption of aspirin in the Observational arm
patient with Contre indication to aspirin or required antithrombotic therapy

Drug:
• Hydroxyurea treatment (HU)
HU maintenance

Locations

Country	Name	City	State
France	Henri Mondor Hospital	Creteil

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (5)

Alvarez-Larrán A, Pereira A, Arellano-Rodrigo E, Hernández-Boluda JC, Cervantes F, Besses C. Cytoreduction plus low-dose aspirin versus cytoreduction alone as primary prophylaxis of thrombosis in patients with high-risk essential thrombocythaemia: an observational study. Br J Haematol. 2013 Jun;161(6):865-71. doi: 10.1111/bjh.12321. Epub 2013 Apr 12. — View Citation

Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, Hehlmann R, Hoffman R, Kiladjian JJ, Kröger N, Mesa R, McMullin MF, Pardanani A, Passamonti F, Vannucchi AM, Reiter A, Silver RT, Verstovsek S, Tefferi A; European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011 Feb 20;29(6):761-70. doi: 10.1200/JCO.2010.31.8436. Epub 2011 Jan 4. — View Citation

Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch H, Kiladijan JJ, Lengfelder E, Mesa R, Mc Mullin MF, Passamonti F, Reilly JT, Vannucchi AM, Barbui T. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol. 2010 Mar;148(6):961-3. doi: 10.1111/j.1365-2141.2009.08019.x. Epub 2009 Nov 23. Review. — View Citation

Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, Kiladjian JJ, Lengfelder E, McMullin MF, Passamonti F, Reilly JT, Vannucchi AM, Barbui T. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. Blood. 2009 May 14;113(20):4829-33. doi: 10.1182/blood-2008-09-176818. Epub 2009 Mar 10. — View Citation

Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian JJ, Lengfelder E, McMullin MF, Passamonti F, Vannucchi AM, Besses C, Gisslinger H, Samuelsson J, Verstovsek S, Hoffman R, Pardanani A, Cervantes F, Tefferi A, Barbui T. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013 Jun 6;121(23):4778-81. doi: 10.1182/blood-2013-01-478891. Epub 2013 Apr 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cumulative incidence of death from vascular origin and other thrombotic and hemorrhagic events (combined endpoint)	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.	at 2-years follow-up
Secondary	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
Secondary	Rate of hematological response every 6 months	Hematological response as assessed by European Leukemia Net (ELN) criteria, revised ELN International Working Group on Myeloproliferative Neoplasms Research and Treatment (ELN -IWG MRT).	at 5 years
Secondary	Adverse event (AE) frequency and incidence, comparison in the two arms		at 5 years
Secondary	Number of HU-related nonhematologic toxicities		at 5 years
Secondary	Cumulative incidence of thrombosis		at 5 years
Secondary	Cumulative incidence of hemorrhagic complications		at 5 years
Secondary	Estimation of the progression-free survival		at 5 years
Secondary	Estimation of overall survival		at 5 years
Secondary	Short Form 36 (SF36) Health Survey	Evaluation of quality of life by using SF36	through study completion, an average of 1 year
Secondary	Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)	Evaluation of quality of life by using (MPN-SAF)	through study completion, an average of 1 year
Secondary	Number of mortality cause.		at 5 years
Secondary	Cumulative incidence of progression to polyglobulia		at 5 years
Secondary	Cumulative incidence of progression to myelofibrosis (MF)		at 5 years
Secondary	Cumulative incidence of progression to myelodysplastic syndrome (MDS)		at 5 years
Secondary	Cumulative incidence of progression AML		at 5 years
Secondary	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
Secondary	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).	responses and intolerance define according to ELN criteria	at 5 years
Secondary	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).	responses and intolerance define according to ELN criteria	at 5 years
Secondary	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.	responses and intolerance define according to ELN criteria	at 5 years