Hydroxyurea Versus Aspirin and Hydroxyurea in Essential Thrombocythemia (FAST)

July 24, 2017 updated by: Assistance Publique - Hôpitaux de Paris

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

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Anticipated)

2250

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: HU without aspirin
Other: Aspirin therapy interruption
Stop the treatment by aspirin 100mg/d in the experimental arm.
Drug: Hydroxyurea treatment (HU)
HU maintenance
Active Comparator: HU + aspirin maintenance
Drug: Hydroxyurea treatment (HU)
HU maintenance
Other: Usual treatment by aspirin 100 mg/d in the active comparator arm
HU+ aspirin maintenance
Other: HU + AAG
Observational arm
Drug: Hydroxyurea treatment (HU)
HU maintenance
Other: No interruption of aspirin in the Observational arm
patient with Contre indication to aspirin or required antithrombotic therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cumulative incidence of death from vascular origin and other thrombotic and hemorrhagic events (combined endpoint)
Time Frame: 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.
at 2-years follow-up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cumulative incidence and characteristics of vascular complications: thrombosis and hemorrhage, (grade, site, recurrence), assessed yearly over a 5-year follow-up period.
Time Frame: at 5 years
at 5 years
Rate of hematological response every 6 months
Time Frame: at 5 years
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
Adverse event (AE) frequency and incidence, comparison in the two arms
Time Frame: at 5 years
at 5 years
Number of HU-related nonhematologic toxicities
Time Frame: at 5 years
at 5 years
Cumulative incidence of thrombosis
Time Frame: at 5 years
at 5 years
Cumulative incidence of hemorrhagic complications
Time Frame: at 5 years
at 5 years
Estimation of the progression-free survival
Time Frame: at 5 years
at 5 years
Estimation of overall survival
Time Frame: at 5 years
at 5 years
Short Form 36 (SF36) Health Survey
Time Frame: through study completion, an average of 1 year
Evaluation of quality of life by using SF36
through study completion, an average of 1 year
Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF)
Time Frame: through study completion, an average of 1 year
Evaluation of quality of life by using (MPN-SAF)
through study completion, an average of 1 year
Number of mortality cause.
Time Frame: at 5 years
at 5 years
Cumulative incidence of progression to polyglobulia
Time Frame: at 5 years
at 5 years
Cumulative incidence of progression to myelofibrosis (MF)
Time Frame: at 5 years
at 5 years
Cumulative incidence of progression to myelodysplastic syndrome (MDS)
Time Frame: at 5 years
at 5 years
Cumulative incidence of progression AML
Time Frame: at 5 years
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 .
Time Frame: at 5 years
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).
Time Frame: at 5 years
responses and intolerance define according to ELN criteria
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).
Time Frame: at 5 years
responses and intolerance define according to ELN criteria
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.
Time Frame: at 5 years
responses and intolerance define according to ELN criteria
at 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Investigators

  • Principal Investigator: Stéphane Giraudier, MD, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 10, 2016

Primary Completion (Anticipated)

November 1, 2019

Study Completion (Anticipated)

November 1, 2022

Study Registration Dates

First Submitted

October 13, 2015

First Submitted That Met QC Criteria

November 19, 2015

First Posted (Estimate)

November 23, 2015

Study Record Updates

Last Update Posted (Actual)

July 26, 2017

Last Update Submitted That Met QC Criteria

July 24, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • P140933

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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