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Hydroxyurea Versus Aspirin and Hydroxyurea in Essential Thrombocythemia (FAST)

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ClinicalTrials.gov Identifier: NCT02611973
Recruitment Status : Recruiting
First Posted : November 23, 2015
Last Update Posted : July 26, 2017
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief 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.


Condition or disease Intervention/treatment Phase
MPN Essential Thrombocythemia Other: Aspirin therapy interruption Other: Usual treatment by aspirin 100 mg/d in the active comparator arm Other: No interruption of aspirin in the Observational arm Drug: Hydroxyurea treatment (HU) Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2250 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: French Aspirin Study in Essential Thrombocythemia: an Open and Randomized Study
Actual Study Start Date : March 10, 2016
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : November 2022


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 Other: Usual treatment by aspirin 100 mg/d in the active comparator arm
HU+ aspirin maintenance

Drug: Hydroxyurea treatment (HU)
HU maintenance

HU + AAG
Observational arm
Other: No interruption of aspirin in the Observational arm
patient with Contre indication to aspirin or required antithrombotic therapy

Drug: Hydroxyurea treatment (HU)
HU maintenance




Primary Outcome Measures :
  1. 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.



Secondary Outcome Measures :
  1. 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 ]
  2. 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).

  3. Adverse event (AE) frequency and incidence, comparison in the two arms [ Time Frame: at 5 years ]
  4. Number of HU-related nonhematologic toxicities [ Time Frame: at 5 years ]
  5. Cumulative incidence of thrombosis [ Time Frame: at 5 years ]
  6. Cumulative incidence of hemorrhagic complications [ Time Frame: at 5 years ]
  7. Estimation of the progression-free survival [ Time Frame: at 5 years ]
  8. Estimation of overall survival [ Time Frame: at 5 years ]
  9. Short Form 36 (SF36) Health Survey [ Time Frame: through study completion, an average of 1 year ]
    Evaluation of quality of life by using SF36

  10. 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)

  11. Number of mortality cause. [ Time Frame: at 5 years ]
  12. Cumulative incidence of progression to polyglobulia [ Time Frame: at 5 years ]
  13. Cumulative incidence of progression to myelofibrosis (MF) [ Time Frame: at 5 years ]
  14. Cumulative incidence of progression to myelodysplastic syndrome (MDS) [ Time Frame: at 5 years ]
  15. Cumulative incidence of progression AML [ Time Frame: at 5 years ]
  16. 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 ]
  17. 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

  18. 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

  19. 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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02611973


Contacts
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Contact: Stéphane Giraudier, MD, PhD (0)149812880 ext +33 stephane.giraudier@aphp.fr

Locations
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France
Henri Mondor Hospital Recruiting
Creteil, France, 94010
Contact: Stéphane Giraudier, MD, PhD    (0)149812880 ext +33    stephane.giraudier@aphp.fr   
Contact: Onja Rarison, CRA    (0)149813387 ext +33    onja.rarison@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Stéphane Giraudier, MD, PhD Assistance Publique - Hôpitaux de Paris

Publications:

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02611973     History of Changes
Other Study ID Numbers: P140933
First Posted: November 23, 2015    Key Record Dates
Last Update Posted: July 26, 2017
Last Verified: July 2017
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Essential Thrombocythemia
Aspirin
Additional relevant MeSH terms:
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Thrombocytosis
Thrombocythemia, Essential
Blood Platelet Disorders
Hematologic Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Blood Coagulation Disorders
Hemorrhagic Disorders
Aspirin
Hydroxyurea
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Antineoplastic Agents
Antisickling Agents
Nucleic Acid Synthesis Inhibitors