Anagrelide Retard vs. Placebo: Efficacy and Safety in "At-risk" Patients With Essential Thrombocythaemia (ARETA)
Essential Thrombocythaemia
About this trial
This is an interventional prevention trial for Essential Thrombocythaemia
Eligibility Criteria
Inclusion Criteria:
- Willing and able to give written informed consent prior to any study specific procedures and able to comply with this protocol
- Male or female subjects aged between 18 and 60 years,
- Confirmed diagnosis of ET according to WHO-criteria 2008 (Appendix A) including assessment of JAK-2 status (central re-evaluation).
- Presence of predisposing risk factors for ET related events confirmed by clinical or laboratory results:
Definition of subjects with potential risk for ET-related Events:
- Platelet count < 1.000 G/L
Additionally at least ONE of the following criteria has to be fulfilled:
- Subjects aged between 40 and 60 years or
- Subjects with ET and disease duration > 3 years (Diagnosis of ET has to be at least 3 years ago and confirmed at time of screening) or
Subjects with ONE of the following risk factors for thrombotic complications:
- JAK- 2 positivity
- Protein C and/or Protein S deficiency
- Antithrombin III deficiency
- Factor V Leiden or Prothrombin mutation
- Cardiovascular risk factors:
- Essential hypertension,
- Smoking (>5 cigarettes/d),
- Obesity (BMI>30),
- Cholesterol (HDL/LDL ratio < 4),
- Hormone replacement therapy,
- Hormonal contraception.
Exclusion Criteria:
- Diagnosis of any other myeloproliferative disorder
- High-risk status (age > 60 years, platelet count ≥ 1.000 G/L, increase of platelet count > 300 G/L within 3 month, history of thrombotic/haemorrhagic or ischemic complications).
- Any known cause for a secondary thrombocytosis
- Previous or current treatment of ET with cytoreductive therapy
- Diagnosis of any malignancy, apart from ET, within the last 3 years
- Known or suspected intolerance to the investigational product
- Known or suspected congestive heart failure
- WBC ≥ 15 G/L
- Severe renal impairment (creatinine clearance <30 ml/min)
- Severe liver impairment (ALT or AST >5 times normal)
- Clinically significant abnormal laboratory values (excluding markers of essential thrombocythaemia)
- Poorly controlled diabetes mellitus
- Infection with hepatitis B, hepatitis C or HIV
- Subjects with a history of drug/alcohol abuse (within the previous 2 years)
- Participation in another investigational study within 6 months prior to enrolment or for a longer duration if specified in local regulations
- Women of childbearing potential with inadequate contraception
- Pregnant or lactating women (pregnancy test to be assessed within 7 days prior to study treatment start)
- Any significant psychiatric disorder that, in the opinion of the investigator, might prohibit the understanding and giving of informed consent or that might prevent the subject from completing the trial.
Women of childbearing potential with inadequate contraception; women with child-bearing potential, receiving oral hormone contraception and aiming to participate in the study, will have to apply an additional effective method of contraception during the study period; male subjects, receiving investigational medicinal product, which have sexual intercourse with females of childbearing potential, should use medically acceptable and reliable method of contraception to prevent pregnancy.
Sites / Locations
- Uniklinik Innsbruck
- Universitätsklinik für Innere Medizin III, Universitätsklinikum Salzburg
- Sozialmedizinisches Zentrum Ost
- Uniklinik für Innere Medizin I
- Hanusch Krankenhaus
- University Multiprofile Hospital for Active Treatment "Dr Georgi Stranski"
- University Multiprofile Hospital for Active Treatment "Sveti Georgi"
- Multiprofile Hospital for Active Treatment, "Tokuda Hospital Sofia"
- National Specialized Hospital for Active Treatment of Hematological Diseases
- SHAT "Joan Pavel"
- Clinical Hospital Dubrava
- Kauno Medicinos Universiteto Klinikos
- Klaipeda Hospital
- Uniwersyteckie Centrum Kliniczne
- SP Szpital Kliniczny im. A. Mieleckiego
- Wojewódzki Szpital Specjalistyczny
- Specjalistyczny Szpital Miejski
- Klinika Hematologiczna, Instytut Hematologii i Transfuzjologii
- Samodzielny Publiczny Centralny Szpital
- Clinical County Hospital "Dr. Constantin Opris"
- "Coltea" Clinic Hospital
- "Fundeni" Clinical Institute
- University Emergency Hospital
- Emergency County Clinic Hospital
- Emergency County Hospital Târgu Mureș
- State Medical Institution Territorial Clinical
- Haematology Research Center of RAMS
- Leningrad Regional Clinical Hospital
- Russian scientific Research Institute for Hematology and Transfusiology
- Saint Petersburg State Institution of Healthcare
- Yaroslavl Regional Clinical Hospital
- University Hospital Bratislava
- Institute of Urgent and Recovery Surgery n.a.
- Kmelnitskiy Regional Hospital
- Institute of Haematology and Transfusiology
- Scientific Center of Radiation Medicine AMS of Ukraine
- Lviv Blood Pathology Institute
Arms of the Study
Arm 1
Arm 2
Experimental
Placebo Comparator
Anagrelide retard
Placebo
Week 1: 1x1 tablet/d of "Anagrelide retard" (1 tablet = 2mg; total dose = 2mg/d will be administered in week 1. Week 2 "Anagrelide retard": Dosing will be titrated up according to response (platelet reduction) to 4 mg/day (=2x1 tablet) in week 2. Week 3 - Week 4 "Anagrelide retard" In week 3 and 4, dose will either be increased or decreased to maintain platelets in the normal or close to normal range. The maximum dose is 4 tablets (=8mg Anagrelide) per day. Maintenance Phase "Anagrelide retard" During maintenance phase (month 2 - month 12) doses of treatment are adjusted at the highest tolerated level which is able to maintain the platelet count within the normal range. Month 2 - month 3: 2x1 tablet/d Month 3 - month 6: 3x1 tablet/d Month 6 - month 9: 4x1 tablet/d Month 9 - month 12: 4x1 tablet/d
Week 1: x1 tablet/d of Placebo will be administered in week 1. Placebo: x1 tablet/d of placebo will be administered in week 2. Placebo: In week 3 and week 4 the maximum dose is 4 tablets per day. Placebo: In order to guarantee blinding of subjects the number of placebo tablets to be taken by the subject will vary during maintenance period: Month 2 - month 3: 2x1 tablet/d Month 3 - month 6: 3x1 tablet/d Month 6 - month 9: 4x1 tablet/d Month 9 - month 12: 4x1 tablet/d