Anagrelide Retard vs. Placebo: Efficacy and Safety in "At-risk" Patients With Essential Thrombocythaemia

Condition(s) targeted: Essential Thrombocythaemia

Intervention: Anagrelide retard (Drug); Placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: AOP Orphan Pharmaceuticals AG

Official(s) and/or principal investigator(s):
Oleh Zahriychuk, MD, Study Director, Affiliation: AOP Orphan Pharmaceuticals AG

Overall contact:
Michael Zörer, Phone: 0043 1 503 72 44, Ext: 46, Email: michael.zoerer@aoporphan.com

This is a multicenter, phase III, randomized, subject and sponsor-blinded, placebo-controlled study to determine the treatment effect of "Anagrelide retard" in subjects with Essential Thrombocythaemia (ET) at "defined risk" (definition of risk criteria: see Inclusion Criteria Section 5. 1) The study is planned as a 2-stage procedure according to Bauer and Köhne: After recruitment of 140 subjects an interim analysis with re-assessment of sample size is planned in an adaptive manner.

As the confirmatory analysis will be based on a time-to-event evaluation (i. e. time to 1st clinically significant ET related event), there is no stipulated observation time identically applying for all subjects. Yet, with an interim analysis being performed after

having recruited 140 subjects - which is expected to be reached after 1 year - the estimated

observation time for a subject in stage I will also be about 1 year. (Details are explained in the section "Statistical Considerations").

Subjects will be randomized in a 1: 1 ratio to one of the following two arms:

Group A: Anagrelide retard Group B: Placebo

An a priori stratification is planned for the JAK-2 mutational status. For exploratory purposes a post hoc stratification is used for obtaining covariate adjusted results, for the following other potentially predictive factors: sex, age, Factor V Leiden, and BMI.

Dosing will be started with 1 tablet per day for week 1 and will be titrated up according to response (platelet reduction) to 2 tablets in week 2. Dosing may be further increased or decreased according to platelet response in week 3 and 4. However, the maximum dose is 4 tablets (=8mg) per day. After week 4, the maximum dose to achieve optimal platelet counts (<450 G/L) should be maintained (for visit schedule see study flow chart section IV).

To verify a treatment response, platelet counts must be evaluated at every visit. The platelet count values will be withheld from the subjects for the duration of stage I or stage II respectively. The subjects have to agree explicitly to this procedure by signing the Informed Consent form.

This is a patient and sponsor-blinded clinical study. The trial medical is packaged in the blinded fashion to keep the patient unaware (blinded) towards the actual treatment group they were randomized to. The sponsor functions (including medical monitor, pharmacovigilance manager, clinical project manager, trial data manager and trial statistician) with stay blinded in the course of the study until the database lock. Randomization scheme will be prepared by an independent statistician (not otherwise involved in the study), and will be stored securely with no access to it by the sponsor functions mentioned above. The process of randomization (provision of the individual drug-allocation information to the subjects) will be carried out by a trained staff by Harrison, in adherence to the procedures to keep the other blinded functions unaware of this information (blinded). Unblinding envelopes, which contain the treatment code per patient number for identification of treatment in case when a safety-relevant unblinding needed, will be stored at the sponsor's site. At the end of the study, verification of the extent of maintaining the blind by checking if the envelopes have been broken, will take place and will be properly documented. If the sealed envelope will broken to provide treatment identification, the date of breaking the code, the initials of the person who broke the code and the reason will be stated on the envelope.

The operational details on the blinding procedures are outlined in the relevant working guidelines (ARETA Study Working Guideline for idv staff, version 3, dated 22. 07. 2010, and ARETA Study Working Guideline for Harrison, version 1. 0, dated 26. 07. 2010).

Investigator will not be blinded in this study, i. e. in case of a medical need individual patient management will be driven by the full knowledge of the trial related interventions. For the case, the sponsor will need to unblind a patient (e. g. due to safety reasons), the above mentioned (in this section) envelopes will be used.

Only treatment naïve subjects, in respect to cytoreductive drugs with confirmed diagnosis of ET (centralized re-evaluation according to WHO, 2008; see Section 6. 2.1) and assessment of JAK-2 status (centralized re-evaluation of JAK-2 status; see Section 6. 2.2) will be enrolled.

As described above, stage I of the study will be considered as closed as soon as 140 subjects have been recruited. The duration of stage II depends on the result of the re-assessment of sample size.

Once stage 1 is finished, stage 1 subjects will enter into an extension period for a maximum of three years.

Official title: A Phase III, Randomized, Multicenter, Subject and Sponsor-blinded, Placebo Controlled Study to Compare the Efficacy and Safety of "Anagrelide Retard" Versus Placebo in "at Risk" Subjects With Essential Thrombocythaemia

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Prevention

Primary outcome: Time to 1st clinically significant ET related event

Secondary outcome: Efficacy and safety

Minimum age: 18 Years. Maximum age: 60 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Willing and able to give written informed consent prior to any study specific procedures and able to comply with this protocol

2. Male or female subjects aged between 18 and 60 years,

3. Confirmed diagnosis of ET according to WHO-criteria 2008 (Appendix A) including assessment of JAK-2 status (central re-evaluation).

4. 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:

1. Diagnosis of any other myeloproliferative disorder

2. 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).

3. Any known cause for a secondary thrombocytosis

4. Previous or current treatment of ET with cytoreductive therapy

5. Diagnosis of any malignancy, apart from ET, within the last 3 years

6. Known or suspected intolerance to the investigational product

7. Known or suspected congestive heart failure

8. WBC ≥ 15 G/L

9. Severe renal impairment (creatinine clearance <30 ml/min)

10. Severe liver impairment (ALT or AST >5 times normal)

11. Clinically significant abnormal laboratory values (excluding markers of essential thrombocythaemia)

12. Poorly controlled diabetes mellitus

13. Infection with hepatitis B, hepatitis C or HIV

14. Subjects with a history of drug/alcohol abuse (within the previous 2 years)

15. Participation in another investigational study within 6 months prior to enrolment or for a longer duration if specified in local regulations

16. Women of childbearing potential with inadequate contraception

17. Pregnant or lactating women (pregnancy test to be assessed within 7 days prior to study treatment start)

18. 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.

Michael Zörer, Phone: 0043 1 503 72 44, Ext: 46, Email: michael.zoerer@aoporphan.com

Uniklinik Innsbruck, Innsbruck, Austria; Active, not recruiting

Universitätsklinik für Innere Medizin III, Universitätsklinikum Salzburg, Salzburg, Austria; Not yet recruiting
AOP investigator

Uniklinik für Innere Medizin I, Vienna, Austria; Recruiting
AOP investigator

Sozialmedizinisches Zentrum Ost, Vienna, Austria; Recruiting
AOP investigator

Hanusch Krankenhaus, Wien, Austria; Recruiting
AOP investigator

University Multiprofile Hospital for Active Treatment "Dr Georgi Stranski", Pleven, Bulgaria; Recruiting
AOP Investigator

University Multiprofile Hospital for Active Treatment "Sveti Georgi", Plovdiv, Bulgaria; Not yet recruiting
AOP Investigator

SHAT "Joan Pavel", Sofia, Bulgaria; Not yet recruiting
AOP Investigator

Multiprofile Hospital for Active Treatment, "Tokuda Hospital Sofia", Sofia, Bulgaria; Recruiting
AOP Investigator

National Specialized Hospital for Active Treatment of Hematological Diseases, Sofia, Bulgaria; Recruiting
AOP Investigator

Clinical Hospital Dubrava, Zagreb, Croatia; Recruiting
AOP investigator

Kauno Medicinos Universiteto Klinikos, Kaunas, Lithuania; Recruiting
AOP investigator

Klaipeda Hospital, Klaipeda, Lithuania; Recruiting
AOP investigator

Uniwersyteckie Centrum Kliniczne, Gdansk, Poland; Recruiting
AOP investigator

SP Szpital Kliniczny im. A. Mieleckiego, Katowice, Poland; Recruiting
AOP investigator

Wojewódzki Szpital Specjalistyczny, Rzeszów, Poland; Not yet recruiting
AOP Investigator

Specjalistyczny Szpital Miejski, Torùn, Poland; Not yet recruiting
AOP Investigator

Klinika Hematologiczna, Instytut Hematologii i Transfuzjologii, Warsaw, Poland; Recruiting
AOP investigator

Samodzielny Publiczny Centralny Szpital, Warsaw, Poland; Recruiting
AOP investigator

Clinical County Hospital "Dr. Constantin Opris", Baia Mare, Romania; Recruiting
AOP Investigator

"Fundeni" Clinical Institute, Bucharest, Romania; Recruiting
AOP investigator

University Emergency Hospital, Bucharest, Romania; Active, not recruiting

"Coltea" Clinic Hospital, Bucharest, Romania; Recruiting
AOP investigator

Emergency County Clinic Hospital, Sibiu, Romania; Recruiting
AOP Investigator

Emergency County Hospital Târgu Mureș, Târgu Mureș, Romania; Recruiting
AOP Investigator

State Medical Institution Territorial Clinical, Krasnodar, Russian Federation; Recruiting
AOP investigator

Haematology Research Center of RAMS, Moscow, Russian Federation; Recruiting
AOP investigator

Russian scientific Research Institute for Hematology and Transfusiology, St. Petersburg, Russian Federation; Recruiting
AOP investigator

Saint Petersburg State Institution of Healthcare, St. Petersburg, Russian Federation; Recruiting
AOP investigator

Leningrad Regional Clinical Hospital, St. Petersburg, Russian Federation; Recruiting
AOP investigator

Yaroslavl Regional Clinical Hospital, Yaroslavl, Russian Federation; Recruiting
AOP investigator

University Hospital Bratislava, Bratislava, Slovakia; Recruiting
AOP investigator

Institute of Urgent and Recovery Surgery n.a., Donetsk, Ukraine; Recruiting
AOP investigator

Kmelnitskiy Regional Hospital, Khmelnitskiy, Ukraine; Recruiting
AOP investigator

Institute of Haematology and Transfusiology, Kiev, Ukraine; Recruiting
AOP investigator

Scientific Center of Radiation Medicine AMS of Ukraine, Kiev, Ukraine; Recruiting
AOP investigator

Lviv Blood Pathology Institute, Lviv, Ukraine; Recruiting
AOP investigator

Starting date: December 2010
Last updated: January 22, 2013