Anagrelide Retard vs. Placebo: Efficacy and Safety in "At-risk" Patients With Essential Thrombocythaemia
Condition: Essential Thrombocythaemia
MeSH terms: Thrombocytosis; Thrombocythemia, Essential
Study type: Interventional
Phase: Phase 3

Summary: 
      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 and ARETA Study Working Guideline for
      Harrison, each in its current version).

      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 I is finished, stage I subjects will enter into an extension period for a maximum
      of three years.
    


Intervention name(s): Anagrelide retard; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; Week 1:
x1 tablet/d of placebo will be administered in week 1.
Week 2
Placebo:
x1 tablet/d of placebo will be administered in week 2.
Week 3 - Week 4
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/
Intervention MeSH terms: Anagrelide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Prevention