Anagrelide Retard vs. Placebo: Efficacy and Safety in "At-risk" Patients With Essential Thrombocythaemia
Status:
Completed
Trial end date:
2015-01-01
Target enrollment:
Participant gender:
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.