Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A phase III randomized, multicenter, double-blind, active controlled study to compare the efficacy and safety of two different anagrelide formulations in patients with Essential Thrombocythemia (TEAM-ET 2.0)

    Summary
    EudraCT number
    		 2013-003410-41
    Trial protocol
    		 AT   LT   BG   PL  
    Global end of trial date
    14 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Feb 2017
    First version publication date
    18 Feb 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AOP18007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AOP Orphan Pharmaceuticals AG
    Sponsor organisation address
    Wilhelminenstraße 91, Wien, Austria, 1160
    Public contact
    Head of Clinical Operations Dr. Michael Zörer, AOP Orphan Pharmaceuticals AG, +43 1503724446, team-et@aoporphan.com
    Scientific contact
    Head of Clinical Operations Dr. Michael Zörer, AOP Orphan Pharmaceuticals AG, +43 1503724446, team-et@aoporphan.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine whether Anagrelide Retard is non-inferior to Thromboreductin® in terms of mean platelet count measured by a central laboratory/centralized method at three time points during the maintenance period.
    Protection of trial subjects
    An IDMC was established, responsible for safeguarding the interests of trial participants, assessing the safety of the interventions during the trial. The DMC met quarterly from the time of first patient randomization until last patient’s study finalization. Protection with regards to reducing individual health risks: Any prophylactic medications to reduce the risk of thrombotic events other than alternative cytoreductive treatments or any medication to control or treat disease related symptoms/adverse events are permitted throughout the study (e.g. paracetamol, Aspirin®). No drugs with an effect to reduce platelet counts are permitted during the whole study. In case of palpitations, a low dose beta-blocker should be used, if clinically indicated. Paracetamol is the preferred drug to treat anagrelide related headache. Standard locally available therapy is to be used in case of diarrhoea (for example loperamide).
    Background therapy
    		 At the discretion of the investigator, any therapy reducing the risk of thrombotic events was allowed, except for cytoreductive drugs.
    Evidence for comparator
    		 According to the EMA ‘Points to consider on the clinical requirements of modified release products submitted as a line extension of an existing marketing authorization’ (CPMP/EWP/1875/03/Final), demonstration of non-inferiority of a modified-release formulation is considered sufficient, unless efficacy and safety of a drug are closely related, or the effect of the product is bi-directional. Therefore, Thromboreductin® was chosen as the comparator.
    Actual start date of recruitment
    26 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Bulgaria: 25
    Country: Number of subjects enrolled
    Lithuania: 8
    Country: Number of subjects enrolled
    Russian Federation: 37
    Worldwide total number of subjects
    112
    EEA total number of subjects
    75
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    72
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 A total of 112 subjects were screened at 18 centers in Austria (3), Bulgaria (2), Lithuania (2), Poland (5) and Russia (6). 6 of these subjects were screening failures. One subject was randomized but did not receive treatment and was classified as screening failure. 107 subjects were randomized and 106 subjects were included in the Safety Set.

    Pre-assignment
    Screening details
    		 Patients with confirmed diagnosis of ET at high risk (age ≥ 60 years, platelet counts ≥ 1000 G/L, increase of platelet count ≥ 300 G/L within 3 months, severe thrombohemorrhagic/ ischemic symptoms) of experiencing ET-related events, being currently treated or (ET treatment or Anagrelide) naïve.

    Period 1
    Period 1 title
    Screening
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Anagrelide Retard
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Analgrelide Retard 2mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Optimal dosing (increase to achieve the target platelet level, decrease in case of toxicity following the SmPC specifications of dosing rules for Thromboreductin were applied to each patient to reduce (for ANA-naive subjects) or maintain platelets (for anagrelide pre-treated subjects) (tbc) the platelet count ≤400 G/L or, in cases in which further dose up-titration was not possible due to poor tolerability, at least below 600 G/L.

    Arm title
    		 Thromboreductin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Thromboreductin® 0.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Optimal dosing (increase to achieve the target platelet level, decrease in case of toxicity following the SmPC specifications of Thromboreductin® were applied to each patient to reduce (for ANA-naive subjects) or maintain (tbc) platelets (for anagrelide pre-treated subjects) the platelet count ≤400 G/L or, in cases in which further dose up-titration was not possible due to poor tolerability, at least below 600 G/L.

    Number of subjects in period 1 [1]
    		Anagrelide Retard Thromboreductin
    Started
    52
    54
    Completed
    52
    54
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 6 of the 112 subjects were screening failures and were subsequently not included.
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Anagrelide Retard
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Analgrelide Retard 2mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Titration Phase: The dose was adjusted weekly up to 12 weeks in order to achieve a “stable platelet count” on two consecutive measurements (main criterion: between 150 and 400 G/L, but further criteria also applied using fluctuation criteria). ANA-naive patients started with dose level 2 (i.e. 2 mg Anagrelide Retard per day). ANA-treated patients were switched to the dose level which was closest to the pre-study anagrelide dose at study start, followed by weekly adjustments if required (platelet response, toxicity). Weekly titration was done in 1 mg with Anagrelide Retard steps with a maximum daily dose of 10 mg. Maintenance Phase: Patients reaching the desired response stable platelet count, were switched to a 4-week maintenance phase at the dose determined. Depending on dose level, IMPs were to be taken once (morning) or twice daily (every 12 hours) after meal intake. From dose level 2 onwards, total daily dose was split in two as near as possible equivalent doses.

    Arm title
    		 Thromboreductin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Thromboreductin® 0.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Titration Phase: The dose was adjusted weekly up to 12 weeks in order to achieve a “stable platelet count” (main criterion defined as between 150 and 400 G/L, but further criteria were also applied using fluctuation criteria) on two consecutive measurements. ANA-naive patients started with dose level 2 (i.e. 2 mg Anagrelide Retard per day). ANA-treated patients were switched to the dose level which was closest to the pre-study anagrelide dose at study start, followed by weekly adjustments if required, according to the platelet response and toxicity. Weekly titration was done in 0.5 mg with Thromboreductin steps. The maximum daily dose was 5 mg Thromboreductin. Maintenance Phase: see Anagrelide retard

    Number of subjects in period 2
    		Anagrelide Retard Thromboreductin
    Started
    52
    54
    Completed
    43
    48
    Not completed
    9
    6
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    3
    4
         unrelated medical condition
    1
    -
         non-compliance
    1
    -
         failure to achieve the target platelet level
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Anagrelide Retard
    Reporting group description
    		 -

    Reporting group title
    Thromboreductin
    Reporting group description
    		 -

    Reporting group values
    		 Anagrelide Retard Thromboreductin Total
    Number of subjects
    		 52 54 106
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.3 ( 15.31 ) 54.7 ( 16.93 ) -
    Gender categorical
    Units: Subjects
        Female
    		 37 35 72
        Male
    		 15 19 34
    Diagnostic criteria for initial diagnosis
    Units: Subjects
        PVSG
    		 3 3 6
        WHO 2001 criteria for ET
    		 4 6 10
        WHO 2008 criteria for ET
    		 43 43 86
        Other
    		 2 2 4
    Demonstration of JAK2V61F
    Units: Subjects
        NEGATIVE
    		 28 25 53
        POSITIVE
    		 24 29 53
    Demonstration of other clonal marker
    Units: Subjects
        No
    		 51 52 103
        Yes
    		 0 2 2
        Missing
    		 1 0 1
    Specification of other clonal marker
    Units: Subjects
        Calreticulin
    		 0 1 1
        Calreticulin Mutation
    		 0 1 1
        Missing
    		 52 52 104
    ANA-pretreatment status (3 classes)
    Category "Missing Anagrelide-naïve" means: Missing Anagrelide-naïve using other cytoreductive treatment than Anagrelide
    Units: Subjects
        Anagrelide-treated
    		 7 8 15
        Anagrelide-truly naïve
    		 23 26 49
        Missing Anagrelide-naïve
    		 22 20 42

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Anagrelide Retard
    Reporting group description
    		 -

    Reporting group title
    Thromboreductin
    Reporting group description
    		 -
    Reporting group title
    Anagrelide Retard
    Reporting group description
    		 -

    Reporting group title
    Thromboreductin
    Reporting group description
    		 -

    Subject analysis set title
    Safety analysis (SA) set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who were randomized and received at least one dose of one of the IMPs.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects of the SA set with at least one measurement of platelet count following at least one dose of IMP.

    Subject analysis set title
    Per Protocol (PP) set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects of the FAS, who entered the maintenance phase, had three valid platelet results and for whom no relevant protocol deviations were documented.

    Primary: Mean platelet count based on three measurements during the maintenance phase

    		 Close Top of page
    End point title
    		 Mean platelet count based on three measurements during the maintenance phase
    End point description
    End point type
    Primary
    End point timeframe
    Visit M1 (day 0 of maintenance phase), Visit M3 (day 14 of maintenance phase), Visit M5 (day 28 of maintenance phase)
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    39
    46
    Units: G/L
        least squares mean (standard error)
    280.7731 ( 1.0525 )
    305.0135 ( 1.0507 )
    Statistical analysis title
    		 Primary analysis of the main endpoint based on PPS
    Statistical analysis description
    The primary efficacy endpoint was analysed by means of a repeated measurement analysis using a mixed model (MMRM).
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Ratio of means
    Point estimate
    0.9205
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.037
    Notes
    [1] - The mixed model included the factors treatment group, time, cross factor time*treatment group, stratification variable treatment status before titration phase and covariates age and cardiovascular medical history. Non-inferiority was concluded if the upper limit of the one-sided 97.5% confidence interval of the treatment difference between Anagrelide and Thromboreductin® did not exceed 1.3 in the ratio of mean platelet count of three measurements of the maintenance phase.
    Statistical analysis title
    		 Supportive analysis using the FAS population
    Statistical analysis description
    The supportive analysis used the same model as applied for the primary analysis (repeated measurement analysis using a mixed model (MMRM)).
    Comparison groups
    Thromboreductin v Anagrelide Retard
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Ratio of means
    Point estimate
    0.8956
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.008
    Notes
    [2] - see main analysis of primary endpoint for PP

    Secondary: Response definition 1 (D1): Achievement of mean platelet level <600 G/L during maintenance phase

    		 Close Top of page
    End point title
    		 Response definition 1 (D1): Achievement of mean platelet level <600 G/L during maintenance phase
    End point description
    Response is evaluated taking the mean of three platelet counts from central laboratory.
    End point type
    Secondary
    End point timeframe
    Visits M1, M3 and M5
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    41
    46
    Units: Number of patients within this category
        Responder D1=no
    2
    0
        Responder D1=yes
    39
    46
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS
    Statistical analysis description
    Comparison of responder rates between treatment groups using Fisher’s exact test (5% significance level) and unconditional two-sided 95% exact confidence intervals for the difference in rates (Anagrelide – Thromboreductin®).
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.219
    Method
    		 Fisher exact
    Parameter type
    		 Risk diff. and confidence interval in %
    Point estimate
    -4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.5
         upper limit
    		 16.2

    Secondary: Response definition 2 (D2): Achievement of increase in platelet level ≤ 300 G/L during maintenance phase

    		 Close Top of page
    End point title
    		 Response definition 2 (D2): Achievement of increase in platelet level ≤ 300 G/L during maintenance phase
    End point description
    Response was evaluated comparing the change from M1. Platelet measurements were taken from the central laboratory.
    End point type
    Secondary
    End point timeframe
    Visits M1 M3 and M5
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    46
    50
    Units: Number of patients within this category
        Responder D2=no
    2
    1
        Responder D2=yes
    44
    49
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS
    Statistical analysis description
    Comparison of responder rates between treatment groups using Fisher’s exact test (5% significance level) and unconditional two-sided 95% exact confidence intervals for the difference in rates (Anagrelide – Thromboreductin).
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.606
    Method
    		 Fisher exact
    Parameter type
    		 Risk diff. and confidence interval in %
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.4
         upper limit
    		 17.8

    Secondary: Response definition 3 (D3): Platelet level during maintenance period ≤ 1000 G/L

    		 Close Top of page
    End point title
    		 Response definition 3 (D3): Platelet level during maintenance period ≤ 1000 G/L
    End point description
    Platelet measurements were taken from the central laboratory.
    End point type
    Secondary
    End point timeframe
    Visits M1, M3 and M5
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    46
    50
    Units: Number of patients within this category
        Responder D3=no
    0
    1
        Responder D3=yes
    46
    49
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS
    Statistical analysis description
    Comparison of responder rates between treatment groups using Fisher’s exact test (5% significance level) and unconditional two-sided 95% exact confidence intervals for the difference in rates (Anagrelide – Thromboreductin®).
    Comparison groups
    Thromboreductin v Anagrelide Retard
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999
    Method
    		 Fisher exact
    Parameter type
    		 Risk diff. and confidence interval in %
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.2
         upper limit
    		 22

    Secondary: Response definition 4 (D4): Platelet level between 150 G/L and 400 G/L during maintenance phase

    		 Close Top of page
    End point title
    		 Response definition 4 (D4): Platelet level between 150 G/L and 400 G/L during maintenance phase
    End point description
    Platelet count had to be within 150 G/L and 400 G/L during the whole maintenance phase. Platelet measurements were taken from the central laboratory.
    End point type
    Secondary
    End point timeframe
    Visits M1, M3 and M5
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    46
    50
    Units: Number of patients within this category
        Responder D4=no
    20
    25
        Responder D4=yes
    26
    25
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS
    Statistical analysis description
    Comparison of responder rates between treatment groups using Fisher’s exact test (5% significance level) and unconditional two-sided 95% exact confidence intervals for the difference in rates (Anagrelide – Thromboreductin®).
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.546
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.7
         upper limit
    		 26.4

    Secondary: Time from randomization until entrance in the maintenance phase

    		 Close Top of page
    End point title
    		 Time from randomization until entrance in the maintenance phase
    End point description
    End point type
    Secondary
    End point timeframe
    Whole observational period.
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    52
    54
    Units: days
        arithmetic mean (standard error)
    46.7 ( 2.86 )
    43.4 ( 2.67 )
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.4073
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.28
    Notes
    [3] - The Cox model used the factors treatment group and the covariates pre-treated/naive subjects, presence of cardiovascular disease and age as a dichotomous variable. Two-sided p-value of the logrank, hazard ratio and corresponding 95% CIs for hazard ratio were included.

    Secondary: Time from randomization until withdrawal

    		 Close Top of page
    End point title
    		 Time from randomization until withdrawal
    End point description
    End point type
    Secondary
    End point timeframe
    whole observational period.
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    52
    54
    Units: days
        arithmetic mean (standard error)
    109.1 ( 4.82 )
    106.3 ( 2.8 )
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS
    Statistical analysis description
    See analysis description for endpoint ‘Time from randomization until entrance in the maintenance phase’
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.5013 [5]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 4.05
    Notes
    [4] - Analysis description for endpoint ‘Time from randomization until entrance in the maintenance phase’
    [5] - p-value from log-rank test

    Secondary: Number of titrations in the titration and maintenance phase

    		 Close Top of page
    End point title
    		 Number of titrations in the titration and maintenance phase
    End point description
    End point type
    Secondary
    End point timeframe
    Titration period
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    52
    54
    Units: number of titrations
        arithmetic mean (standard deviation)
    2.5 ( 1.86 )
    2.3 ( 1.83 )
    No statistical analyses for this end point

    Secondary: Maintenance dose

    		 Close Top of page
    End point title
    		 Maintenance dose
    End point description
    Maintenance dose, as taken at entry to maintenance period dose in mg used during maintenance phase
    End point type
    Secondary
    End point timeframe
    Maintenance period
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    45
    48
    Units: mg
        Dose level 1 (1mg/0.5mg)
    4
    1
        Dose level 2 (2mg/1mg)
    10
    4
        Dose level 3 (3mg/1.5mg)
    11
    18
        Dose level 4 (4mg/2mg)
    9
    8
        Dose level 5 (5mg/2.5mg)
    8
    10
        Dose level 6 (6mg/3mg)
    1
    4
        Dose level 7 (7mg/3.5mg)
    1
    2
        Dose level 8 (8mg/4mg)
    0
    1
        Dose level 9 (9mg/4.5mg)
    0
    0
        Dose level 10 (10mg/5mg)
    1
    0
    No statistical analyses for this end point

    Secondary: Quality of Life EQ-5D-3L - Weighted Index Score T1

    		 Close Top of page
    End point title
    		 Quality of Life EQ-5D-3L - Weighted Index Score T1
    End point description
    End point type
    Secondary
    End point timeframe
    Titration period T1
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    52
    54
    Units: G/L
        arithmetic mean (standard deviation)
    0.811 ( 0.1639 )
    0.853 ( 0.157 )
    No statistical analyses for this end point

    Secondary: Quality of Life EQ-5D-3L - Weighted Index Score M1

    		 Close Top of page
    End point title
    		 Quality of Life EQ-5D-3L - Weighted Index Score M1
    End point description
    End point type
    Secondary
    End point timeframe
    Maintenance phase M1
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    44
    47
    Units: G/L
        arithmetic mean (standard deviation)
    0.847 ( 0.1847 )
    0.87 ( 0.1607 )
    No statistical analyses for this end point

    Secondary: Quality of Life EQ-5D-3L - Weighted Index Score M5

    		 Close Top of page
    End point title
    		 Quality of Life EQ-5D-3L - Weighted Index Score M5
    End point description
    End point type
    Secondary
    End point timeframe
    Maintenance phase M5
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    48
    52
    Units: G/L
        arithmetic mean (standard deviation)
    0.847 ( 0.1649 )
    0.875 ( 0.1509 )
    No statistical analyses for this end point

    Secondary: Mean platelet count during titration phase

    		 Close Top of page
    End point title
    		 Mean platelet count during titration phase
    End point description
    Mean platelet value for each time point during titration phase. Time points during titration phase run from T2 to T12 (weekly) at maximum. Results are referring to local laboratory.
    End point type
    Secondary
    End point timeframe
    Titration period
    End point values
    		 Anagrelide Retard Thromboreductin
    Number of subjects analysed
    52
    54
    Units: G/L
    least squares mean (confidence interval 95%)
        T2
    639.2564 (568.1331 to 719.2834)
    618.4118 (553.4826 to 690.9578)
        T3
    429.3448 (345.9588 to 532.8293)
    461.3066 (375.978 to 566.0006)
        T4
    425.3496 (329.0591 to 549.8171)
    414.2949 (323.5496 to 530.4912)
        T5
    381.3893 (289.9106 to 501.7333)
    391.4326 (301.5132 to 508.1683)
        T6
    378.8447 (278.8502 to 514.6967)
    352.0067 (266.1607 to 465.5411)
        T7
    403.3565 (259.9157 to 625.9587)
    388.8185 (261.7483 to 577.5769)
        T8
    371.3544 (252.7565 to 545.6005)
    383.545 (278.3144 to 528.5632)
        T9
    501.6619 (230.9258 to 1089.807)
    458.0205 (199.8996 to 1049.44)
        T10
    392.7461 (230.705 to 668.6008)
    333.4875 (208.7979 to 532.6389)
        T11
    746.2463 (475.585 to 1170.944)
    414.6818 (294.1042 to 584.6941)
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T2
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.5451
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0337
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9275
         upper limit
    		 1.152
    Notes
    [6] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T3
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.4854
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9307
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7592
         upper limit
    		 1.1409
    Notes
    [7] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T4
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.8308
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0267
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8039
         upper limit
    		 1.3112
    Notes
    [8] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T6
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.63
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0762
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7938
         upper limit
    		 1.4593
    Notes
    [9] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T7
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.8506
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0374
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6999
         upper limit
    		 1.5376
    Notes
    [10] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T8
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.8463
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9682
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.3586
    Notes
    [11] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T9
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.6921
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.0953
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.7642
    Notes
    [12] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T10
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.6261
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.1777
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5703
         upper limit
    		 2.432
    Notes
    [13] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T5
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.8496
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.9743
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7417
         upper limit
    		 1.2799
    Notes
    [14] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.
    Statistical analysis title
    		 Secondary endpoint analysis based on FAS T11
    Statistical analysis description
    The change from baseline in platelet counts at each visit during titration was analyzed using an ANCOVA model of the original log-transformed data of absolute platelet count with the same covariates as used for the analysis of the primary efficacy parameter including the log-transformed baseline platelet value in addition and excluding the factor visit. ANCOVAs were run for each visit.
    Comparison groups
    Anagrelide Retard v Thromboreductin
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.0447
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.7996
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.0208
         upper limit
    		 3.1723
    Notes
    [15] - Least square estimates of each treatment group and the difference thereof and corresponding standard deviations, two-sided 95% CIs and corresponding p-values for the treatment difference and covariates were derived. Data from local laboratory were taken for this kind of analysis.

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Screening Period: V 1, d -7 to -1 Titration Period: V 2, d 1 V 3, d 8 V 4, d 15 V 5, d 22 V 6, d 29 V 7 up to V 13, d 36 up to 78 Maintenance Period: V 14, d 85 V 15, d 92 V 16, d 99 V 17, d 106 V 18, d 113 V 19, 28d after V 18
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Anagrelide Retard
    Reporting group description
    		 -

    Reporting group title
    Thromboreductin
    Reporting group description
    		 -

    Serious adverse events
    		 Anagrelide Retard Thromboreductin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 52 (21.15%)
    1 / 54 (1.85%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastrointestinal Stromal Tumour
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic thrombosis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden hearing loss
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric artery thrombosis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lobar pneumonia
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Anagrelide Retard Thromboreductin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 52 (80.77%)
    42 / 54 (77.78%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibroma
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 52 (9.62%)
    4 / 54 (7.41%)
         occurrences all number
    6
    6
    Hypotension
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 54 (1.85%)
         occurrences all number
    6
    1
    Haematoma
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Dental implantation
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 54 (5.56%)
         occurrences all number
    4
    3
    Peripheral swelling
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 54 (1.85%)
         occurrences all number
    4
    1
    Fatigue
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 54 (3.70%)
         occurrences all number
    3
    2
    Pyrexia
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 54 (1.85%)
         occurrences all number
    3
    1
    Asthenia
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 54 (1.85%)
         occurrences all number
    2
    1
    Adverse drug reaction
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Chills
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Condition aggravated
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    4
    0
    Pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Breast cyst
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Erectile dysfunction
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 54 (3.70%)
         occurrences all number
    1
    2
    Dyspnoea exertional
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 54 (3.70%)
         occurrences all number
    0
    2
    Epistaxis
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 54 (0.00%)
         occurrences all number
    3
    0
    Catarrh
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Obstructive airways disorder
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 54 (3.70%)
         occurrences all number
    4
    3
    Agitation
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 54 (1.85%)
         occurrences all number
    3
    1
    Blood creatine increased
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 54 (3.70%)
         occurrences all number
    0
    2
    C-reactive protein increased
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 54 (1.85%)
         occurrences all number
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 54 (1.85%)
         occurrences all number
    1
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Blood iron decreased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Blood pressure increased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    2
    Brain natriuretic peptide increased
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Eosinophil count increased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Overdose
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    16 / 52 (30.77%)
    15 / 54 (27.78%)
         occurrences all number
    33
    31
    Tachycardia
         subjects affected / exposed
    5 / 52 (9.62%)
    2 / 54 (3.70%)
         occurrences all number
    7
    15
    Sinus bradycardia
         subjects affected / exposed
    0 / 52 (0.00%)
    5 / 54 (9.26%)
         occurrences all number
    0
    6
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 54 (3.70%)
         occurrences all number
    0
    2
    Atrial flutter
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Bradycardia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Coronary artery disease
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Defect conduction intraventricular
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Extrasystoles
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Right ventricular failure
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 52 (36.54%)
    19 / 54 (35.19%)
         occurrences all number
    62
    56
    Dizziness
         subjects affected / exposed
    5 / 52 (9.62%)
    3 / 54 (5.56%)
         occurrences all number
    5
    5
    Paraesthesia
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 54 (0.00%)
         occurrences all number
    2
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    7
    0
    Somnolence
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 54 (1.85%)
         occurrences all number
    3
    3
    Anaemia
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 54 (0.00%)
         occurrences all number
    3
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    3
    0
    Pancytopenia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 54 (1.85%)
         occurrences all number
    1
    1
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Eye haemorrhage
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Eye oedema
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    2
    Visual impairment
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    10 / 52 (19.23%)
    3 / 54 (5.56%)
         occurrences all number
    13
    3
    Abdominal pain
         subjects affected / exposed
    5 / 52 (9.62%)
    5 / 54 (9.26%)
         occurrences all number
    7
    5
    Diarrhoea
         subjects affected / exposed
    5 / 52 (9.62%)
    5 / 54 (9.26%)
         occurrences all number
    5
    5
    Nausea
         subjects affected / exposed
    5 / 52 (9.62%)
    4 / 54 (7.41%)
         occurrences all number
    5
    8
    Dyspepsia
         subjects affected / exposed
    4 / 52 (7.69%)
    2 / 54 (3.70%)
         occurrences all number
    4
    2
    Vomiting
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 54 (0.00%)
         occurrences all number
    4
    0
    Constipation
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Eructation
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Food poisoning
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    2
    0
    Hepatocellular injury
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 54 (3.70%)
         occurrences all number
    0
    2
    Dry skin
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Rash generalised
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Skin irritation
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Nocturia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Renal impairment
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 54 (5.56%)
         occurrences all number
    4
    3
    Pain in extremity
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 54 (0.00%)
         occurrences all number
    6
    0
    Back pain
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 54 (0.00%)
         occurrences all number
    2
    0
    Myalgia
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 54 (1.85%)
         occurrences all number
    2
    1
    Arthritis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Bursitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Muscle swelling
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Muscular weakness
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 54 (1.85%)
         occurrences all number
    4
    1
    Ear infection
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 54 (1.85%)
         occurrences all number
    1
    1
    Oral herpes
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 54 (3.70%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    2
    Cystitis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Dermatophytosis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Hordeolum
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 54 (1.85%)
         occurrences all number
    1
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 54 (1.85%)
         occurrences all number
    1
    2
    Decreased appetite
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0
    Gout
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    3
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 54 (1.85%)
         occurrences all number
    0
    1
    Iron deficiency
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 54 (0.00%)
         occurrences all number
    1
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jun 2014
    - an exclusion criterion was updated to add electrolyte imbalance - subjects were to be monitored for evidence of cardiovascular effects during treatment. - subjects who benefited from the study treatment could be further treated with an anagrelide formulation instead as previously stated Thromboreductin after the end of the study. - changes to the protocol-specified analyses • statistical model and main hypothesis • definition of response rates • change to baseline of platelet count • extent of exposure • adverse events

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Sat May 04 02:46:57 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA