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    Clinical Trial Results:
    A Phase IIIb, randomised, open label study to compare the safety, efficacy and tolerability of anagrelide hydrochloride versus hydroxyurea in high-risk essential thrombocythaemia patients.

    Summary
    EudraCT number
    		 2004-004061-15
    Trial protocol
    		 BE   IE   ES   IT   SK   CZ   SI   BG   PL  
    Global end of trial date
    15 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Oct 2016
    First version publication date
    29 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPD422-403
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00202644
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire Pharmaceutical Development Ltd
    Sponsor organisation address
    Hampshire International Business Park, Chineham, Basingstoke, Hampshire, United Kingdom, RG24 8EP
    Public contact
    Study Physician, Shire, +1 866-842-5335,
    Scientific contact
    Study Physician, Shire, +1 866-842-5335,
    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
    15 Dec 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to compare the safety of anagrelide and hydroxyurea in short and long term usage of up to three years with particular reference to cardiovascular safety (as assessed by echocardiography).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) of Good Clinical Practice (GCP), the principles of the Declaration of Helsinki, and other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jan 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 34
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Portugal: 9
    Country: Number of subjects enrolled
    Serbia: 18
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Spain: 7
    Worldwide total number of subjects
    146
    EEA total number of subjects
    128
    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)
    111
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 183 subjects were screened, 149 subjects were randomized at 29 sites across 10 countries. Four (4) subjects randomized but withdrawn prior to treatment and 1 subject not randomized but treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Anagrelide
    Arm description
    		 Subjects received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Subjects followed for up to 3 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Anagrelide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Subjects followed for up to 3 years.

    Arm title
    		 Hydroxyurea
    Arm description
    		 Subjects received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Subjects followed for up to 3 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Hydroxyurea
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Subjects followed for up to 3 years.

    Number of subjects in period 1
    		Anagrelide Hydroxyurea
    Started
    76
    70
    Completed
    41
    43
    Not completed
    35
    27
         Consent withdrawn by subject
    8
    6
         Adverse event, non-fatal
    12
    13
         Unspecified
    9
    1
         Lost to follow-up
    -
    1
         Lack of efficacy
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Anagrelide
    Reporting group description
    		 Subjects received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Subjects followed for up to 3 years.

    Reporting group title
    Hydroxyurea
    Reporting group description
    		 Subjects received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Subjects followed for up to 3 years.

    Reporting group values
    		 Anagrelide Hydroxyurea Total
    Number of subjects
    		 76 70 146
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 58 53 111
        From 65-84 years
    		 18 17 35
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.1 ( 16.1 ) 52.9 ( 15.8 ) -
    Gender, Male/Female
    The safety population was defined as all subjects who received at least 1 dose of study medication.
    Units: subjects
        Female
    		 56 45 101
        Male
    		 20 25 45

    End points

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    End points reporting groups
    Reporting group title
    Anagrelide
    Reporting group description
    		 Subjects received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Subjects followed for up to 3 years.

    Reporting group title
    Hydroxyurea
    Reporting group description
    		 Subjects received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Subjects followed for up to 3 years.

    Primary: Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time

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    End point title
    		 Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time [1]
    End point description
    The LVEF was considered a sufficiently sensitive measure to evaluate any changes in cardiac function. The Full Analysis Set (FAS) population included all randomized subjects who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, n = Number of subjects analyzed for specified category at the specified time points in each arm respectively.
    End point type
    Primary
    End point timeframe
    Baseline and Month 1, 2, 3, 6, 9, 12, 18, 24, 30 and 36
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analysis was planned for this end-point.
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    73
    68
    Units: percentage of ejection fraction
    arithmetic mean (standard deviation)
        Baseline (n=73,68)
    66.4 ( 4.81 )
    66.9 ( 4.59 )
        Change at Month 1 (n=71,64)
    0.5 ( 4.68 )
    -1.1 ( 4.73 )
        Change at Month 2 (n=68,63)
    1.2 ( 5.8 )
    0 ( 5.03 )
        Change at Month 3 (n=67,62)
    0.1 ( 5.31 )
    -0.4 ( 3.94 )
        Change at Month 6 (n=59,60)
    -0.5 ( 5.68 )
    -0.6 ( 3.95 )
        Change at Month 9 (n=52,52)
    -0.8 ( 4.78 )
    -1.5 ( 5.15 )
        Change at Month 12 (n=45,52)
    -0.8 ( 6.61 )
    -0.6 ( 5.67 )
        Change at Month 18 (n=41,48)
    -2 ( 5.54 )
    -1.2 ( 4.84 )
        Change at Month 24 (n=40,49)
    -1.8 ( 6.81 )
    -1.7 ( 6.17 )
        Change at Month 30 (n=40,45)
    -1.8 ( 5.84 )
    -0.2 ( 5.38 )
        Change at Month 36 (n=40,44)
    -1.7 ( 6.55 )
    -0.6 ( 5.46 )
    No statistical analyses for this end point

    Primary: Platelet Count at Month 6

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    End point title
    		 Platelet Count at Month 6
    End point description
    Platelet count was evaluated. The FAS population included all randomized subjects who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, N = Number of subjects analyzed in each arm for this endpoint.
    End point type
    Primary
    End point timeframe
    Month 6
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    60
    58
    Units: 10^9 per liter
        arithmetic mean (standard deviation)
    418.6 ( 135.96 )
    396 ( 144.07 )
    Statistical analysis title
    		 Anagrelide Vs Hydroxyurea
    Comparison groups
    Hydroxyurea v Anagrelide
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Least Square Mean
    Point estimate
    -100.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -179.42
         upper limit
    		 -21.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    39.93
    Notes
    [2] - Non-inferiority of anagrelide could be concluded if lower limit of 95% Confidence Interval for the difference between treatment groups (Hydroxyurea - Anagrelide) was > -100 x 10^9/Liter.

    Secondary: Change From Baseline in Platelet Counts at Month 3 and 36

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    End point title
    		 Change From Baseline in Platelet Counts at Month 3 and 36
    End point description
    Platelet count was evaluated throughout the study. The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded with last observation carried forward (LOCF). Here, n=number of subjects analysed for specified category at specified time points in each arm respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 3 and 36
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    73
    68
    Units: 10^9 per liter
    arithmetic mean (standard deviation)
        Change at Month 3 (n=73, 68)
    575.3 ( 36.11 )
    462.2 ( 37.54 )
        Change at Month 36 (n=73, 68)
    531 ( 42.14 )
    462.8 ( 43.81 )
    Statistical analysis title
    		 Anagrelide Vs Hydroxyurea: Month 3
    Comparison groups
    Anagrelide v Hydroxyurea
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Least Square Mean
    Point estimate
    -113.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -187.4
         upper limit
    		 -38.83
    Variability estimate
    Standard error of the mean
    Dispersion value
    37.56
    Notes
    [3] - Non-inferiority of anagrelide could be concluded if lower limit of 95% Confidence Interval for the difference between treatment groups (Hydroxyurea - Anagrelide) was > -100 x 10^9/Liter.
    Statistical analysis title
    		 Anagrelide Vs Hydroxyurea: Month 36
    Comparison groups
    Anagrelide v Hydroxyurea
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Least Square Mean
    Point estimate
    -68.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -154.95
         upper limit
    		 18.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    43.83
    Notes
    [4] - Non-inferiority of anagrelide could be concluded if lower limit of 95% Confidence Interval for the difference between treatment groups (Hydroxyurea - Anagrelide) was > -100 x 10^9/Liter.

    Secondary: Percentage of Subjects With Complete Response

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    End point title
    		 Percentage of Subjects With Complete Response
    End point description
    A complete response was defined as a platelet count of less than (<) 400x10^9/Liter which was confirmed over 2 consecutive visits at least 28 days apart. The FAS population included all randomized subjects who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 36
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    73
    68
    Units: percentage of subjects
        number (not applicable)
    58.9
    58.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Partial Response

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    End point title
    		 Percentage of Subjects With Partial Response
    End point description
    A partial response is defined as a platelet count of 400-600 x 10^9/Liter and a reduction in platelet count of at least 200 x 10^9/Liter from baseline which was confirmed over 2 consecutive visits at least 28 days apart. The FAS population included all randomized subjects who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 36
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    73
    68
    Units: percentage of subjects
        number (not applicable)
    21.9
    27.9
    No statistical analyses for this end point

    Secondary: Time to Complete Response

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    End point title
    		 Time to Complete Response
    End point description
    Time in days from the date of the first dose of study medication to the date of the first visit at which response was classified. If a subject did not achieve response then they were censored at their last visit in the study (Month 36 or withdrawal). The FAS population included all randomized subjects who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 36
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    73
    68
    Units: days
        median (confidence interval 95%)
    177 (129 to 548)
    123 (90 to 554)
    No statistical analyses for this end point

    Secondary: Time to Partial Response

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    End point title
    		 Time to Partial Response
    End point description
    Time in days from the date of the first dose of study medication to the date of the first visit at which response was classified. If a subject did not achieve response then they were censored at their last visit in the study (Month 36 or withdrawal). The FAS population included all randomized subjects who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 36
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    73
    68
    Units: days
        median (confidence interval 95%)
    61 (43 to 85)
    47 (41 to 57)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Thrombotic and Haemorrhagic Events

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    End point title
    		 Number of Subjects With Thrombotic and Haemorrhagic Events
    End point description
    Thrombohaemorrhagic events are a well-known complication of the underlying essential thrombocythemia (ET) and disease progression. Events such as arterial and venous thrombosis, serious haemorrhage (including gastrointestinal haemorrhage), and death from vascular causes have been reported in subjects who received cytoreductive treatment. The FAS population included all randomized subjects who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.
    End point type
    Secondary
    End point timeframe
    From the signing of informed consent until the last study-related visit (Month 36)
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    73
    68
    Units: subjects
        number (not applicable)
    30
    16
    No statistical analyses for this end point

    Secondary: Change From Baseline in White Blood Cell Count Over Time

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    End point title
    		 Change From Baseline in White Blood Cell Count Over Time
    End point description
    White blood cell count was evaluated throughout the study. The FAS population included all randomized subjects who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, n = Number of subjects analyzed for specified category at the specified time points in each arm respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 6, 12, 18, 24, 30 and 36
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    73
    68
    Units: 10^9 per liter
    arithmetic mean (standard deviation)
        Baseline (n=73,68)
    9.13 ( 2.159 )
    10.2 ( 3.491 )
        Change at Month 6 (n=60,58)
    -0.38 ( 4.257 )
    -5.02 ( 2.525 )
        Change at Month 12 (n=45,51)
    -1 ( 2.001 )
    -4.79 ( 2.779 )
        Change at Month 18 (n=42,49)
    -1.18 ( 2.184 )
    -4.46 ( 2.664 )
        Change at Month 24 (n=40,49)
    -1.24 ( 2.283 )
    -4.82 ( 2.692 )
        Change at Month 30 (n=40,45)
    -1 ( 2.316 )
    -4.59 ( 3.391 )
        Change at Month 36 (n=40,43)
    -1.63 ( 2.234 )
    -4.46 ( 3.312 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Red Blood Cell Count Over Time

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    End point title
    		 Change From Baseline in Red Blood Cell Count Over Time
    End point description
    Red blood cell count was evaluated throughout the study. The FAS population included all randomized subjects who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, n = Number of subjects analyzed for specified category at the specified time points in each arm respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 6, 12, 18, 24, 30 and 36
    End point values
    		 Anagrelide Hydroxyurea
    Number of subjects analysed
    73
    68
    Units: 10^12 per liter
    arithmetic mean (standard deviation)
        Baseline (n=73,68)
    4.757 ( 0.5897 )
    4.787 ( 0.6002 )
        Change at Month 6 (n=60,58)
    -0.227 ( 0.4134 )
    -1.467 ( 0.6563 )
        Change at Month 12 (n=45,51)
    -0.246 ( 0.4292 )
    -1.398 ( 0.5744 )
        Change at Month 18 (n=42,49)
    -0.225 ( 0.4224 )
    -1.323 ( 0.7278 )
        Change at Month 24 (n=40,49)
    -0.299 ( 0.5811 )
    -1.281 ( 0.7219 )
        Change at Month 30 (n=40,45)
    -0.295 ( 0.5713 )
    -1.339 ( 0.6509 )
        Change at Month 36 (n=40,43)
    -0.366 ( 0.4328 )
    -1.362 ( 0.6586 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the signing of informed consent until the last study-related visit (Month 36)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Hydroxyurea
    Reporting group description
    		 Subjects received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Subjects followed for up to 3 years.

    Reporting group title
    Anagrelide
    Reporting group description
    		 Subjects received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Subjects followed for up to 3 years.

    Serious adverse events
    		 Hydroxyurea Anagrelide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 70 (18.57%)
    17 / 76 (22.37%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoid cystic carcinoma
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral nerve sheath tumour malignant
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         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
    Foot fracture
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic amputation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neurological decompensation
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis cerebral
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Scleroderma
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon calcification
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 76 (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
    Ear infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 76 (1.32%)
         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
    		 Hydroxyurea Anagrelide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 70 (38.57%)
    46 / 76 (60.53%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 70 (1.43%)
    9 / 76 (11.84%)
         occurrences all number
    1
    12
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 70 (0.00%)
    18 / 76 (23.68%)
         occurrences all number
    0
    29
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 70 (1.43%)
    19 / 76 (25.00%)
         occurrences all number
    1
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 70 (11.43%)
    4 / 76 (5.26%)
         occurrences all number
    9
    6
    Leukopenia
         subjects affected / exposed
    7 / 70 (10.00%)
    1 / 76 (1.32%)
         occurrences all number
    7
    1
    Neutropenia
         subjects affected / exposed
    5 / 70 (7.14%)
    0 / 76 (0.00%)
         occurrences all number
    8
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 76 (6.58%)
         occurrences all number
    6
    6
    Chest pain
         subjects affected / exposed
    1 / 70 (1.43%)
    4 / 76 (5.26%)
         occurrences all number
    1
    7
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 70 (0.00%)
    5 / 76 (6.58%)
         occurrences all number
    0
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 70 (4.29%)
    6 / 76 (7.89%)
         occurrences all number
    3
    7
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 76 (5.26%)
         occurrences all number
    2
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 70 (2.86%)
    6 / 76 (7.89%)
         occurrences all number
    2
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 70 (7.14%)
    2 / 76 (2.63%)
         occurrences all number
    8
    2
    Pharyngitis
         subjects affected / exposed
    6 / 70 (8.57%)
    2 / 76 (2.63%)
         occurrences all number
    8
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 70 (1.43%)
    4 / 76 (5.26%)
         occurrences all number
    1
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 70 (2.86%)
    4 / 76 (5.26%)
         occurrences all number
    2
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 May 2005
    1. Details of the Medical Toxicology Unit Information Services were added to the emergency contact list. 2. Administrative changes were made to address inconsistency between synopsis and main text. 3. The requirement to formally document drug compliance in the electronic case report form (eCRF) was removed. 4. The serious adverse events (SAE) reporting requirements were clarified.
    03 Nov 2005
    1. The principal investigator, project physician, and study manager were changed. 2. The exclusion criterion related to renal and hepatic impairment was updated to exclude not only subjects with severe renal or hepatic impairment but also those with moderate impairment. 3. New participating countries were added. 4. Requirements for subject identification were updated to comply with local requirements.
    08 Aug 2006
    1. The contract research organization (CRO) and respective contact details were changed. 2. The emergency contact details were changed. 3. The responsible Shire Project Physician was changed. 4. Listed participating countries were deleted and recruitment expanded to other European Union (EU) territories.
    11 Feb 2008
    1. Holter monitoring to diagnose cardiac symptoms which may indicate arrhythmia was added. 2. The CRO conducting and reading echocardiographs was changed. 3. The sample subject information and consent form and information for subjects requiring bone marrow biopsy or aspiration was removed from the appendix. 4. Drug accountability records were clarified.
    20 Apr 2009
    1. The principal coordinating investigator was changed. 2. Shire staff contact information on Emergency Contact Information page was updated. 3. Study Design was updated to state that overall study duration was estimated to be at least 7 years. 4. Number and Source of Subjects was updated to state that 184 high-risk essential thrombocythemia (ET) subjects would be enrolled across 50 sites. 5. The cross reference was removed from the heading to after the statement diagnosis of ET. 6. The sentence “Subjects may however participate in study SPD422-403 whilst still enrolled in this study.” was removed. 7. The following sentence was added Withdrawal of Subjects: “Subjects who withdraw from the study will return to the routine clinical care of their physician. 8. The following text regarding hydroxycarbamide capsules was added to Investigational Product[s]: “There are 10 capsules per blister pack and 10 blister packs are provided in a carton.” 9. The following text was deleted in Labeling, Packaging, Storage, and Handling: “provided that the blind of the study is not compromised”. 10. Echocardiogram and Holter Monitoring to Diagnose Cardiovascular Symptoms were updated to include the name of the CRO, the central reader of the Echocardiograms and Echocardiographs. 11. The following sentence was added to Serious Adverse Event Procedures: “The reference for safety information for this study is the current Investigator Brochure.” 12. The appendices were updated to include CRO vendors for Bone Marrow Biopsy Review and Interactive Voice Response System (IVRS). 13. The reference for European Union (EU) Clinical Trial Directive 2001/20/EC was added.

    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
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