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    Clinical Trial Results:
    Initially entitled: A Medical Research Council randomised trial to compare ASPIRIN versus HYDROXYUREA / ASPIRIN in ‘INTERMEDIATE RISK’ Primary Thrombocythaemia and HYDROXYUREA / ASPIRIN versus ANAGRELIDE / ASPIRIN in ‘HIGH RISK’ Primary Thrombocythaemia. Following closure of the high risk arm: A randomised trial to compare ASPIRIN versus HYDROXYUREA/ASPIRIN in 'intermediate risk' primary thrombocythaemia and ASPIRIN only with observation in 'Low risk' primary thrombocythaemia.

    Summary
    EudraCT number
    2004-000245-38
    Trial protocol
    FR  
    Global end of trial date
    10 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Jul 2018
    First version publication date
    12 Jul 2018
    Other versions
    Summary report(s)
    Appendix 3

    Trial information

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    Trial identification
    Sponsor protocol code
    PT1
    Additional study identifiers
    ISRCTN number
    ISRCTN72251782
    US NCT number
    NCT00175838
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    R&D No.: A05033
    Sponsors
    Sponsor organisation name
    University of Cambridge & Cambridge University Hospitals NHS Foundation Trust
    Sponsor organisation address
    Addenbrookes Hospital, Hills Road, Cambridge, United Kingdom, CB2 0QQ
    Public contact
    Julia Cook, University of Cambridge, 44 01223 348091, julia.cook@addenbrookes.nhs.uk
    Scientific contact
    Prof. Anthony Green, University of Cambridge, 44 01223 762668, haem-pa2@cimr.cam.ac.uk
    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
    31 May 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) In low risk patients (aged > or = 18 years and < 40 years, no high risk factors): What is the incidence of thrombosis and major haemorrhage while receiving aspirin only? 2) In intermediate risk patients (aged > or = 40 years and < 60 years, no high risk factors): Does hydroxyurea reduce thrombosis and major haemorrhage when added to aspirin? 3) In high risk patients (aged > or = 60, or other risk factors as defined below in this document): does anagrelide reduce vascular occlusive events as effectively as hydroxyurea? 4) In high risk patients (aged >or = 60, or other risk factors as defined below in this document): is anagrelide as effective as hydroxyurea in reducing elevated platelet counts? 5) What is the effect of the treatment modalities on quality of life?
    Protection of trial subjects
    All treatments used on the study were already considered standard therapy for essential thrombocythaemia. Patients gave informed consent to enter the study and the collection of additional samples including blood and bone marrow were voluntary.
    Background therapy
    Aspirin is an oral antiplatelet drug, used extensively worldwide in patients at risk of strokes and heart attacks. All patients were advised to take aspirin 75 mg daily (100 mg in Australia) or an alternative antiplatelet agent if aspirin was contraindicated. Aspirin is considered to be a background therapy for this trial as it was administered to each of the clinical trial subjects as standard care regardless of risk group or randomisation group.
    Evidence for comparator
    Evidence from a randomised prospective study of 'high-risk' patients demonstrated that cytoreduction with hydroxyurea significantly reduced vascular occlusion. The observed reduction in this prospective study of 29 months median duration was from 24% for those not given cytoreductive treatment to 3.6% for those receiving hydroxyurea — approximately a six-fold reduction. In another prospective study where all patients received hydroxyurea, an incidence of major thrombotic events was 5.6%/year. Anagrelide is a quinazolin compound developed as a potent inhibitor of platelet aggregation. It was additionally found to produce thrombocytopenia at lower plasma concentrations than required for its anti-aggregating effect and this has led to its use in patients with thrombocythaemia. Analysis of the bone marrow of patients receiving anagrelide has demonstrated a reduction in megakaryocyte size and ploidy, but not in number, suggesting inhibition of megakaryocyte maturation.
    Actual start date of recruitment
    21 Jul 1997
    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
    France: 54
    Country: Number of subjects enrolled
    Australia: 48
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    New Zealand: 37
    Country: Number of subjects enrolled
    United Kingdom: 1317
    Worldwide total number of subjects
    1459
    EEA total number of subjects
    1374
    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)
    1
    Adults (18-64 years)
    1109
    From 65 to 84 years
    345
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    198 centres in 5 countries entered patients. Republic of Ireland closed to all recruitment and follow up in May 2006 as no co-ordinating PI could be found for the country as required by the Irish Medicines Board. Recruitment closure dates in all other countries were: Low risk: 30 Apr 2013 Intermediate risk: 31 Jul 2012 High risk: 15 Aug 2002

    Pre-assignment
    Screening details
    Patients with a diagnosis of Essential Thrombocythaemia were assessed for study inclusion according to standard diagnostic criteria (PVSG criteria). Medical history & physical exam including splenic size were performed to determine risk group. Blood samples, blood films, bone marrow aspirate & bone marrow trephines collected as appropriate.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    High Risk - Anagrelide
    Arm description
    Patients were classified as at high risk if they met one or more of the following criteria: an age of at least 60 years; current or previous platelet counts of 1 million per cubic millimeter or more; a history of ischemia, thrombosis, or embolism; hemorrhage caused by essential thrombocythemia; hypertension requiring therapy; and diabetes requiring the administration of a hypoglycemic agent. Eligible patients were randomized to receive anagrelide and aspirin (in a 1:1 ratio vs hydroxycarbamide and aspirin). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.
    Arm type
    Experimental

    Investigational medicinal product name
    Anagrelide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The routine initial dosage of anagrelide should be 0.5mg b.d. (the formulation of anagrelide is in 0.5mg capsules). The count should be checked one week after starting therapy because occasional patients respond rapidly. If the platelet count is not falling after two weeks, the daily dose can be increased by 0.5mg/day every 1 - 2 weeks. The average dose of anagrelide required to control the platelet count adequately is between 2 and 2.5mg/day. The maximum dose of anagrelide should not exceed 10mg/day or 3mg in a single dose.

    Arm title
    High Risk - Hydroxycarbamide
    Arm description
    Patients were classified as at high risk if they met one or more of the following criteria: an age of at least 60 years; current or previous platelet counts of 1 million per cubic millimeter or more; a history of ischemia, thrombosis, or embolism; hemorrhage caused by essential thrombocythemia; hypertension requiring therapy; and diabetes requiring the administration of a hypoglycemic agent. Eligible patients were randomized to receive hydroxycarbamide and aspirin (in a 1:1 ratio vs anagrelide and aspirin). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.
    Arm type
    Experimental

    Investigational medicinal product name
    Hydroxycarbamide
    Investigational medicinal product code
    Other name
    Hydroxyurea
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients assigned to hydroxycarbamide were treated with 0.5 to 2 g oral hydroxycarbamide daily, adjusted to maintain the platelet count within the range 200-400x10^9/L.

    Arm title
    Intermediate Risk - Hydroxycarbamide
    Arm description
    Intermediate risk patients were aged 40 to ≤ 59 years with no high risk features. Eligible patients were randomized to receive hydroxycarbamide and aspirin (in a 1:1 ratio vs aspirin alone). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.
    Arm type
    Experimental

    Investigational medicinal product name
    Hydroxycarbamide
    Investigational medicinal product code
    Other name
    Hydroxyurea
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients assigned to hydroxycarbamide were treated with 0.5 to 2 g oral hydroxycarbamide daily, adjusted to maintain the platelet count within the range 200-400x10^9/L.

    Arm title
    Intermediate Risk
    Arm description
    Intermediate risk patients were aged 40 to ≤ 59 years with no high risk features. Eligible patients were randomized to receive aspirin alone (in a 1:1 ratio vs hydroxycarbamide and aspirin). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Low Risk
    Arm description
    Low risk patients were aged 18 to ≤ 39 years with no high risk features Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    High Risk - Anagrelide High Risk - Hydroxycarbamide Intermediate Risk - Hydroxycarbamide Intermediate Risk Low Risk
    Started
    408
    407
    192
    190
    262
    Completed
    405
    404
    182
    176
    256
    Not completed
    3
    3
    10
    14
    6
         Protocol deviation
    3
    3
    10
    14
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    High Risk - Anagrelide
    Reporting group description
    Patients were classified as at high risk if they met one or more of the following criteria: an age of at least 60 years; current or previous platelet counts of 1 million per cubic millimeter or more; a history of ischemia, thrombosis, or embolism; hemorrhage caused by essential thrombocythemia; hypertension requiring therapy; and diabetes requiring the administration of a hypoglycemic agent. Eligible patients were randomized to receive anagrelide and aspirin (in a 1:1 ratio vs hydroxycarbamide and aspirin). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Reporting group title
    High Risk - Hydroxycarbamide
    Reporting group description
    Patients were classified as at high risk if they met one or more of the following criteria: an age of at least 60 years; current or previous platelet counts of 1 million per cubic millimeter or more; a history of ischemia, thrombosis, or embolism; hemorrhage caused by essential thrombocythemia; hypertension requiring therapy; and diabetes requiring the administration of a hypoglycemic agent. Eligible patients were randomized to receive hydroxycarbamide and aspirin (in a 1:1 ratio vs anagrelide and aspirin). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Reporting group title
    Intermediate Risk - Hydroxycarbamide
    Reporting group description
    Intermediate risk patients were aged 40 to ≤ 59 years with no high risk features. Eligible patients were randomized to receive hydroxycarbamide and aspirin (in a 1:1 ratio vs aspirin alone). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Reporting group title
    Intermediate Risk
    Reporting group description
    Intermediate risk patients were aged 40 to ≤ 59 years with no high risk features. Eligible patients were randomized to receive aspirin alone (in a 1:1 ratio vs hydroxycarbamide and aspirin). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Reporting group title
    Low Risk
    Reporting group description
    Low risk patients were aged 18 to ≤ 39 years with no high risk features Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Reporting group values
    High Risk - Anagrelide High Risk - Hydroxycarbamide Intermediate Risk - Hydroxycarbamide Intermediate Risk Low Risk Total
    Number of subjects
    408 407 192 190 262 1459
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 1 1
        Adults (18-64 years)
    240 228 191 189 261 1109
        From 65-84 years
    165 178 1 1 0 345
        85 years and over
    3 1 0 0 0 4
    Age continuous
    Units: years
        median (full range (min-max))
    61 (23 to 88) 62 (21 to 88) 52 (40 to 75) 51 (26 to 74) 33 (17 to 40) -
    Gender categorical
    Units: Subjects
        Female
    243 225 126 102 192 888
        Male
    165 182 66 88 70 571

    End points

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    End points reporting groups
    Reporting group title
    High Risk - Anagrelide
    Reporting group description
    Patients were classified as at high risk if they met one or more of the following criteria: an age of at least 60 years; current or previous platelet counts of 1 million per cubic millimeter or more; a history of ischemia, thrombosis, or embolism; hemorrhage caused by essential thrombocythemia; hypertension requiring therapy; and diabetes requiring the administration of a hypoglycemic agent. Eligible patients were randomized to receive anagrelide and aspirin (in a 1:1 ratio vs hydroxycarbamide and aspirin). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Reporting group title
    High Risk - Hydroxycarbamide
    Reporting group description
    Patients were classified as at high risk if they met one or more of the following criteria: an age of at least 60 years; current or previous platelet counts of 1 million per cubic millimeter or more; a history of ischemia, thrombosis, or embolism; hemorrhage caused by essential thrombocythemia; hypertension requiring therapy; and diabetes requiring the administration of a hypoglycemic agent. Eligible patients were randomized to receive hydroxycarbamide and aspirin (in a 1:1 ratio vs anagrelide and aspirin). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Reporting group title
    Intermediate Risk - Hydroxycarbamide
    Reporting group description
    Intermediate risk patients were aged 40 to ≤ 59 years with no high risk features. Eligible patients were randomized to receive hydroxycarbamide and aspirin (in a 1:1 ratio vs aspirin alone). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Reporting group title
    Intermediate Risk
    Reporting group description
    Intermediate risk patients were aged 40 to ≤ 59 years with no high risk features. Eligible patients were randomized to receive aspirin alone (in a 1:1 ratio vs hydroxycarbamide and aspirin). Minimization was used to ensure that equal numbers of patients were assigned to each group, both overall and within subgroups defined by previous treatment (no treatment or aspirin or cytoreductive therapy or both). Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Reporting group title
    Low Risk
    Reporting group description
    Low risk patients were aged 18 to ≤ 39 years with no high risk features Patients who were identified to have the incorrect diagnosis or risk group after randomisation were ineligible and not included in the analysis.

    Primary: Arterial or venous thrombosis, serious hemorrhage, or death from thrombosis or hemorrhage

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    End point title
    Arterial or venous thrombosis, serious hemorrhage, or death from thrombosis or hemorrhage
    End point description
    The composite primary end point was the time from randomization until the patient died from thrombosis or haemorrhage or had a serious hemorrhage or thrombotic event.
    End point type
    Primary
    End point timeframe
    All end points that occurred following randomization and were reported before July 31, 2004 in the high risk group and all end points that occurred following randomization to May 31, 2013 and were reported before October 31, 2013 in other groups.
    End point values
    High Risk - Anagrelide High Risk - Hydroxycarbamide Intermediate Risk - Hydroxycarbamide Intermediate Risk Low Risk
    Number of subjects analysed
    405 [1]
    404 [2]
    182 [3]
    176 [4]
    256 [5]
    Units: Events
    55
    36
    11
    11
    19
    Notes
    [1] - Excludes ineligible patients
    [2] - Excludes ineligible patients
    [3] - Excludes ineligible patients
    [4] - Excludes ineligible patients
    [5] - Excludes ineligible patients
    Statistical analysis title
    High risk, primary endpoint
    Comparison groups
    High Risk - Anagrelide v High Risk - Hydroxycarbamide
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.03
    Method
    Logrank
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    2.37
    Statistical analysis title
    Intermediate risk, primary endpoint
    Comparison groups
    Intermediate Risk - Hydroxycarbamide v Intermediate Risk
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 1
    Method
    Logrank
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    2.25

    Secondary: Patient survival

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    End point title
    Patient survival
    End point description
    End point type
    Secondary
    End point timeframe
    All end points that occurred following randomization and were reported before July 31, 2004 in the high risk group and all end points that occurred following randomization to May 31, 2013 and were reported before October 31, 2013 in other groups.
    End point values
    High Risk - Anagrelide High Risk - Hydroxycarbamide Intermediate Risk - Hydroxycarbamide Intermediate Risk Low Risk
    Number of subjects analysed
    405
    404
    182
    176
    256
    Units: Events
    31
    27
    10
    7
    0
    Statistical analysis title
    High risk, secondary endpoint, survival
    Comparison groups
    High Risk - Anagrelide v High Risk - Hydroxycarbamide
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.6 [6]
    Method
    Logrank
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.93
    Notes
    [6] - NS - not significant
    Statistical analysis title
    Int risk, secondary endpoint, survival
    Comparison groups
    Intermediate Risk - Hydroxycarbamide v Intermediate Risk
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.5
    Method
    Logrank
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    3.61

    Secondary: Disease transformation to myelofibrosis, AML or myelodysplasia

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    End point title
    Disease transformation to myelofibrosis, AML or myelodysplasia [7]
    End point description
    End point type
    Secondary
    End point timeframe
    All end points that occurred following randomization to May 31, 2013 and were reported before October 31, 2013.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are not reported for the High Risk arms here as they are broken out into separate end points of myelofibrosis alone and AML + myelodysplasia as noted below.
    End point values
    Intermediate Risk - Hydroxycarbamide Intermediate Risk Low Risk
    Number of subjects analysed
    182
    176
    256
    Units: Events
    5
    6
    1
    Statistical analysis title
    Int risk, secondary endpoint, transformation
    Comparison groups
    Intermediate Risk - Hydroxycarbamide v Intermediate Risk
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.7
    Method
    Logrank
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.24
         upper limit
    2.58

    Secondary: Disease transformation to myelofibrosis

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    End point title
    Disease transformation to myelofibrosis [8]
    End point description
    End point type
    Secondary
    End point timeframe
    All end points that occurred following randomization and were reported before July 31, 2004.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are not reported for the Intermediate Risk or Low Risk arms here as they are amalgamated into one end point of myelofibrosis + AML + myelodysplasia as noted above.
    End point values
    High Risk - Anagrelide High Risk - Hydroxycarbamide
    Number of subjects analysed
    405
    404
    Units: Events
    16
    5
    Statistical analysis title
    High risk, secondary endpoint, transformation
    Comparison groups
    High Risk - Anagrelide v High Risk - Hydroxycarbamide
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.01
    Method
    Logrank
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.24
         upper limit
    6.86

    Secondary: Disease transformation to AML or myelodysplasia

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    End point title
    Disease transformation to AML or myelodysplasia [9]
    End point description
    End point type
    Secondary
    End point timeframe
    All end points that occurred following randomization and were reported before July 31, 2004.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are not reported for the Intermediate Risk or Low Risk arms here as they are amalgamated into one end point of myelofibrosis + AML + myelodysplasia as noted above.
    End point values
    High Risk - Anagrelide High Risk - Hydroxycarbamide
    Number of subjects analysed
    405
    404
    Units: Events
    4
    6
    Statistical analysis title
    High risk, secondary endpoint, transformation
    Comparison groups
    High Risk - Anagrelide v High Risk - Hydroxycarbamide
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.5 [10]
    Method
    Logrank
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    2.33
    Notes
    [10] - NS - not significant

    Secondary: Disease transformation to polycythaemia vera

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    End point title
    Disease transformation to polycythaemia vera
    End point description
    End point type
    Secondary
    End point timeframe
    All end points that occurred following randomization and were reported before July 31, 2004 in the high risk group and all end points that occurred following randomization to May 31, 2013 and were reported before October 31, 2013 in other groups.
    End point values
    High Risk - Anagrelide High Risk - Hydroxycarbamide Intermediate Risk - Hydroxycarbamide Intermediate Risk Low Risk
    Number of subjects analysed
    405
    404
    182
    176
    256
    Units: Events
    1
    1
    0
    6
    2
    Statistical analysis title
    High risk, secondary endpoint, transformation
    Comparison groups
    High Risk - Anagrelide v High Risk - Hydroxycarbamide
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 1 [11]
    Method
    Logrank
    Parameter type
    Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    1.6
    Notes
    [11] - NS - not significant
    Statistical analysis title
    Int risk, secondary endpoint, transformation
    Comparison groups
    Intermediate Risk - Hydroxycarbamide v Intermediate Risk
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.01
    Method
    Logrank
    Parameter type
    Odds ratio (OR)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0

    Secondary: Quality of life

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    End point title
    Quality of life [12]
    End point description
    Quality of life (QL) was assessed using the EORTC QLQ-C30 version 2 questionnaire at randomization and yearly thereafter for five years. Scoring was according to guidelines provided by the EORTC QL Group with scores interpreted so that increased functional status indicates a benefit whereas increased symptoms indicate a poorer quality of life.
    End point type
    Secondary
    End point timeframe
    The first five years on the trial for patients in Intermediate risk group.
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As specified in the protocol, this end point does not apply to all arms of the study.
    End point values
    Intermediate Risk - Hydroxycarbamide Intermediate Risk
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Score
    Attachments
    Appendix 1
    Notes
    [13] - See attached figure (Appendix 1).
    [14] - See attached figure (Appendix 1).
    No statistical analyses for this end point

    Secondary: Platelet count control

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    End point title
    Platelet count control [15]
    End point description
    Data points were based on patients with a platelet count recorded within one month of each time point and remaining on their assigned treatment.
    End point type
    Secondary
    End point timeframe
    Platelet counts were recorded at 3 monthly intervals from randomization to 24 months post entry.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As specified in the protocol, this end point only applies to the treatment groups in the High Risk arm of the study.
    End point values
    High Risk - Anagrelide High Risk - Hydroxycarbamide
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: Platelet count (x10^9/L)
    Attachments
    Appendix 2
    Notes
    [16] - See attached graph (Appendix 2).
    [17] - See attached graph (Appendix 2).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    AEs were recorded from study registration until the last follow up visit attended by the patient.
    Adverse event reporting additional description
    Please see Appendix 3 attached.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    None
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: SAE listings provided as an attachment

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 May 2005
    The following changes were made to the protocol and patient documents: - Due to the closure of the high risk arms all references to this group were removed. - The low and intermediate risk arms of the study were previously supported by the Medical Research Council, but are now supported by the NCRI. - Definition of low and intermediate risk groups was altered to include patients with platelet counts up to 1500x109/l (those with platelet counts >1000x109/l were originally deemed to be high risk). - Details of the additional Pregnancy in PT survey added to protocol - General updates in order to conform to the EU Directive 2001/20/EC including new details on serious adverse event reporting - Inclusion of a GP letter
    20 Feb 2008
    The protocol was updated in line with current regulations and reformatted to Sponsor’s new template. Exemption from drug accountability and labelling requirements was requested. The majority of changes were regarding trial conduct; the science of the study and overall methodology, objectives and outcomes remained unchanged. In summary: - Update of pharmacovigilance section including introduction of NCI grading of adverse events and a new SAE form - Increased information of study drug - UK only references removed to become international protocol - Clarification of procedures, objectives and assessments - Removal of pregnancy survey
    22 Apr 2009
    Addition of annual follow-up blood sample collection and annual buccal swab sample collection in order to monitor the natural progression of the disease and molecular changes over time.
    04 Jan 2010
    Changes were made to the protocol, patient information sheet and consent forms as outlined below: - Transfer of data management and randomisation for the trial from the CTSU in Oxford to the CCTC in Cambridge. - Clarification on wording regarding the drug labelling exemption and the request for samples of constitutional DNA.
    09 Aug 2012
    Changes made to the end date of the trial. The protocol, patient information sheet and consent forms were updated to reflect the new information. In summary: - Recruitment to the intermediate risk arm of the trial was extended to 31 July 2012. - Recruitment to the low risk arm of the trial was extended to 30 April 2014. - Removal of wording in the protocol regarding accrual into the intermediate risk arm. - Removal of wording in the protocol regarding hydroxycarbamide (hydroxyurea) as an IMP for the trial.
    20 Jan 2014
    Extension of follow up period for a further 10 years - end of study expected in April 2024.
    01 Nov 2016
    - Follow up period reduced to end in 2016 - Change to definition of End of Study - Changes to the locations where samples should be sent and where they will be stored

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/16000354
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