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    Clinical Trial Results:
    A PROSPECTIVE, RANDOMIZED, OPEN LABEL, BLINDED END-POINT (PROBE) TRIAL TO EVALUATE WHETHER, AT COMPARABLE BLOOD PRESSURE CONTROL, ACE INHIBITOR THERAPY MORE EFFECTIVELY THAN NON RAS INHIBITOR THERAPY REDUCES CARDIOVASCULAR MORBIDITY AND MORTALITY IN CHRONIC DIALYSIS PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY AND/OR ARTERIAL HYPERTENSION (ARCADIA Study)

    Summary
    EudraCT number
    		 2008-003529-17
    Trial protocol
    		 IT  
    Global end of trial date
    01 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2021
    First version publication date
    20 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ARCADIA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00985322
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS
    Sponsor organisation address
    V. G. B. Camozzi, 3, Ranica / Bergamo, Italy, 24010
    Public contact
    Dip. Renal Medicine, Clinical Research Center for Rare Diseases "Aldo &Cele Daccò", 0039 035 45351, piero.ruggenenti@marionegri.it
    Scientific contact
    Dip. Renal Medicine, Clinical Research Center for Rare Diseases "Aldo &Cele Daccò", 0039 035 45351, piero.ruggenenti@marionegri.it
    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 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether, at comparable BP control, ACE inhibitor as compared to non-RAS inhibitor therapy reduces the incidence of a combined end-point of CV death (including sudden cardiac death and cardiac arrest resuscitation) and myocardial infarction or non-fatal stroke.
    Protection of trial subjects
    An independent Safety Committee periodically reviewed in an unblinded fashion Serious adverse events (SAEs) and non-SAEs. This study was conducted in conformance with Declaration of Helsinki, Good Clinical Practice standards and applicable country regulations regarding ethical committee review, informed consent, protection of human subjects participating in biomedical research and privacy.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2009
    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
    Italy: 269
    Worldwide total number of subjects
    269
    EEA total number of subjects
    269
    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)
    139
    From 65 to 84 years
    125
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were included by 28 Italian Centers between July 2009 and February 2014. Of 314 patients assessed for eligibility, 45 were excluded because they did not meet the selection criteria. Of the remaining 269 patients who were included and centrally randomized.

    Pre-assignment
    Screening details
    		 One month wash-out period from previous RAS inhibitor therapy and stratification by center and presence or absence of diabetes, an independent investigator at the sponsoring institution allocated each participant by block-size randomization on a 1:1 basis to either ramipril or non-RAS inhibitor

    Pre-assignment period milestones
    Number of subjects started
    		 314 [1]
    Number of subjects completed
    		 269

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 9
    Reason: Number of subjects
    		 did not fulfil eligibility criteria: 24
    Reason: Number of subjects
    		 Unsatisfactory compliance: 3
    Reason: Number of subjects
    		 Protocol deviation: 1
    Reason: Number of subjects
    		 Adverse event, serious fatal: 4
    Reason: Number of subjects
    		 Adverse event, non-fatal: 2
    Reason: Number of subjects
    		 renal transplant: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of 314 patients assessed for eligibility, 45 were excluded because they did not meet the selection criteria. Of the remaining 269 patients who were included and randomized
    Period 1
    Period 1 title
    Ramipril/No-RAS inhibitor therapy (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ramipril
    Arm description
    		 Ramipril was started at 1.25 mg/day and was uptitrated to 2.5 mg/day, to 5 mg/day, and then to 10 mg/day, according to blood pressure control and tolerability.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ramipril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ramipril was started at 1.25 mg/day and was uptitrated to 2.5 mg/day, to 5 mg/day, and then to 10 mg/day, according to blood pressure control and tolerability.

    Arm title
    		 Non-RAS Inhibitor
    Arm description
    		 Non-RAS Inhibitor therapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Non RAS inibithor therapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage and the administration detail were according to the Centre clinical practice to achieve the blood pressure targets in patients randomized a non Ramipril therapy. All therapy were collected in the eCRF and described into the appendix.

    Number of subjects in period 1
    		Ramipril Non-RAS Inhibitor
    Started
    140
    129
    Completed
    93
    90
    Not completed
    47
    39
         Adverse event, serious fatal
    13
    9
         Consent withdrawn by subject
    7
    7
         Adverse event, non-fatal
    1
    1
         Other
    2
    -
         renal transplant
    23
    21
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ramipril
    Reporting group description
    		 Ramipril was started at 1.25 mg/day and was uptitrated to 2.5 mg/day, to 5 mg/day, and then to 10 mg/day, according to blood pressure control and tolerability.

    Reporting group title
    Non-RAS Inhibitor
    Reporting group description
    		 Non-RAS Inhibitor therapy

    Reporting group values
    		 Ramipril Non-RAS Inhibitor Total
    Number of subjects
    		 140 129 269
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 72 67 139
        From 65-84 years
    		 65 60 125
        85 years and over
    		 3 2 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64 ± 12 62 ± 14 -
    Gender categorical
    Units: Subjects
        Female
    		 41 47 88
        Male
    		 99 82 181
    Smoker
    Units: Subjects
        Current or former smoker
    		 70 42 112
        No smoker
    		 70 87 157
    Baseline stratification data arterial hypertension
    Units: Subjects
        Arterial Hypertension
    		 140 128 268
        No arterial hypertension
    		 0 1 1
    Prior to transplant
    Units: Subjects
        Prior to transplant
    		 15 22 37
        No prior to transplant
    		 125 107 232
    Dialysis type
    Units: Subjects
        Low-flux hemodialysis
    		 47 39 86
        High flux hemodialysis
    		 41 33 74
        Hemodiafiltration
    		 51 54 105
        Not available
    		 1 3 4
    Dialysis frequency
    Units: Subjects
        Twice week
    		 21 15 36
        Three tymes week
    		 118 112 230
        Not available
    		 1 2 3
    Vascular acces
    Units: Subjects
        Arteriovenous fistula
    		 114 112 226
        Arteriovenous graft
    		 8 5 13
        Central venous catheter
    		 17 10 27
        Not available
    		 1 2 3
    Previous cardiovascular history
    Units: Subjects
        Coronary
    		 34 24 58
        Cerebrovascular
    		 11 11 22
        Peripheral artery disease
    		 27 21 48
        Gastrointestinal ischemia
    		 1 1 2
        No cardiovascular event
    		 67 72 139
    Other antihypertensive agents - Diuretic therapies
    Units: Subjects
        Diuretics
    		 74 54 128
        No diuretic therapies
    		 66 75 141
    Lipid lowering agents
    Units: Subjects
        Statins
    		 47 43 90
        Omega-3 fatty acid
    		 12 12 24
        Fibrates
    		 1 0 1
        No therapy
    		 80 74 154
    Anti-platelet therapy/Anti-thrombotic agents
    Units: Subjects
        Anti-platelet therapy
    		 89 74 163
        No Therapy
    		 51 55 106
    Anti-thrombotic agents
    Units: Subjects
        Anti-thrombotic agents
    		 23 30 53
        No therapy
    		 117 99 216
    Baseline stratification data Left ventricular hypertrophy
    Units: Subjects
        Left ventricular hypertrophy
    		 95 83 178
        No Left ventricular hypertrophy
    		 45 46 91
    Baseline stratification data Diabetes mellitus
    Units: Subjects
        Diabetes mellitus
    		 37 28 65
        No Diabetes mellitus
    		 103 101 204
    Other antihypertensive agents - Calcium-channel blockers
    Units: Subjects
        Calcium-channel blockers
    		 77 62 139
        No Calcium-channel blockers therapies
    		 63 67 130
    Other antihypertensive agents - Beta Blockers
    Units: Subjects
        Beta Blockers
    		 69 70 139
        No Beta Blockers therapies
    		 71 59 130
    Pre-dialysis BMI
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 25.6 ± 4.4 25 ± 4.2 -
    SBP before dialysis
    Units: mmHg
        arithmetic mean (standard deviation)
    		 145 ± 19 143 ± 20 -
    DBP before dialysis
    Units: mmHg
        arithmetic mean (standard deviation)
    		 75 ± 13 76 ± 13 -
    SBP after dialysis
    Units: mmHg
        arithmetic mean (standard deviation)
    		 145 ± 22 138 ± 22 -
    DBP after dialysis
    Units: mmHg
        arithmetic mean (standard deviation)
    		 78 ± 16 75 ± 14 -
    Duration of dialysis
    Units: Months
        median (inter-quartile range (Q1-Q3))
    		 30 (15 to 63) 37 (13 to 76) -
    eKT/V
    Units: eKT/V
        arithmetic mean (standard deviation)
    		 1.1 ± 0.2 1.1 ± 0.3 -
    Interdialytic weight change
    Units: Kg
        arithmetic mean (standard deviation)
    		 2.6 ± 1.1 2.5 ± 1 -
    Total cholesterol
    Units: mg/dL
        median (inter-quartile range (Q1-Q3))
    		 148 (129 to 181) 159 (132 to 188) -
    Triglycerides
    Units: mg/dL
        median (inter-quartile range (Q1-Q3))
    		 133 (104 to 185) 153 (112 to 196) -
    Hemoglobin
    Units: g/dL
        arithmetic mean (standard deviation)
    		 11.3 ± 1.2 11.1 ± 1.3 -
    Hematocrit
    Units: percent
        arithmetic mean (standard deviation)
    		 34.9 ± 3.9 34.9 ± 3.9 -
    Serum potassium
    Units: mEq/L
        arithmetic mean (standard deviation)
    		 5.3 ± 0.8 5.3 ± 0.8 -
    C-reactive protein
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    		 1.05 (0.29 to 2.63) 0.6 (0.2 to 3.2) -

    End points

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    End points reporting groups
    Reporting group title
    Ramipril
    Reporting group description
    		 Ramipril was started at 1.25 mg/day and was uptitrated to 2.5 mg/day, to 5 mg/day, and then to 10 mg/day, according to blood pressure control and tolerability.

    Reporting group title
    Non-RAS Inhibitor
    Reporting group description
    		 Non-RAS Inhibitor therapy

    Primary: Primary composite end point of major cardiovascular events

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    End point title
    		 Primary composite end point of major cardiovascular events
    End point description
    To assess whether, at comparable BP control, ACE inhibitor as compared to non-RAS inhibitor therapy reduces the incidence of a combined end-point of CV death (including sudden cardiac death and cardiac arrest resuscitation) and myocardial infarction. Sudden cardiac death is a natural death due to cardiac causes, heralded by abrupt loss of consciousness and effective circulation within 1 hour of the onset of acute symptoms such as arrhythmias, hypotension, chest pain, dyspnea or lightheadedness and followed by failure of resuscitation or failure of electrical, mechanical, or CNS function after initial resuscitation. Preexisting heart disease may or may not have been known to be present, but the time and mode of death are unexpected.
    End point type
    Primary
    End point timeframe
    During a median [IQR] follow-up of 33 [17-42] months,
    End point values
    		 Ramipril Non-RAS Inhibitor
    Number of subjects analysed
    140
    129
    Units: Events
    23
    24
    Statistical analysis title
    		 Primary End Point
    Statistical analysis description
    Reduction of the incidence of a combined end-point of CV death (including sudden cardiac death and cardiac arrest resuscitation) and myocardial infarction in patient with ACE inhibitor as compared to non-RAS inhibitor therapy
    Comparison groups
    Ramipril v Non-RAS Inhibitor
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval

    Secondary: Fatal cardiovascular event considered as a single endpoint

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    End point title
    		 Fatal cardiovascular event considered as a single endpoint
    End point description
    To compare the incidence of the single components of the combined end-point: Fatal cardiovascular event
    End point type
    Secondary
    End point timeframe
    During the observation period
    End point values
    		 Ramipril Non-RAS Inhibitor
    Number of subjects analysed
    140
    129
    Units: Event
    11
    17
    No statistical analyses for this end point

    Secondary: New-onset or recurrent atrial fibrillation as a single endpoint

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    End point title
    		 New-onset or recurrent atrial fibrillation as a single endpoint
    End point description
    To compare the incidence of the single components of the combined end-point: new onset of atrial fibrillation in one of its three forms (paroxysmal, persistent and permanent) Atrial fibrillation is defined as paroxysmal in case of spontaneous resolution of the arrhythmia, persistent when pharmacological or electrical cardioversion was needed to interrupt it and permanent when it could not be interrupted either spontaneously, by using drugs or by cardioversion.
    End point type
    Secondary
    End point timeframe
    During the observational period
    End point values
    		 Ramipril Non-RAS Inhibitor
    Number of subjects analysed
    140
    129
    Units: Event
    10
    17
    No statistical analyses for this end point

    Secondary: Hospitalization because of symptomatic fluid overload as a single endpoint

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    End point title
    		 Hospitalization because of symptomatic fluid overload as a single endpoint
    End point description
    To compare the incidence of the single components of the combined end-point: patients hospitalized during the study period because of symptomatic fluid overload.
    End point type
    Secondary
    End point timeframe
    All study period
    End point values
    		 Ramipril Non-RAS Inhibitor
    Number of subjects analysed
    140
    129
    Units: Event
    10
    15
    No statistical analyses for this end point

    Secondary: Stenosis and thrombosis of the arteriovenous fistula as a single endpoint

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    End point title
    		 Stenosis and thrombosis of the arteriovenous fistula as a single endpoint
    End point description
    To compare the incidence of the single components of the combined end-point: Stenosis and thrombosis of the arteriovenous fistula.
    End point type
    Secondary
    End point timeframe
    During the observational period
    End point values
    		 Ramipril Non-RAS Inhibitor
    Number of subjects analysed
    140
    129
    Units: Event
    28
    19
    No statistical analyses for this end point

    Secondary: Non-fatal stroke considered as a single endpoint

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    End point title
    		 Non-fatal stroke considered as a single endpoint
    End point description
    To compare the incidence of the single components of the combined end-point: non-fatal stroke event
    End point type
    Secondary
    End point timeframe
    During the observational period
    End point values
    		 Ramipril Non-RAS Inhibitor
    Number of subjects analysed
    140
    129
    Units: Event
    4
    2
    No statistical analyses for this end point

    Post-hoc: Explorative composite endpoint

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    End point title
    		 Explorative composite endpoint
    End point description
    To comapre the incidence of progression to the explorative composite endpoint of cardiovascular death, myocardial infarction, unstable angina, stroke, coronary artery revascularization, hospitalization for fluid overload or resuscitated cardiac arrest
    End point type
    Post-hoc
    End point timeframe
    During the observational period
    End point values
    		 Ramipril Non-RAS Inhibitor
    Number of subjects analysed
    140
    129
    Units: Event
    34
    43
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events will be reported during whole study up to 30 days after last dose of study drug.
    Adverse event reporting additional description
    SAE: we indicated the number of events occuring for the first time in single patients AE: we indicated the number of patient who at least one no-SAE and total number of AEs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Ramipril
    Reporting group description
    		 Ramipril was started at 1.25 mg/day and was uptitrated to 2.5 mg/day, to 5 mg/day, and then to 10 mg/day, according to blood pressure control and tolerability.

    Reporting group title
    Non-RAS Inhibitor
    Reporting group description
    		 Non-RAS Inhibitor therapy

    Serious adverse events
    		 Ramipril Non-RAS Inhibitor
    Total subjects affected by serious adverse events
         subjects affected / exposed
    91 / 140 (65.00%)
    86 / 129 (66.67%)
         number of deaths (all causes)
    26
    30
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastrointestinal cancer
         subjects affected / exposed
    6 / 140 (4.29%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Any Cancer
         subjects affected / exposed
    20 / 140 (14.29%)
    9 / 129 (6.98%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 9
         deaths causally related to treatment / all
    0 / 7
    0 / 1
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    54 / 140 (38.57%)
    68 / 129 (52.71%)
         occurrences causally related to treatment / all
    0 / 54
    0 / 68
         deaths causally related to treatment / all
    0 / 11
    0 / 20
    Stroke/Myocardial Infarction
         subjects affected / exposed
    13 / 140 (9.29%)
    7 / 129 (5.43%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unstable Angina
         subjects affected / exposed
    4 / 140 (2.86%)
    7 / 129 (5.43%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    12 / 140 (8.57%)
    21 / 129 (16.28%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 140 (2.14%)
    7 / 129 (5.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary and peripheral artery revascularization
         subjects affected / exposed
    16 / 140 (11.43%)
    23 / 129 (17.83%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HD vascular acces thrombosis/interventions
         subjects affected / exposed
    13 / 140 (9.29%)
    17 / 129 (13.18%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Any cardiovascular event
         subjects affected / exposed
    54 / 140 (38.57%)
    68 / 129 (52.71%)
         occurrences causally related to treatment / all
    0 / 54
    0 / 68
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Other fatal event
         subjects affected / exposed
    5 / 140 (3.57%)
    4 / 129 (3.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 5
    0 / 4
    Other non fatal events
         subjects affected / exposed
    21 / 140 (15.00%)
    18 / 129 (13.95%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Any events
         subjects affected / exposed
    91 / 140 (65.00%)
    86 / 129 (66.67%)
         occurrences causally related to treatment / all
    0 / 91
    0 / 86
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other non-fatal events
         subjects affected / exposed
    21 / 140 (15.00%)
    18 / 129 (13.95%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood and metabolic non fatal events
         subjects affected / exposed
    5 / 140 (3.57%)
    4 / 129 (3.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections
         subjects affected / exposed
    38 / 140 (27.14%)
    37 / 129 (28.68%)
         occurrences causally related to treatment / all
    0 / 38
    0 / 37
         deaths causally related to treatment / all
    0 / 3
    0 / 5
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ramipril Non-RAS Inhibitor
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    140 / 140 (100.00%)
    129 / 129 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm bening, malignant and unspecific
         subjects affected / exposed
    4 / 140 (2.86%)
    7 / 129 (5.43%)
         occurrences all number
    4
    7
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    59 / 140 (42.14%)
    23 / 129 (17.83%)
         occurrences all number
    94
    41
    General disorders and administration site conditions
    General disorder and administration site conditions
         subjects affected / exposed
    22 / 140 (15.71%)
    17 / 129 (13.18%)
         occurrences all number
    34
    25
    Immune system disorders
    Immune system disorder
         subjects affected / exposed
    2 / 140 (1.43%)
    0 / 129 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Reproductive system and breast disorder
         subjects affected / exposed
    10 / 140 (7.14%)
    4 / 129 (3.10%)
         occurrences all number
    10
    4
    Respiratory, thoracic and mediastinal disorders
    Respisratory, thoracic and mediastinal disorders
         subjects affected / exposed
    36 / 140 (25.71%)
    21 / 129 (16.28%)
         occurrences all number
    50
    29
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    13 / 140 (9.29%)
    10 / 129 (7.75%)
         occurrences all number
    16
    13
    Product issues
    Product issue
         subjects affected / exposed
    0 / 140 (0.00%)
    1 / 129 (0.78%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    37 / 140 (26.43%)
    21 / 129 (16.28%)
         occurrences all number
    55
    32
    Congenital, familial and genetic disorders
    Congenital familial and genetic disorder
         subjects affected / exposed
    0 / 140 (0.00%)
    3 / 129 (2.33%)
         occurrences all number
    0
    3
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    37 / 140 (26.43%)
    33 / 129 (25.58%)
         occurrences all number
    46
    49
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    24 / 140 (17.14%)
    16 / 129 (12.40%)
         occurrences all number
    30
    26
    Blood and lymphatic system disorders
    Blood and lymphatic system disorder
         subjects affected / exposed
    9 / 140 (6.43%)
    5 / 129 (3.88%)
         occurrences all number
    9
    6
    Ear and labyrinth disorders
    Ear and labyrinth disorder
         subjects affected / exposed
    4 / 140 (2.86%)
    1 / 129 (0.78%)
         occurrences all number
    4
    1
    Eye disorders
    Eye disorder
         subjects affected / exposed
    9 / 140 (6.43%)
    8 / 129 (6.20%)
         occurrences all number
    11
    9
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    41 / 140 (29.29%)
    34 / 129 (26.36%)
         occurrences all number
    82
    67
    Hepatobiliary disorders
    Hepatobiliary disorder
         subjects affected / exposed
    4 / 140 (2.86%)
    3 / 129 (2.33%)
         occurrences all number
    5
    3
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    12 / 140 (8.57%)
    6 / 129 (4.65%)
         occurrences all number
    16
    7
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    6 / 140 (4.29%)
    5 / 129 (3.88%)
         occurrences all number
    8
    12
    Endocrine disorders
    Endocrin disorder
         subjects affected / exposed
    14 / 140 (10.00%)
    15 / 129 (11.63%)
         occurrences all number
    17
    18
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    26 / 140 (18.57%)
    23 / 129 (17.83%)
         occurrences all number
    43
    47
    Infections and infestations
    Infections and infestatations
         subjects affected / exposed
    48 / 140 (34.29%)
    34 / 129 (26.36%)
         occurrences all number
    90
    64
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    46 / 140 (32.86%)
    33 / 129 (25.58%)
         occurrences all number
    61
    50

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Sep 2010
    Amendemnt 3: make some of the selection criteria provided by the protocol less restrictive, in order to facilitate the inclusion of patients without changing the design, objectives, or general philosophy of the initial project.
    13 Apr 2012
    Amendment 8: despite the change in the selection criteria, the expansion of the number of participating Centers and the progressive selection of the more "compliant" Centers to the commitments foreseen by the study, the enrollment trend is still not entirely satisfactory. We then revised the criteria for the sample estimate to see if it was possible to reduce the study size without changing the power of analysis. Assuming that the effect of treatment does not change, the number of patients to be randomized decreases from 312 per group to 133 per group, for a total of 266 patients (instead of the 624 originally expected).
    05 Oct 2012
    Amendment 9: updating of the participating centers list
    18 Feb 2015
    Amendment 11: Change of the Principal Investigator of the Coordinating Centre

    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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