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    Clinical Trial Results:
    A phase III, international, multicenter, randomized and openlabel study to evaluate the efficacy on LDLc and blood pressure reduction and safety of Trinomia® versus usual care in patients with high cardiovascular risk without previous cardiovascular event. The VULCANO trial.

    Summary
    EudraCT number
    		 2016-004015-13
    Trial protocol
    		 ES   PT  
    Global end of trial date
    11 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Dec 2021
    First version publication date
    02 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FMD-TRI-2016-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ferrer Internacional, S. A.
    Sponsor organisation address
    Diagonal 549 5th floor, Barcelona, Spain, 08029
    Public contact
    Emili Gil (Medical Director) , Ferrer Internacional, S. A., +34 936003700, egil@ferrer.com
    Scientific contact
    Emili Gil (Medical Director) , Ferrer Internacional, S. A., +34 936003700, egil@ferrer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine, in patients at high or very high cardiovascular risk with no previous event, whether treatment with Trinomia® after a period of 16 weeks is at least non-inferior to the usual treatment alone, in terms of SBP (systolic blood pressure) and c-LDL plasma levels.
    Protection of trial subjects
    The information disclosed and obtained during this study was considered confidential and treated as such at all times. The patients included in the study were identified only by a numerical code so that no personal data could be identified the patient collected in the database of the study sponsor. The sponsor, therefore, worked with dissociated data.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jun 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 445
    Country: Number of subjects enrolled
    Portugal: 20
    Country: Number of subjects enrolled
    Mexico: 55
    Worldwide total number of subjects
    520
    EEA total number of subjects
    465
    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)
    235
    From 65 to 84 years
    282
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 At least the minimum data necessary to confirm the selection criteria (AST/ALT, glomerular filtration, albuminuria and/or proteinuria), and and primary/secondary objectives (LDLc, total cholesterol, HDLc and triglycerides) had to be available in a blood test conducted within the previous 4 weeks.

    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
    Yes

    Arm title
    		 Trinomia
    Arm description
    		 Trinomia: acetylsalicylic acid 100 mg, atorvastatin (20 mg or 40 mg) and ramipril (2.5 mg, 5 mg or 10 mg) administered orally once a day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trinomia
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    The polypill (acetylsalicylic acid 100 mg, atorvastatin 20 or 40mg and ramipril 2.5, 5 or 10 mg) was administered orally as a single capsule per day

    Arm title
    		 Control
    Arm description
    		 The usual treatment that was being prescribed by the patients’ doctors, including the different separate drugs that the patients were already receiving before their inclusion in the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Control treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients assigned to control group continued receiving the usual treatment they were already receiving prior to inclusion in the study, maintaining the time of administration of the medication.

    Number of subjects in period 1 [1]
    		Trinomia Control
    Started
    247
    245
    Completed
    223
    236
    Not completed
    24
    9
         Consent withdrawn by subject
    -
    1
         Screening failure
    -
    1
         Adverse event, non-fatal
    16
    3
         MG/D
    1
    -
         Error in conversion of baseline medication
    1
    -
         Modification in antihypertensive treatment
    1
    -
         The patient abandons treatment
    1
    -
         Non-compliance of the study procedures
    -
    1
         Change of treatment
    1
    -
         Lost to follow-up
    -
    3
         Protocol deviation
    3
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In this study, the ITT data set was the population for the analysis of baseline characteristics, that is, all subjects who received at least one dose of the study treatment after randomisation (n=492). That is why the number of subjects reported to be in the baseline population does not coincide with the worldwide number enrolled in the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trinomia
    Reporting group description
    		 Trinomia: acetylsalicylic acid 100 mg, atorvastatin (20 mg or 40 mg) and ramipril (2.5 mg, 5 mg or 10 mg) administered orally once a day.

    Reporting group title
    Control
    Reporting group description
    		 The usual treatment that was being prescribed by the patients’ doctors, including the different separate drugs that the patients were already receiving before their inclusion in the study.

    Reporting group values
    		 Trinomia Control Total
    Number of subjects
    		 247 245 492
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 106 118 224
        From 65-84 years
    		 139 126 265
        85 years and over
    		 2 1 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.3 ± 8.3 64.0 ± 9.1 -
    Gender categorical
    Units: Subjects
        Female
    		 108 95 203
        Male
    		 139 150 289
    Race
    Units: Subjects
        Caucasian
    		 221 209 430
        Asian
    		 0 2 2
        Black
    		 1 2 3
        Pure indigenous
    		 24 29 53
        Not pure indigenous
    		 1 3 4
    Study level
    Units: Subjects
        No studies
    		 11 15 26
        Elementary education
    		 104 91 195
        Secondary education
    		 83 74 157
        University education
    		 48 64 112
        Other
    		 1 1 2
    Work situation
    Units: Subjects
        Employed
    		 71 91 162
        Unemployed
    		 23 11 34
        Retired
    		 146 139 285
        Unable/time off
    		 3 2 5
        Other
    		 4 2 6
    Baseline antiplatelet medication (acetylsalicylic acid)
    Units: Subjects
        Yes
    		 129 128 257
        No
    		 118 117 235
    Baseline dyslipidemia medication
    Units: Subjects
        Yes
    		 247 245 492
        No
    		 0 0 0
    Baseline hypertension medication
    Units: Subjects
        Yes
    		 247 245 492
        No
    		 0 0 0
    Baseline diabetes medication
    Units: Subjects
        Yes
    		 192 182 374
        No
    		 55 63 118
    Hypertension
    Units: Subjects
        Yes
    		 245 245 490
        No
    		 2 0 2
    Diabetes
    Units: Subjects
        Yes
    		 195 186 381
        No
    		 52 59 111
    Hypercholesterolemia
    Units: Subjects
        Yes
    		 240 235 475
        No
    		 7 10 17
    Hypertriglyceridemia
    Units: Subjects
        Yes
    		 46 52 98
        No
    		 185 174 359
        Missing
    		 16 19 35
    Chronic renal failure
    Units: Subjects
        Yes
    		 33 25 58
        No
    		 214 220 434
    Family history of heart disease
    Units: Subjects
        Yes
    		 21 27 48
        No
    		 205 200 405
        Missing
    		 21 18 39
    Smoking habit
    Units: Subjects
        Yes
    		 32 34 66
        No
    		 215 211 426
    Treatment with metformine
    Units: Subjects
        yes
    		 167 161 328
        No
    		 80 84 164
    Treatment with insulin glargine
    Units: Subjects
        Yes
    		 36 20 56
        No
    		 211 225 436
    Treatment with dapagliflozin
    Units: Subjects
        Yes
    		 32 22 54
        No
    		 215 223 438
    Treatment with losartan
    Units: Subjects
        Yes
    		 43 36 79
        No
    		 204 209 413
    Treatment with hydrochlorothiazide
    Units: Subjects
        Yes
    		 77 78 155
        No
    		 170 167 337
    Treatment with enalapril
    Units: Subjects
        Yes
    		 79 61 140
        No
    		 168 184 352
    Treatment with amlodipine
    Units: Subjects
        Yes
    		 52 42 94
        No
    		 195 203 398
    Treatment with atorvastatin
    Units: Subjects
        Yes
    		 89 113 202
        No
    		 158 132 290
    Treatment with simvastatin
    Units: Subjects
        Yes
    		 98 72 170
        No
    		 149 173 322
    Smoking years
    Units: years
        median (standard deviation)
    		 36.6 ± 15.0 41.0 ± 12.3 -
    Cigars per day
    Units: number of cigars
        median (standard deviation)
    		 13.1 ± 8.5 19.3 ± 38.9 -
    Albumin
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 36.8 ± 290.0 15.1 ± 33.3 -
    Proteins
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 8.8 ± 27.0 12.0 ± 36.3 -
    Albumin/Creatinine (ratio)
    Units: Ratio
        arithmetic mean (standard deviation)
    		 50.2 ± 108.2 76.7 ± 226.1 -
    Subject analysis sets

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who received at least one dose of the study treatment.

    Subject analysis set title
    Modified intention-to-treat
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized subjects who received at least one dose of the study treatment and have at least one post-baseline primary endpoint measurement.

    Subject analysis sets values
    		 Intention to treat Modified intention-to-treat
    Number of subjects
    492
    439
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    224
    195
        From 65-84 years
    265
    241
        85 years and over
    3
    3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.6 ± 8.7
    64.7 ± 8.9
    Gender categorical
    Units: Subjects
        Female
    203
    177
        Male
    289
    262
    Race
    Units: Subjects
        Caucasian
    430
    382
        Asian
    2
    1
        Black
    3
    3
        Pure indigenous
    53
    50
        Not pure indigenous
    4
    3
    Study level
    Units: Subjects
        No studies
    26
    22
        Elementary education
    195
    174
        Secondary education
    117
    142
        University education
    112
    99
        Other
    2
    2
    Work situation
    Units: Subjects
        Employed
    162
    141
        Unemployed
    34
    28
        Retired
    285
    259
        Unable/time off
    5
    5
        Other
    6
    6
    Baseline antiplatelet medication (acetylsalicylic acid)
    Units: Subjects
        Yes
    257
    233
        No
    235
    206
    Baseline dyslipidemia medication
    Units: Subjects
        Yes
    492
    439
        No
    0
    0
    Baseline hypertension medication
    Units: Subjects
        Yes
    492
    439
        No
    0
    0
    Baseline diabetes medication
    Units: Subjects
        Yes
    374
    333
        No
    118
    106
    Hypertension
    Units: Subjects
        Yes
    490
    437
        No
    2
    2
    Diabetes
    Units: Subjects
        Yes
    381
    340
        No
    111
    99
    Hypercholesterolemia
    Units: Subjects
        Yes
    475
    425
        No
    17
    14
    Hypertriglyceridemia
    Units: Subjects
        Yes
    98
    86
        No
    359
    322
        Missing
    35
    31
    Chronic renal failure
    Units: Subjects
        Yes
    58
    51
        No
    434
    388
    Family history of heart disease
    Units: Subjects
        Yes
    48
    39
        No
    405
    366
        Missing
    39
    34
    Smoking habit
    Units: Subjects
        Yes
    66
    59
        No
    426
    380
    Treatment with metformine
    Units: Subjects
        yes
    328
    294
        No
    164
    145
    Treatment with insulin glargine
    Units: Subjects
        Yes
    56
    47
        No
    436
    392
    Treatment with dapagliflozin
    Units: Subjects
        Yes
    54
    46
        No
    438
    393
    Treatment with losartan
    Units: Subjects
        Yes
    79
    70
        No
    413
    369
    Treatment with hydrochlorothiazide
    Units: Subjects
        Yes
    155
    138
        No
    377
    301
    Treatment with enalapril
    Units: Subjects
        Yes
    140
    131
        No
    352
    308
    Treatment with amlodipine
    Units: Subjects
        Yes
    94
    82
        No
    398
    357
    Treatment with atorvastatin
    Units: Subjects
        Yes
    202
    179
        No
    290
    260
    Treatment with simvastatin
    Units: Subjects
        Yes
    170
    151
        No
    322
    288
    Smoking years
    Units: years
        median (standard deviation)
    38.8 ± 13.7
    39.1 ± 13.7
    Cigars per day
    Units: number of cigars
        median (standard deviation)
    16.3 ± 28.5
    16.5 ± 30.2
    Albumin
    Units: mg/dL
        arithmetic mean (standard deviation)
    26.3 ± 209.8
    27.1 ± 222.7
    Proteins
    Units: mg/dL
        arithmetic mean (standard deviation)
    10.4 ± 32.0
    9.8 ± 29.5
    Albumin/Creatinine (ratio)
    Units: Ratio
        arithmetic mean (standard deviation)
    62.7 ± 174.4
    63.1 ± 179.0

    End points

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    End points reporting groups
    Reporting group title
    Trinomia
    Reporting group description
    		 Trinomia: acetylsalicylic acid 100 mg, atorvastatin (20 mg or 40 mg) and ramipril (2.5 mg, 5 mg or 10 mg) administered orally once a day.

    Reporting group title
    Control
    Reporting group description
    		 The usual treatment that was being prescribed by the patients’ doctors, including the different separate drugs that the patients were already receiving before their inclusion in the study.

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who received at least one dose of the study treatment.

    Subject analysis set title
    Modified intention-to-treat
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized subjects who received at least one dose of the study treatment and have at least one post-baseline primary endpoint measurement.

    Primary: Between-group difference in change in SBP from randomization to 16 weeks

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    End point title
    		 Between-group difference in change in SBP from randomization to 16 weeks
    End point description
    Primary SBP outcome was analysed in the Modified intent-to-treat (mITT) population.
    End point type
    Primary
    End point timeframe
    From randomisation to 16 weeks
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    1.14 (-0.46 to 2.73)
    -0.30 (-1.89 to 1.28)
    Statistical analysis title
    		 Primary analysis for non-inferiority
    Statistical analysis description
    To determine whether the treatment with Trinomia is non-inferior to usual care in terms of blood pressure reductions after 16 weeks of follow-up.
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.2099
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.437
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 3.69
    Notes
    [1] - The non-inferiority margin of change in SBP was 3

    Primary: Between-group difference in change in LDL cholesterol from randomization to 16 weeks

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    End point title
    		 Between-group difference in change in LDL cholesterol from randomization to 16 weeks
    End point description
    Primary LDL cholesterol outcome was analysed in the Modified intent-to-treat (mITT) population.
    End point type
    Primary
    End point timeframe
    From randomisation to week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: mg/dL
        arithmetic mean (confidence interval 95%)
    -11.50 (-14.54 to -8.46)
    -3.01 (-6.03 to 0.01)
    Statistical analysis title
    		 Primary analysis for non-inferiority
    Statistical analysis description
    To determine whether the treatment with Trinomia is non-inferior to usual care in terms of LDLc reductions after 16 weeks of follow-up.
    Comparison groups
    Control v Trinomia
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -8.489
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.78
         upper limit
    		 -4.2
    Notes
    [2] - The non-inferiority margin of change in LDLc was 10

    Secondary: Change in diastolic blood pressure at 16 weeks

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    End point title
    		 Change in diastolic blood pressure at 16 weeks
    End point description
    Secondary DBP outcome was analysed in the Modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    From randomisation to 16 weeks
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    0.12 (-0.88 to 1.11)
    -0.54 (-1.53 to 0.45)
    Statistical analysis title
    		 Analysis of change in diastolic BP
    Statistical analysis description
    The difference between the two treatment arms in the mean change in DBP from randomization to 6 months
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.3559
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.74
         upper limit
    		 2.06
    Notes
    [3] - Descriptive statistics and two sided 95% CIs

    Secondary: Change in total cholesterol at 16 weeks

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    End point title
    		 Change in total cholesterol at 16 weeks
    End point description
    Secondary total cholesterol outcome was analysed in the Modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    From randomisation to 16 weeks
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: mg/dL
        arithmetic mean (confidence interval 95%)
    -10.37 (-14.00 to -6.73)
    -0.98 (-4.59 to 2.63)
    Statistical analysis title
    		 Analysis of change in total cholesterol
    Statistical analysis description
    The difference between the two treatment arms in the mean change in total cholesterol from randomization to 6 months
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.0004
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -9.386
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.52
         upper limit
    		 -4.25
    Notes
    [4] - Descriptive statistics and two-sided 95% CIs.

    Secondary: Change in HDL cholesterol at 16 weeks

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    End point title
    		 Change in HDL cholesterol at 16 weeks
    End point description
    Secondary HDL cholesterol outcome was analysed in the Modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    From randomisation to 16 weeks
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: mg/dL
        arithmetic mean (confidence interval 95%)
    -0.47 (-1.97 to 1.03)
    -0.76 (-2.25 to 0.73)
    Statistical analysis title
    		 Analysis of change in HDL cholesterol
    Statistical analysis description
    The difference between the two treatment arms in the mean change in HDLc from randomization to 6 months
    Comparison groups
    Control v Trinomia
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.7897
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.287
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.826
         upper limit
    		 2.399
    Notes
    [5] - Descriptive statistics and two-sided 95% CIs.

    Secondary: Change in non-HDL cholesterol at 16 weeks

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    End point title
    		 Change in non-HDL cholesterol at 16 weeks
    End point description
    Secondary non-HDL cholesterol outcome was analysed in the Modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    From randomisation to 16 weeks
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: mg/dL
        arithmetic mean (confidence interval 95%)
    -10.88 (-14.58 to -7.19)
    -2.61 (-6.20 to 0.97)
    Statistical analysis title
    		 Analysis of change in non-HDL cholesterol
    Statistical analysis description
    The difference between the two treatment arms in the mean change in non-HDL cholesterol from randomization to 6 months
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.0017
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -8.269
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.42
         upper limit
    		 -3.11
    Notes
    [6] - Descriptive statistics and two-sided 95% CIs

    Secondary: Change in triglycerides at 16 weeks

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    End point title
    		 Change in triglycerides at 16 weeks
    End point description
    Secondary triglycerides outcome was analysed in the Modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    From randomisation to 16 weeks
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: mg/dL
        arithmetic mean (confidence interval 95%)
    -3.97 (-11.39 to 4.58)
    0.56 (-7.37 to 8.49)
    Statistical analysis title
    		 Analysis of change in triglycerides
    Statistical analysis description
    The difference between the two treatment arms in the mean change in triglycerides from randomization to 6 months
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.488
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.22
         upper limit
    		 7.28
    Notes
    [7] - Descriptive statistics and two-sided 95% CIs

    Secondary: Patients with blood pressure control at week 16

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    End point title
    		 Patients with blood pressure control at week 16
    End point description
    Secondary BP control outcome was analysed in the Modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: Count
        Yes
    78
    93
        No
    140
    128
    Statistical analysis title
    		 Analysis of blood pressure control at week 16
    Statistical analysis description
    The difference between the two treatment arms in the percentage of patients who achieve BP control at 16 weeks
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.2057
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [8] - Descriptive statistics

    Secondary: Patients with LDL control at week 16

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    End point title
    		 Patients with LDL control at week 16
    End point description
    Secondary BP control outcome was analysed in the Modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: Count
        Yes
    82
    63
        No
    136
    158
    Statistical analysis title
    		 Analysis of LDL control at week 16
    Statistical analysis description
    The difference between the two treatment arms in the percentage of patients who achieve LDL control at 16 weeks
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.054
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [9] - Descriptive statistics

    Secondary: Maintenance of blood pressure in patients controlled at baseline

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    End point title
    		 Maintenance of blood pressure in patients controlled at baseline
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    70
    83
    Units: Count
        Yes
    42
    61
        No
    28
    22
    Statistical analysis title
    		 Maintenance of blood pressure control
    Statistical analysis description
    To compare between groups the percentage of patients controlled at baseline who maintain BP control of BP at week 16
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    153
    Analysis specification
    Post-hoc
    Analysis type
    		 other [10]
    P-value
    		 = 0.0864
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [10] - Descriptive statistics

    Secondary: Maintenance of LDL in patients controlled at baseline

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    End point title
    		 Maintenance of LDL in patients controlled at baseline
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    52
    51
    Units: Count
        Yes
    38
    31
        No
    14
    20
    Statistical analysis title
    		 Maintenance of LDL control
    Statistical analysis description
    To compare between groups the percentage of patients controlled at baseline who maintain LDL control of BP at week 16
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    103
    Analysis specification
    Post-hoc
    Analysis type
    		 other [11]
    P-value
    		 = 0.21
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [11] - Descriptive statistics

    Secondary: Mean of cardiovascular risk SCORE at 16 weeks

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    End point title
    		 Mean of cardiovascular risk SCORE at 16 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: Percentage of risk at 10 years
        arithmetic mean (confidence interval 95%)
    5.68 (5.48 to 5.89)
    5.93 (5.73 to 6.13)
    Statistical analysis title
    		 Between-group difference in CVrisk SCORE at week16
    Statistical analysis description
    To evaluate and compare between the two treatment arms the cardiovascular risk SCORE at 10 years, in percent
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.089
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.248
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 0.04
    Notes
    [12] - Descriptive statistics

    Secondary: Patients with BP and cLDL control at week 16

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    End point title
    		 Patients with BP and cLDL control at week 16
    End point description
    Secondary BP and cLDL control was analyzed in the Modified Intent-to-Treat (mITT) population
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: Count
        Yes
    33
    32
        No
    185
    189
    Statistical analysis title
    		 Analysis of BP and LDL control at week 16
    Statistical analysis description
    The difference between the two treatment arms in the percentage of patients who achieve BP and LDC control at 16 weeks
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.8939
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [13] - Descriptive statistics

    Secondary: Mean of cardiovascular risk PCE at 16 weeks

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    End point title
    		 Mean of cardiovascular risk PCE at 16 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: Percentage of risk at 10 years
        arithmetic mean (confidence interval 95%)
    23.27 (22.58 to 23.96)
    23.96 (23.26 to 24.65)
    Statistical analysis title
    		 Between-group difference in CVrisk PCE at week16
    Statistical analysis description
    To evaluate and compare between the two treatment arms the cardiovascular risk PCE at 10 years, in percent
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.168
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.688
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.67
         upper limit
    		 0.29
    Notes
    [14] - Descriptive statistics

    Post-hoc: Cardiovascular risk SCORE at week 16, by categories

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    End point title
    		 Cardiovascular risk SCORE at week 16, by categories
    End point description
    End point type
    Post-hoc
    End point timeframe
    Week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    182
    168
    Units: Count
        < 1% (Low risk)
    25
    30
        1-5% (Moderate risk)
    75
    79
        5-10% (High risk)
    45
    46
        >10% (Very high risk)
    37
    33
    Statistical analysis title
    		 Analysis of CV risk SCORE by categories
    Statistical analysis description
    To compare between the two treatment arms the CV risk SCORE, by categories
    Comparison groups
    Control v Trinomia
    Number of subjects included in analysis
    350
    Analysis specification
    Post-hoc
    Analysis type
    		 other [15]
    P-value
    		 = 0.434
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [15] - Descriptive statistcs

    Post-hoc: Reduction in the CV risk SCORE at week16

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    End point title
    		 Reduction in the CV risk SCORE at week16
    End point description
    End point type
    Post-hoc
    End point timeframe
    From randomisation to week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    179
    185
    Units: Count
        Yes
    15
    18
        No
    164
    167
    Statistical analysis title
    		 Reduction in the CV risk SCORE at week 16
    Statistical analysis description
    To evaluate and compare between arms the number of patients who reduced the CV risk SCORE at week 16
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    364
    Analysis specification
    Post-hoc
    Analysis type
    		 other [16]
    P-value
    		 = 0.716
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [16] - Descriptive statistics

    Post-hoc: Cardiovascular risk PCE at week 16, by categories

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    End point title
    		 Cardiovascular risk PCE at week 16, by categories
    End point description
    End point type
    Post-hoc
    End point timeframe
    Week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: Count
        < 5% (Low risk)
    11
    13
        ≥ 5%- <7.5% (Moderate risk)
    9
    10
        ≥7.5%-<20% (High risk)
    66
    66
        ≥20% (Very high risk)
    99
    94
    Statistical analysis title
    		 Analysis of CV risk PCE by categories
    Statistical analysis description
    To compare between the two treatment arms the CV risk PCE, by categories
    Comparison groups
    Control v Trinomia
    Number of subjects included in analysis
    439
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.6123
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [17] - Descriptive statistcs

    Post-hoc: Reduction in the CV risk PCE at week 16

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    End point title
    		 Reduction in the CV risk PCE at week 16
    End point description
    End point type
    Post-hoc
    End point timeframe
    From randomisation to week 16
    End point values
    		 Trinomia Control
    Number of subjects analysed
    218
    221
    Units: Count
        Yes
    15
    11
        No
    170
    172
    Statistical analysis title
    		 Reduction in the CV risk PCE at week 16
    Statistical analysis description
    To evaluate and compare between arms the number of patients who reduced the CV risk PCE at week 16
    Comparison groups
    Trinomia v Control
    Number of subjects included in analysis
    439
    Analysis specification
    Post-hoc
    Analysis type
    		 other [18]
    P-value
    		 = 0.5426
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [18] - Descriptive statistics

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization up to 28 days after the End-of Treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Polypill
    Reporting group description
    		 Polypill: acetylsalicylic acid 100 mg, atorvastatin (20 mg or 40 mg) and ramipril (2.5 mg, 5 mg or 10 mg) administered orally once a day.

    Reporting group title
    Control
    Reporting group description
    		 The usual treatment that was being prescribed by the patients’ doctors, including the different separate drugs that the patients were already receiving before their inclusion in the study.

    Serious adverse events
    		 Polypill Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 247 (2.43%)
    3 / 245 (1.22%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm malignant
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Polypill Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 247 (25.51%)
    47 / 245 (19.18%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Skin papilloma
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Prostate cancer
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 247 (1.21%)
    1 / 245 (0.41%)
         occurrences all number
    3
    1
    Hypotension
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Blood pressure inadequately controlled
         subjects affected / exposed
    3 / 247 (1.21%)
    0 / 245 (0.00%)
         occurrences all number
    3
    0
    Surgical and medical procedures
    Circumcision
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Transurethral bladder resection
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Tumour excision
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Cataract operation
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 245 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Polyp
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Prostatism
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Aphonia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Catarrh
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 245 (0.82%)
         occurrences all number
    1
    2
    Cough
         subjects affected / exposed
    5 / 247 (2.02%)
    0 / 245 (0.00%)
         occurrences all number
    6
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Nervousness
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Stress
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 247 (0.40%)
    3 / 245 (1.22%)
         occurrences all number
    1
    3
    Blood creatinine increased
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Blood glucose abnormal
         subjects affected / exposed
    3 / 247 (1.21%)
    1 / 245 (0.41%)
         occurrences all number
    3
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 247 (1.21%)
    6 / 245 (2.45%)
         occurrences all number
    3
    6
    Injury, poisoning and procedural complications
    Tendon rupture
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Wound dehiscence
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 245 (0.00%)
         occurrences all number
    2
    0
    Dizziness
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 245 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Balance disorder
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Cognitive disorder
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Microcytic anaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    3 / 247 (1.21%)
    2 / 245 (0.82%)
         occurrences all number
    3
    3
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Abdominal distension
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    4 / 247 (1.62%)
    0 / 245 (0.00%)
         occurrences all number
    4
    0
    Constipation
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Diverticulum
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 245 (0.00%)
         occurrences all number
    2
    0
    Flatulence
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 247 (0.81%)
    0 / 245 (0.00%)
         occurrences all number
    2
    0
    Melaena
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Large intestine polyp
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Psoriasis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    3 / 247 (1.21%)
    1 / 245 (0.41%)
         occurrences all number
    3
    1
    Urticaria
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Ecchymosis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Lower urinary tract symptoms
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 245 (0.82%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    4 / 247 (1.62%)
    3 / 245 (1.22%)
         occurrences all number
    4
    3
    Gouty arthritis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    3 / 247 (1.21%)
    0 / 245 (0.00%)
         occurrences all number
    3
    0
    Neck pain
         subjects affected / exposed
    1 / 247 (0.40%)
    1 / 245 (0.41%)
         occurrences all number
    1
    1
    Osteitis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Fibromyalgia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Seronegative arthritis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Muscle contracture
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Balanitis candida
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Cellulitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 247 (0.40%)
    2 / 245 (0.82%)
         occurrences all number
    1
    2
    Subcutaneous abscess
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Skin bacterial infection
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Upper respiratory fungal infection
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Acarodermatitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 247 (1.21%)
    1 / 245 (0.41%)
         occurrences all number
    3
    1
    Prostate infection
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    5 / 247 (2.02%)
    3 / 245 (1.22%)
         occurrences all number
    5
    3
    Onychomycosis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 245 (0.41%)
         occurrences all number
    2
    1
    Hyperglycaemia
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 245 (0.41%)
         occurrences all number
    2
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    2 / 247 (0.81%)
    1 / 245 (0.41%)
         occurrences all number
    2
    1
    Iron deficiency
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 245 (0.00%)
         occurrences all number
    1
    0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 245 (0.41%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jan 2017
    ▪ The exclusion criteria “Patients with grade III hypertension (blood pressure> 180/110 mmHg) is added. ▪ The information on the criteria for premature withdrawal is expanded. Specifically, it adds “The recommendations of the document-Recommendations related to contraception and pregnancy testing in clinical trials-prepared by the European Clinical Trials Facilitation Group (CTFG) will be followed. ▪ The information is expanded in the definitions section.
    02 May 2017
    ▪ Change in exclusion criteria. ▪ Modification of exclusion criteria. ▪ Modification and inclusion of new information in the criteria for premature withdrawal. ▪ Inclusion of the Benefit-risk analysis section.
    15 Jan 2018
    ▪ Change the selection period. ▪ Add the time of days in telephone calls. ▪ Update the inclusion and exclusion criteria. ▪ Extend the validity period of a previous analysis from 2 to 4 weeks, and detail the minimum parameters required.
    27 Jul 2018
    ▪ Change the writing of the study objectives and variables. ▪ Modify inclusion and exclusion criteria. ▪ Add new equivalences of ACE inhibitors, statins and indapamid. ▪ Update / correct analytical parameters necessary for the randomization of patients ▪ Update statistical methods.
    08 May 2019
    ▪ Update monitoring and pharmacovigilance data of the sponsor. ▪ Update equivalences of IECAS and ARAII. ▪ Update non-inferiority limit for LDL from 6% to 10 mg/dl and assumptions of the sample size calculation. ▪ Correction of typographical errors and clarifications in the writing.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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