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    Clinical Trial Results:
    A multicentre, randomised, open-label, parallel-group trial to study the safety and efficacy of a new therapeutic strategy (Trinomia®*) versus usual care on LDLc and blood pressure levels in patients with atherothrombotic cardiovascular disease: The APOLO trial.

    Summary
    EudraCT number
    		 2017-002343-14
    Trial protocol
    		 IE   ES   PT  
    Global end of trial date
    09 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Oct 2022
    First version publication date
    27 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FMD-TRI-2017-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ferrer Internacional S.A.
    Sponsor organisation address
    Avinguda Diagonal, 549, Barcelona, Spain, 08029
    Public contact
    Ferrer, Ferrer Internacional S.A., +34 936 00 37 00, clinicaldevelopment@ferrer.com
    Scientific contact
    Clinical Development Lead, Ferrer Internacional S.A., +34 662 213 660, raldonza@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
    24 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to determine whether the treatment with a new therapeutic strategy (Trinomia®)) is at least non-inferior to usual care in terms of low-density lipoprotein cholesterol (LDLc) and systolic blood pressure reductions in subjects with atherothrombotic cardiovascular disease after 6 months of treatment.
    Protection of trial subjects
    This clinical trial was conducted in accordance with the protocol, the principles established in the current revised version of the Declaration of Helsinki (Fortaleza, Brazil; October 2013), the Harmonized Tripartite Guidelines for Good Clinical Practice and applicable regulatory requirements. The study was not started until approval by the ethics committee and other pertinent authorities was obtained. By signing the protocol, the investigator agreed to adhere to the instructions and procedures described in the protocol and therefore to comply the principles of good clinical practice they entail. Any amendment changing the risk-benefit relationship for the patient was, after signature by the sponsor, submitted for evaluation by the ethics committees and the regulatory authorities for approval. The study investigators were also informed and gave their written approval for the amendment. Informed consent for participation in the study was freely granted before performing any study-specific procedure.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jun 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 192
    Country: Number of subjects enrolled
    Spain: 252
    Country: Number of subjects enrolled
    Ireland: 28
    Country: Number of subjects enrolled
    Ukraine: 83
    Worldwide total number of subjects
    555
    EEA total number of subjects
    472
    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)
    262
    From 65 to 84 years
    292
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between June 2018 and March 2021, 555 patients were enrolled in this study. Eleven patients from the Hospital Universitario Virgen del Rocío, 52 from the Hospital Gregorio Marañón, and nine from the Hospital San Juan were excluded because of an inspection and audits. Of the remaining 483 patients, 37 were screening failures and 446 were randomized.

    Pre-assignment
    Screening details
    		 Subjects ≥18 with atherothrombotic cardiovascular disease and at least one of them: previous acute myocardial infarction, cardiac revascularization with coronary stent, coronary artery bypass grafting, diagnosis of stable angina, previous ischemic stroke or peripheral artery disease. Excluded for any contraindication to the cardiovascular polypill.

    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 group
    Arm description
    		 Patients in the Trinomia group incorporated the cardiovascular polypill in their therapeutic strategy. Therefore, patients substituted the angiotensin converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB), statin and acetylsalicylic acid by the cardiovascular polypill. In addition, patients may have taken any other medication that they were taking before. Replacing the cardiovascular polypill should have been done on the basis that patients were stable and no changes in medication for LDLc and was planned. According to these premises, the doses of atorvastatin (20 or 40 mg) and ramipril (2,5 to 10 mg) were chosen according to the equivalent doses of ARBs/ACEIs and statins that he/she had been taken before entering the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cardiovascular polypill
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Each capsule contains 100 mg of acetylsalicylic acid, 20 mg or 40 mg of atorvastatin and 2.5 mg, 5 mg, or 10 mg of ramipril. Excipients with known effect: 73.61 mg of lactose monohydrate and 0.48 mg of soy lecithin. Size 0 hard gelatine capsules with opaque pale pink-coloured cap and body (the cardiovascular polypill 100 mg/ 20 or 40 mg/ 10 mg), opaque pale pink-coloured cap and opaque pale grey-coloured body (the cardiovascular polypill 100 mg/ 20 or 40 mg/ 5 mg) or opaque pale grey-coloured cap and body (the cardiovascular polypill 100 mg/20 or 40 mg/ 2.5 mg), imprinted with “AAR 100/20/10”, “AAR 100/40/10”, “AAR 100/20/5”, “AAR 100/40/5”, “AAR 100/20/2.5”, or “AAR 100/40/2.5”. The capsules contain: 2 white or nearly white film-coated tables engraved “AS” of 50 mg of acetylsalicylic acid; 2 greenish-brownish film-coated tablets engraved “AT” of 10 or 20 mg of atorvastatin; 1 pale yellow film-coated tablet engraved “R1”, “R5” or “R2” of 10, 5 or 2.5 mg of ramipril, respectively.

    Arm title
    		 Control group
    Arm description
    		 Patients assigned to group B continued receiving the usual treatment they were already receiving prior to inclusion in the study, maintaining the time of administration of the medication. When necessary, the patient collected the prescribed treatment at the local pharmacy as per routine clinical practice, according to the characteristics of each country. Patients were instructed not to modify the treatment regimen they had been following prior to their inclusion in the study. Likewise, the patient was instructed about the need to maintain the same diet and physical activity that he/she had been doing before entering the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Control treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The treatment for cardiovascular prevention considered as optimal by the investigator at patient’s enrolment, including acetylsalicylic acid, lipid-lowering agents (statins) and renin-angiotensin-aldosterone system blockers. Pharmaceutical form used for clinical practice.

    Number of subjects in period 1 [1]
    		Trinomia group Control group
    Started
    218
    226
    Completed
    187
    201
    Not completed
    31
    25
         Consent withdrawn by subject
    4
    -
         Other
    5
    3
         Adverse events or toxicities
    9
    2
         Concomitant disease
    1
    -
         Lost to follow-up
    4
    8
         Modification of study treatment
    3
    8
         Protocol deviation
    5
    4
    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: 72 patients were excluded because of inspections/audits and 37 for screen failure reasons. Additionally, 2 patients from Trinomia group didn't take medication and were also excluded.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trinomia group
    Reporting group description
    		 Patients in the Trinomia group incorporated the cardiovascular polypill in their therapeutic strategy. Therefore, patients substituted the angiotensin converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB), statin and acetylsalicylic acid by the cardiovascular polypill. In addition, patients may have taken any other medication that they were taking before. Replacing the cardiovascular polypill should have been done on the basis that patients were stable and no changes in medication for LDLc and was planned. According to these premises, the doses of atorvastatin (20 or 40 mg) and ramipril (2,5 to 10 mg) were chosen according to the equivalent doses of ARBs/ACEIs and statins that he/she had been taken before entering the study.

    Reporting group title
    Control group
    Reporting group description
    		 Patients assigned to group B continued receiving the usual treatment they were already receiving prior to inclusion in the study, maintaining the time of administration of the medication. When necessary, the patient collected the prescribed treatment at the local pharmacy as per routine clinical practice, according to the characteristics of each country. Patients were instructed not to modify the treatment regimen they had been following prior to their inclusion in the study. Likewise, the patient was instructed about the need to maintain the same diet and physical activity that he/she had been doing before entering the study.

    Reporting group values
    		 Trinomia group Control group Total
    Number of subjects
    		 218 226 444
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.30 ( 9.83 ) 65.97 ( 8.73 ) -
    Gender categorical
    Units: Subjects
        Female
    		 43 52 95
        Male
    		 175 174 349
    Race/ethnicity
    Units: Subjects
        White
    		 217 222 439
        African American
    		 1 2 3
        Hispanic American
    		 0 1 1
        Black
    		 0 1 1
    Hypertension
    Units: Subjects
        Yes
    		 198 210 408
        No
    		 18 15 33
        Not available
    		 2 1 3
    Diabetes Mellitus
    Units: Subjects
        Type 1
    		 3 1 4
        Type 2
    		 77 76 153
        No
    		 136 148 284
        Not available
    		 2 1 3
    Hypercholesterolemia
    Units: Subjects
        Yes
    		 170 180 350
        No
    		 46 45 91
        Not available
    		 2 1 3
    Hypertriglyceridemia
    Units: Subjects
        Yes
    		 20 26 46
        No
    		 166 185 351
        Not available
    		 32 15 47
    Chronic renal disease
    Units: Subjects
        Stage I
    		 0 1 1
        Stage II
    		 2 4 6
        Stage IIIA
    		 9 8 17
        No
    		 202 208 410
        Not available
    		 5 5 10
    Family history premature cardiovascular events
    Units: Subjects
        Yes
    		 21 16 37
        No
    		 157 166 323
        Not available
    		 40 44 84
    Alcohol consumption
    Units: Subjects
        < 4 units per week
    		 31 38 69
        4-8 units per week
    		 12 24 36
        > 8 units per week
    		 16 24 40
        No
    		 129 113 242
        Not available
    		 30 27 57
    Acute myocardial infarction
    Units: Subjects
        Yes
    		 83 84 167
        No
    		 133 141 274
        Not available
    		 2 1 3
    Cardiac revascularization with coronary stent
    Units: Subjects
        Yes
    		 63 74 137
        No
    		 153 151 304
        Not available
    		 2 1 3
    Cardiac revascularization with coronary artery bypass grafting
    Units: Subjects
        Yes
    		 23 25 48
        No
    		 193 200 393
        Not available
    		 2 1 3
    Stable angina
    Units: Subjects
        Yes
    		 26 31 57
        No
    		 190 194 384
        Not available
    		 2 1 3
    Ischemic stroke
    Units: Subjects
        Yes
    		 82 87 169
        No
    		 134 138 272
        Not available
    		 2 1 3
    Extracranial stenosis
    Units: Subjects
        Yes
    		 19 23 42
        No
    		 63 63 126
        Not available
    		 136 140 276
    Intracranial stenosis
    Units: Subjects
        Yes
    		 16 13 29
        No
    		 66 73 139
        Not available
    		 136 140 276
    Lacunar infarction
    Units: Subjects
        Yes
    		 37 44 81
        No
    		 45 42 87
        Not available
    		 136 140 276
    Peripheral artery disease
    Units: Subjects
        Yes
    		 54 54 108
        No
    		 162 171 333
        Not available
    		 2 1 3
    Antiplatelet and anticoagulant medication: Aspirin
    Units: Subjects
        Yes
    		 213 225 438
        No
    		 3 0 3
        Not available
    		 2 1 3
    Antiplatelet and anticoagulant medication: Other
    Units: Subjects
        Yes
    		 42 38 80
        No
    		 174 187 361
        Not available
    		 2 1 3
    Subjects with at least one antiplatelet medication
    Units: Subjects
        Clopidogrel
    		 24 18 42
        Prasugrel
    		 0 1 1
        Ticagrelor
    		 7 6 13
        Other
    		 6 10 16
        None
    		 181 191 372
    Subjects with at least one anticoagulant medication
    Units: Subjects
        Acenocumarol (sintrom)
    		 2 0 2
        Rivaroxaban
    		 1 1 2
        Other
    		 1 1 2
        None
    		 214 224 438
    Subjects with at least one medication for dyslipidaemia
    Units: Subjects
        Yes
    		 216 225 441
        Not available
    		 2 1 3
    Medication for dyslipidaemia: Atorvastatin
    Units: Subjects
        Yes
    		 138 148 286
        No
    		 80 78 158
    Medication for dyslipidaemia: Ezetimibe
    Units: Subjects
        Yes
    		 23 23 46
        No
    		 195 203 398
    Medication for dyslipidaemia: Rosuvastatin
    Units: Subjects
        Yes
    		 47 43 90
        No
    		 171 183 354
    Medication for dyslipidaemia: Simvastatin
    Units: Subjects
        Yes
    		 21 27 48
        No
    		 197 199 396
    Subjects with at least one medication for hypertension
    Units: Subjects
        Yes
    		 216 225 441
        Not available
    		 2 1 3
    Medication for hypertension: ACEI-Enalapril
    Units: Subjects
        Yes
    		 44 33 77
        No
    		 174 193 367
    Medication for hypertension: ACEI-Ramipril
    Units: Subjects
        Yes
    		 70 86 156
        No
    		 148 140 288
    Medication for hypertension: Beta-blockers-Bisoprolol
    Units: Subjects
        Yes
    		 58 55 113
        No
    		 160 171 331
    Medication for hypertension: Calcium antagonists-Amlodipine
    Units: Subjects
        Yes
    		 44 35 79
        No
    		 174 191 365
    Medication for hypertension: Thiazide diuretics-Hidrochlorothiazide
    Units: Subjects
        Yes
    		 28 29 57
        No
    		 190 197 387
    Smoking habits
    Units: Subjects
        Yes
    		 38 41 79
        No
    		 164 178 342
        Not available
    		 16 7 23

    End points

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    End points reporting groups
    Reporting group title
    Trinomia group
    Reporting group description
    		 Patients in the Trinomia group incorporated the cardiovascular polypill in their therapeutic strategy. Therefore, patients substituted the angiotensin converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB), statin and acetylsalicylic acid by the cardiovascular polypill. In addition, patients may have taken any other medication that they were taking before. Replacing the cardiovascular polypill should have been done on the basis that patients were stable and no changes in medication for LDLc and was planned. According to these premises, the doses of atorvastatin (20 or 40 mg) and ramipril (2,5 to 10 mg) were chosen according to the equivalent doses of ARBs/ACEIs and statins that he/she had been taken before entering the study.

    Reporting group title
    Control group
    Reporting group description
    		 Patients assigned to group B continued receiving the usual treatment they were already receiving prior to inclusion in the study, maintaining the time of administration of the medication. When necessary, the patient collected the prescribed treatment at the local pharmacy as per routine clinical practice, according to the characteristics of each country. Patients were instructed not to modify the treatment regimen they had been following prior to their inclusion in the study. Likewise, the patient was instructed about the need to maintain the same diet and physical activity that he/she had been doing before entering the study.

    Primary: Changes in SBP from baseline to month 6 (mITT)

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    End point title
    		 Changes in SBP from baseline to month 6 (mITT)
    End point description
    The mean ± SD SBP at baseline was 133.80 ± 15.6 mmHg for the Trinomia group and 136.10 ± 16.25 mmHg for the control group. The model-adjusted mean (95% CI) at 6 months was 140.17 (137.97; 142.38) mmHg for the Trinomia group and 136.56 (134.44; 138.69) mmHg for the control group.
    End point type
    Primary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [1]
    193 [2]
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    5.19 (2.82 to 7.56)
    1.40 (-0.88 to 3.69)
    Notes
    [1] - mITT population
    [2] - mITT population
    Statistical analysis title
    		 ANCOVA analysis
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0022
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 6.99

    Primary: Changes in LDLc from baseline to month 6 (mITT)

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    End point title
    		 Changes in LDLc from baseline to month 6 (mITT)
    End point description
    The mean ± SD LDLc at baseline was 80.20 ± 31.74 mg/dl in the Trinomia group and 83.51 ± 33.90 mg/dl for the control group. The model-adjusted mean (95% CI) at 6 months was 78.80 (75.42; 82.17) mg/dl for the Trinomia group and 80.07 (76.83; 73.32) mg/dl for the control group.
    End point type
    Primary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [3]
    193 [4]
    Units: mg/dl
        arithmetic mean (confidence interval 95%)
    -3.15 (-6.52 to 0.23)
    -1.87 (-5.11 to 1.38)
    Notes
    [3] - mITT population
    [4] - mITT population
    Statistical analysis title
    		 ANCOVA analysis
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.5828
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.84
         upper limit
    		 3.29

    Primary: Changes in SBP from baseline to month 6 (PP)

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    End point title
    		 Changes in SBP from baseline to month 6 (PP)
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    73 [5]
    111 [6]
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    7.54 (3.91 to 11.17)
    0.94 (-2.10 to 3.99)
    Notes
    [5] - PP population
    [6] - PP population
    Statistical analysis title
    		 ANCOVA analysis
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0044
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    6.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.08
         upper limit
    		 11.11

    Primary: Changes in LDLc from baseline to month 6 (PP)

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    End point title
    		 Changes in LDLc from baseline to month 6 (PP)
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    73 [7]
    111 [8]
    Units: mg /dl
        arithmetic mean (confidence interval 95%)
    -1.01 (-6.09 to 4.07)
    -2.06 (-6.29 to 2.17)
    Notes
    [7] - PP population
    [8] - PP population
    Statistical analysis title
    		 ANCOVA analysis
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.7443
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.29
         upper limit
    		 7.38

    Primary: Changes in SBP from baseline to month 6 (ITT)

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    End point title
    		 Changes in SBP from baseline to month 6 (ITT)
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    218
    226
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    4.72 (2.42 to 7.02)
    1.36 (-0.88 to 3.60)
    Statistical analysis title
    		 ANCOVA analysis
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0039
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 6.48

    Primary: Changes in LDLc from baseline to month 6 (ITT)

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    End point title
    		 Changes in LDLc from baseline to month 6 (ITT)
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    218
    226
    Units: mg /dl
        arithmetic mean (confidence interval 95%)
    -3.46 (-6.81 to -0.12)
    -2.14 (-5.36 to 1.64)
    Statistical analysis title
    		 ANCOVA analysis
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.5648
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.86
         upper limit
    		 3.2

    Secondary: Changes in SBP from baseline to month 6 by atherothrombotic cardiovascular disease

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    End point title
    		 Changes in SBP from baseline to month 6 by atherothrombotic cardiovascular disease
    End point description
    Na = number of patients of Trinomia group for each disease. Nb = number of patients of control group for each disease.
    End point type
    Secondary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [9]
    193 [10]
    Units: mmHg
    arithmetic mean (confidence interval 95%)
        Coronary artery disease (Na=79; Nb=89)
    3.04 (-0.00 to 6.09)
    2.90 (0.03 to 5.77)
        Stroke (Na=56; Nb=67)
    2.90 (-0.36 to 6.16)
    -0.61 (-3.59 to 2.37)
        Peripheral artery disease (Na=39; Nb=37)
    9.84 (3.99 to 15.69)
    -2.16 (-8.16 to 3.85)
    Notes
    [9] - mITT population
    [10] - mITT population
    Statistical analysis title
    		 ANCOVA analysis (coronary artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    P-value
    		 = 0.9459
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.07
         upper limit
    		 4.36
    Notes
    [11] - Subjects in this analysis: 168
    Statistical analysis title
    		 ANCOVA analysis (stroke)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    P-value
    		 = 0.119
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 7.93
    Notes
    [12] - Subjects in this analysis: 123
    Statistical analysis title
    		 ANCOVA analysis (peripheral artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    P-value
    		 = 0.0057
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.61
         upper limit
    		 20.39
    Notes
    [13] - Subjects in this analysis: 76

    Secondary: Changes in LDLc from baseline to month 6 by atherothrombotic cardiovascular disease

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    End point title
    		 Changes in LDLc from baseline to month 6 by atherothrombotic cardiovascular disease
    End point description
    Na = number of patients of Trinomia group for each disease. Nb = number of patients of control group for each disease.
    End point type
    Secondary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [14]
    193 [15]
    Units: mg /dl
    arithmetic mean (confidence interval 95%)
        Coronary artery disease (Na=79; Nb=89)
    -4.86 (-10.02 to 0.30)
    -2.43 (-7.29 to 2.43)
        Stroke (Na=56; Nb=67)
    -2.82 (-8.22 to 2.57)
    -1.05 (-5.98 to 3.88)
        Peripheral artery disease (Na=39; Nb=37)
    -0.10 (-7.40 to 7.21)
    -2.12 (-9.63 to 5.38)
    Notes
    [14] - mITT population
    [15] - mITT population
    Statistical analysis title
    		 ANCOVA analysis (coronary artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [16]
    P-value
    		 = 0.5001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.52
         upper limit
    		 4.68
    Notes
    [16] - Subjects in this analysis: 168
    Statistical analysis title
    		 ANCOVA analysis (stroke)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [17]
    P-value
    		 = 0.6322
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.09
         upper limit
    		 5.54
    Notes
    [17] - Subjects in this analysis: 123
    Statistical analysis title
    		 ANCOVA analysis (peripheral artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [18]
    P-value
    		 = 0.7007
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.45
         upper limit
    		 12.5
    Notes
    [18] - Subjects in this analysis: 76

    Secondary: Evaluation of patients with LDLc and SBP under control according to 2016 European Guidelines

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    End point title
    		 Evaluation of patients with LDLc and SBP under control according to 2016 European Guidelines
    End point description
    End point type
    Secondary
    End point timeframe
    At month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [19]
    193 [20]
    Units: patients
        Patients under LDLc control
    47
    59
        Patients under SBP control
    48
    65
        Patients under LDLc & SBP control
    16
    22
    Notes
    [19] - mITT population
    [20] - mITT population
    Statistical analysis title
    		 Fisher's exact test (LDLc)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.423
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.37
         upper limit
    		 12.79
    Statistical analysis title
    		 Fisher's exact test (SBP)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.171
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.81
         upper limit
    		 15.81
    Statistical analysis title
    		 Fisher's exact test (LDLc and SBP)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.352
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 9

    Secondary: Evaluation of changes in diastolic blood pressure (DBP)

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    End point title
    		 Evaluation of changes in diastolic blood pressure (DBP)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [21]
    193 [22]
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    0.95 (-0.28 to 2.18)
    0.41 (-0.75 to 1.58)
    Notes
    [21] - mITT population
    [22] - mITT population
    Statistical analysis title
    		 ANCOVA analysis
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.5338
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 2.23

    Secondary: Evaluation of changes in lipid profile

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    End point title
    		 Evaluation of changes in lipid profile
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [23]
    193 [24]
    Units: mg/dl
    arithmetic mean (confidence interval 95%)
        Total Cholesterol
    -2.68 (-6.44 to 1.07)
    0.27 (-3.30 to 3.84)
        HDLc
    0.75 (-0.86 to 2.36)
    0.67 (-0.86 to 2.20)
        non-HDLc
    -7.01 (-11.18 to -2.84)
    -0.71 (-4.58 to 3.17)
        Triglycerides
    -5.85 (-12.43 to 0.73)
    -0.64 (-6.89 to 5.61)
    Notes
    [23] - mITT population
    [24] - mITT population
    Statistical analysis title
    		 ANCOVA analysis (Total Cholesterol)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.2636
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.14
         upper limit
    		 2.23
    Statistical analysis title
    		 ANCOVA analysis (HDLc)
    Comparison groups
    Control group v Trinomia group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9421
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.14
         upper limit
    		 2.3
    Statistical analysis title
    		 ANCOVA analysis (non-HDLc)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0302
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12
         upper limit
    		 0.61
    Statistical analysis title
    		 ANCOVA analysis (Triglycerides)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.2597
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.29
         upper limit
    		 3.87

    Secondary: Diastolic blood pressure (DBP) by atherothrombotic cardiovascular diseases

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    End point title
    		 Diastolic blood pressure (DBP) by atherothrombotic cardiovascular diseases
    End point description
    Na = number of patients of Trinomia group for each disease. Nb = number of patients of control group for each disease.
    End point type
    Secondary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [25]
    193 [26]
    Units: mmHg
    arithmetic mean (confidence interval 95%)
        Coronary artery disease (Na=79; Nb=89)
    1.01 (-0.73 to 2.74)
    2.12 (0.48 to 3.76)
        Stroke (Na=56; Nb=67)
    -1.31 (-3.64 to 1.02)
    -0.86 (-2.99 to 1.27)
        Peripheral artery disease (Na=39; Nb=37)
    4.10 (1.63 to 6.57)
    -1.42 (-3.96 to 1.12)
    Notes
    [25] - mITT population
    [26] - mITT population
    Statistical analysis title
    		 ANCOVA analysis (coronary artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [27]
    P-value
    		 = 0.3588
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 1.28
    Notes
    [27] - Subjects in this analysis: 168
    Statistical analysis title
    		 ANCOVA analysis (stroke)
    Comparison groups
    Control group v Trinomia group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [28]
    P-value
    		 = 0.78
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 2.71
    Notes
    [28] - Subjects in this analysis: 123
    Statistical analysis title
    		 ANCOVA analysis (peripheral artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [29]
    P-value
    		 = 0.0028
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    5.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.97
         upper limit
    		 9.07
    Notes
    [29] - Subjects in this analysis: 76

    Secondary: Total Cholesterol by atherothrombotic cardiovascular diseases

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    End point title
    		 Total Cholesterol by atherothrombotic cardiovascular diseases
    End point description
    Na = number of patients of Trinomia group for each disease. Nb = number of patients of control group for each disease.
    End point type
    Secondary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [30]
    193 [31]
    Units: mg/dl
    arithmetic mean (confidence interval 95%)
        Coronary artery disease (Na=79; Nb=89)
    -3.74 (-9.58 to 2.10)
    1.93 (-3.58 to 7.43)
        Stroke (Na=56; Nb=67)
    -3.62 (-9.38 to 2.15)
    -1.04 (-6.30 to 4.23)
        Peripheral artery disease (Na=39; Nb=37)
    0.60 (-8.43 to 9.62)
    -1.13 (-10.40 to 8.13)
    Notes
    [30] - mITT population
    [31] - mITT population
    Statistical analysis title
    		 ANCOVA analysis (coronary artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [32]
    P-value
    		 = 0.1659
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.71
         upper limit
    		 2.37
    Notes
    [32] - Subjects in this analysis:168
    Statistical analysis title
    		 ANCOVA analysis (stroke)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [33]
    P-value
    		 = 0.5141
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.39
         upper limit
    		 5.23
    Notes
    [33] - Subjects in this analysis: 76
    Statistical analysis title
    		 ANCOVA analysis (peripheral artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [34]
    P-value
    		 = 0.7909
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (net)
    Point estimate
    1.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.22
         upper limit
    		 14.67
    Notes
    [34] - Subjects in this analysis: 123

    Secondary: HDLc by atherothrombotic cardiovascular diseases

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    End point title
    		 HDLc by atherothrombotic cardiovascular diseases
    End point description
    Na = number of patients of Trinomia group for each disease. Nb = number of patients of control group for each disease.
    End point type
    Secondary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [35]
    193 [36]
    Units: mg/dl
    arithmetic mean (confidence interval 95%)
        Coronary artery disease (Na=79; Nb=89)
    0.83 (-0.70 to 2.35)
    3.07 (1.64 to 4.51)
        Stroke (Na=56; Nb=67)
    0.33 (-2.99 to 3.64)
    -2.18 (-5.21 to 0.85)
        Peripheral artery disease (Na=39; Nb=37)
    0.74 (-2.77 to 4.25)
    0.53 (-3.07 to 4.13)
    Notes
    [35] - mITT population
    [36] - mITT population
    Statistical analysis title
    		 ANCOVA analysis (coronary artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [37]
    P-value
    		 = 0.0353
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.35
         upper limit
    		 0.16
    Notes
    [37] - Subjects in this analysis: 168
    Statistical analysis title
    		 ANCOVA analysis (stroke)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [38]
    P-value
    		 = 0.2735
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 7.01
    Notes
    [38] - Subjects in this analysis: 123
    Statistical analysis title
    		 ANCOVA analysis (peripheral artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [39]
    P-value
    		 = 0.9338
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.82
         upper limit
    		 5.24
    Notes
    [39] - Subjects in this analysis: 76

    Secondary: non-HDLc by atherothrombotic cardiovascular diseases

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    End point title
    		 non-HDLc by atherothrombotic cardiovascular diseases
    End point description
    Na = number of patients of Trinomia group for each disease. Nb = number of patients of control group for each disease.
    End point type
    Secondary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [40]
    193 [41]
    Units: mg/dl
    arithmetic mean (confidence interval 95%)
        Coronary artery disease (Na=79; Nb=89)
    -7.58 (-14.05 to -1.11)
    -2.09 (-8.07 to 3.88)
        Stroke (Na=56; Nb=67)
    -6.81 (-13.40 to -0.21)
    0.20 (-5.79 to 6.18)
        Peripheral artery disease (Na=39; Nb=37)
    -5.88 (-15.81 to 4.04)
    1.52 (-8.23 to 11.27)
    Notes
    [40] - mITT population
    [41] - mITT population
    Statistical analysis title
    		 ANCOVA analysis (coronary artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [42]
    P-value
    		 = 0.2204
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.3
         upper limit
    		 3.32
    Notes
    [42] - Subjects in this analysis: 168
    Statistical analysis title
    		 ANCOVA analysis (stroke)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [43]
    P-value
    		 = 0.1225
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.93
         upper limit
    		 1.92
    Notes
    [43] - Subjects in this analysis: 123
    Statistical analysis title
    		 ANCOVA analysis (peripheral artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [44]
    P-value
    		 = 0.2906
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.32
         upper limit
    		 6.51
    Notes
    [44] - Subjects in this analysis: 76

    Secondary: Triglycerides by atherothrombotic cardiovascular diseases

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    End point title
    		 Triglycerides by atherothrombotic cardiovascular diseases
    End point description
    Na = number of patients of Trinomia group for each disease. Nb = number of patients of control group for each disease.
    End point type
    Secondary
    End point timeframe
    From baseline to month 6
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [45]
    193 [46]
    Units: mg/dl
    arithmetic mean (confidence interval 95%)
        Coronary artery disease (Na=79; Nb=89)
    -8.35 (-17.60 to 0.90)
    -0.44 (-9.15 to 8.28)
        Stroke (Na=56; Nb=67)
    -8.52 (-19.58 to 2.54)
    -0.71 (-10.83 to 9.40)
        Peripheral artery disease (Na=39; Nb=37)
    2.24 (-14.22 to 18.71)
    -0.16 (-17.07 to 16.75)
    Notes
    [45] - mITT population
    [46] - mITT population
    Statistical analysis title
    		 ANCOVA analysis (coronary artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [47]
    P-value
    		 = 0.2209
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -7.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.62
         upper limit
    		 4.8
    Notes
    [47] - Subjects in this analysis:
    Statistical analysis title
    		 ANCOVA analysis (peripheral artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [48]
    P-value
    		 = 0.305
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -7.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.8
         upper limit
    		 7.2
    Notes
    [48] - Subjects in this analysis: 123
    Statistical analysis title
    		 ANCOVA analysis (peripheral artery disease)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [49]
    P-value
    		 = 0.8403
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.27
         upper limit
    		 26.07
    Notes
    [49] - Subjects in this analysis: 76

    Secondary: Total Score of treatment Satisfaction Questionnaire for medication (TSQM-9)

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    End point title
    		 Total Score of treatment Satisfaction Questionnaire for medication (TSQM-9)
    End point description
    The questions of TSQM-9 refer to three dimensions: effectiveness (questions 1 to 3), convenience (questions 4 to 6) and global satisfaction (questions 7 to 9). In addition to the calculation of the total score for the nine individual questions of TSQM-9, a score can also be calculated for the three dimensions of effectiveness, convenience and global satisfaction. In this calculation also,the total score of the three dimensions can be between 0 and 100. A higher total score equates to greater satisfaction.
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174 [50]
    193 [51]
    Units: score
    number (not applicable)
        Efectiveness
    69.2
    65.3
        Convenience
    73.1
    65.1
        Global satisfaction
    69.1
    66.6
    Notes
    [50] - mITT population
    [51] - mITT population
    Statistical analysis title
    		 Mann-Whitney test (effectiveness)
    Comparison groups
    Control group v Trinomia group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Mann-Whitney test (Convenience)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Mann-Whitney test (Global satisfaction)
    Comparison groups
    Trinomia group v Control group
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0678
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Ad-hoc questions. How practical is it to take the cardiovascular?

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    End point title
    		 Ad-hoc questions. How practical is it to take the cardiovascular?
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174
    193
    Units: patients
        Very practical
    139
    0
        Relatively practical
    25
    0
        Relatively unpractical
    1
    0
        Very unpractical
    1
    0
        No answer/non-applicable
    8
    193
    No statistical analyses for this end point

    Secondary: Ad-hoc questions. Which would you choose?

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    End point title
    		 Ad-hoc questions. Which would you choose?
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174
    193
    Units: patients
        Cardiovascular polypill
    157
    0
        3 drugs separately
    9
    0
        No answer/non-applicable
    8
    193
    No statistical analyses for this end point

    Secondary: Ad-hoc questions. Which of the 2 options seems more convenient or practical for you?

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    End point title
    		 Ad-hoc questions. Which of the 2 options seems more convenient or practical for you?
    End point description
    End point type
    Secondary
    End point timeframe
    throughout the study
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174
    193
    Units: patients
        Cardiovascular polypill
    161
    0
        3 drugs separately
    5
    0
        No answer/ non-applicable
    8
    193
    No statistical analyses for this end point

    Secondary: Ad-hoc questions. Which of the 2 options seems the most trustworthy?

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    End point title
    		 Ad-hoc questions. Which of the 2 options seems the most trustworthy?
    End point description
    End point type
    Secondary
    End point timeframe
    throughout the study
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174
    193
    Units: patients
        Cardiovascular polypill
    148
    0
        3 drugs separately
    18
    0
        No answer/ non-applicable
    8
    193
    No statistical analyses for this end point

    Secondary: Ad-hoc questions. Would you switch to the cardiovascular polypill?

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    End point title
    		 Ad-hoc questions. Would you switch to the cardiovascular polypill?
    End point description
    End point type
    Secondary
    End point timeframe
    throughout the study
    End point values
    		 Trinomia group Control group
    Number of subjects analysed
    174
    193
    Units: patients
        Yes, absolutely
    0
    95
        I would have to think about it
    0
    59
        No, never
    0
    11
        I do not know/no reply
    0
    19
        No answer/ non-applicable
    174
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    7 months approximately
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Trisomia group (safety population)
    Reporting group description
    		 -

    Reporting group title
    Control group (safety population)
    Reporting group description
    		 -

    Serious adverse events
    		 Trisomia group (safety population) Control group (safety population)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 174 (3.45%)
    13 / 193 (6.74%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal cancer
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypovolaemic shock
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular tachycardia
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Implantable defibrillator insertion
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 193 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Boutonneuse fever
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (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
    		 Trisomia group (safety population) Control group (safety population)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 174 (25.86%)
    35 / 193 (18.13%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Breast cancer
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Polycythaemia vera
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Renal cancer
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Skin papilloma
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Renal cell carcinoma
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 174 (2.30%)
    2 / 193 (1.04%)
         occurrences all number
    4
    2
    Haematoma
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Hypovolaemic shock
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Peripheral ischaemia
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Embolism
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Surgical and medical procedures
    Implantable defibrillator insertion
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 174 (0.57%)
    2 / 193 (1.04%)
         occurrences all number
    1
    2
    Fatigue
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Illness
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 193 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 193 (0.00%)
         occurrences all number
    2
    0
    Dyspnoea
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Mood altered
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Psychomotor retardation
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 193 (0.00%)
         occurrences all number
    2
    0
    Blood potassium increased
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 193 (0.00%)
         occurrences all number
    2
    0
    Liver function test abnormal
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 193 (1.04%)
         occurrences all number
    0
    2
    Atrial fibrillation
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 193 (1.04%)
         occurrences all number
    0
    2
    Ventricular tachycardia
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 193 (1.04%)
         occurrences all number
    0
    3
    Acute myocardial infarction
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Bundle branch block right
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 193 (0.00%)
         occurrences all number
    2
    0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Ischaemic stroke
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Epigastric discomfort
         subjects affected / exposed
    2 / 174 (1.15%)
    1 / 193 (0.52%)
         occurrences all number
    2
    1
    Abdominal discomfort
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Colitis ischaemic
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Dysphagia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Cutaneous vasculitis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Xerotic dermatitis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Skin disorder
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 193 (0.00%)
         occurrences all number
    2
    0
    Renal colic
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Acute kidney injury
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 174 (1.15%)
    1 / 193 (0.52%)
         occurrences all number
    2
    1
    Neck pain
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 193 (0.00%)
         occurrences all number
    2
    0
    Groin pain
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 193 (1.04%)
         occurrences all number
    0
    2
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 193 (0.00%)
         occurrences all number
    2
    0
    COVID-19
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 193 (1.04%)
         occurrences all number
    0
    2
    Boutonneuse fever
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Localised infection
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Haematoma infection
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 193 (0.52%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 174 (0.00%)
    2 / 193 (1.04%)
         occurrences all number
    0
    2
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 193 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2017
    Initial submission in Spain. Request of additional information by INFARMED and the EC in Portugal; addition of new exclusion criteria and clarification of Baseline Visit procedures.
    22 Dec 2017
    Only for Spain and Ireland. An exclusion criterion is added, the recruitment period is modified, clarifications are added regarding concomitant medication and study treatment. Correction of mistakes.
    12 Apr 2018
    Exclusion criteria are added at the request of INFARMED (Portugal) and clarifications of the Baseline visit procedures. Also applied to Spain and Ireland.
    15 Jun 2018
    Inclusion of 12 new sites in Portugal.
    04 Oct 2018
    Notice to inform study participants on the protection of personal data in Portugal.
    11 Jan 2019
    Title adaptation, IMP renaming, rewording of study objectives and endpoints, changes in inclusion/exclusion criteria, addition of new equivalence to ramipril and atorvastatine (inlcuidng the addition of ezetimibe 10 mg or atorvastatin 40 mg for patients taking atorvastatine 80 mg), update and correction of lab test parameters necessary for randomisation, update of statistical methods and non inferiority limit for LDL, changes in the assumptions for the sample size calculations and changes in sample size . Administrative changes.
    22 Feb 2019
    Include central laboratory in Ukraine.
    28 May 2019
    Only for Portugal. New version of the General PIS/ICF (version 2.4, dated 27 August 2019), the PIS/ICF for Pregnancy Follow-up (version 2.4, dated 27 August 2019) and Patient Card (version 1.1, dated 14 May 2019): inclusion of a new site.
    01 Oct 2019
    Inclusion of 3 new sites in Portugal.
    20 Dec 2019
    Inclusion of 4 new sites in Ireland.

    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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