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    Clinical Trial Results:
    Secondary Prevention of Cardiovascular Disease in the Elderly Trial (SECURE)

    Summary
    EudraCT number
    		 2015-002868-17
    Trial protocol
    		 DE   ES   CZ   HU   IT  
    Global end of trial date
    31 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2024
    First version publication date
    18 Aug 2024
    Other versions
    Summary report(s)
    		 Synopsis

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    633765
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02596126
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC) (FSP)
    Sponsor organisation address
    C/ Melchor Fernandez Almagro 3, Madrid, Spain, 28029
    Public contact
    Antonio Jesús Quesada Navidad, Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC) (FSP), 34 91 453 12 00 1163, aquesada@cnic.es
    Scientific contact
    Jose Maria Castellano , Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC) (FSP), 34 91 453 12 00, jmcastellano.cardio@gmail.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
    10 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of a polypill strategy containing aspirin (100 mg), ramipril (2.5, 5 or 10 mgs), and atorvastatin (40 or 20 mgs) compared with the standard of care (usual care according to the local clinical practices at each participating country) in secondary prevention of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and urgent revascularization).
    Protection of trial subjects
    No relevant safety information has been generated during the trial. Moreover, no safety problems which could present a non-major benefit-risk consideration were presented during the trial so that the PVG department did not see any reason to take any different or special safety measure or even considering the premature discontinuation of this study.
    Background therapy
    		 The main aim of SECURE is to evaluate the efficacy of a polypill strategy containing aspirin (100 mg), ramipril (2.5, 5 or 10 mgs), and atorvastatin (40 or 20 mgs) compared with the standard of care (usual care according to the local clinical practices at each participating country) in secondary prevention of major cardiovascular events.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 May 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 60 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 124
    Country: Number of subjects enrolled
    Spain: 859
    Country: Number of subjects enrolled
    Czechia: 174
    Country: Number of subjects enrolled
    France: 144
    Country: Number of subjects enrolled
    Germany: 372
    Country: Number of subjects enrolled
    Hungary: 92
    Country: Number of subjects enrolled
    Italy: 734
    Worldwide total number of subjects
    2499
    EEA total number of subjects
    2499
    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)
    0
    From 65 to 84 years
    2499
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients will be recruited across seven countries in Europe (Spain, Italy, Germany, France, Hungary, Poland, and Czech Republic). Patients were ≥65 years old and diagnosed with a type 1 myocardial infarction within 6 months prior to study enrolment.

    Pre-assignment
    Screening details
    		 Patients can be screened at any time within the first 8 weeks after index event (type 1 myocardial infarction) whenever they are clinically stable and ready to receive secondary prevention therapy, including the hospital phase. Patients with ventricular arrhythmias needing further evaluation of therapy.

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    DESIGN: Multicenter, open-label, randomized, open-label, repeated-dose, adaptive parallel two arms trial, as we are comparing the pollypil with the standard of care by jugment of the physician

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard of Care
    Arm description
    		 Standard of care for secondary prevention carried out according to current ESC clinical guidelines
    Arm type
    		 Standard of Care

    Investigational medicinal product name
    Ramipril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Atorvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Rosuvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Pravastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Lovastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Pitavastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Fluvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Enalapril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Perindopril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Investigational medicinal product name
    Lisinopril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    according to current ESC clinical guidelines.

    Arm title
    		 Intervention Arm
    Arm description
    		 Patients randomized to Cardiovascular Combination Pill AAR ASA 100 mg, Atorvastatin (40) mg, Ramipril 2.5 / 5 / 10) mg. If considered necessary and per investigators’ judgment, the Cardiovascular Combination Polypill AAR 40 may be switched to Cardiovascular Combination Polypill AAR 20 (Atorvastatin 20 mg, ASA 100mg and Ramipril 2.5, 5 or 10 mg)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Acetylsalicylic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg daily

    Investigational medicinal product name
    Ramipril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 / 5 / 10 mg according to physician's criteria

    Investigational medicinal product name
    Atorvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 / 40 mg according to physician's criteria

    Number of subjects in period 1
    		Standard of Care Intervention Arm
    Started
    1241
    1258
    Completed
    1222
    1228
    Not completed
    19
    30
         Lost to follow-up
    12
    21
         Protocol deviation
    7
    9

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Standard of Care
    Reporting group description
    		 Standard of care for secondary prevention carried out according to current ESC clinical guidelines

    Reporting group title
    Intervention Arm
    Reporting group description
    		 Patients randomized to Cardiovascular Combination Pill AAR ASA 100 mg, Atorvastatin (40) mg, Ramipril 2.5 / 5 / 10) mg. If considered necessary and per investigators’ judgment, the Cardiovascular Combination Polypill AAR 40 may be switched to Cardiovascular Combination Polypill AAR 20 (Atorvastatin 20 mg, ASA 100mg and Ramipril 2.5, 5 or 10 mg)

    Reporting group values
    		 Standard of Care Intervention Arm Total
    Number of subjects
    		 1241 1258 2499
    Age categorical
    Units: Subjects
        From 65-84 years
    		 1241 1258 2499
    Gender categorical
    Units: Subjects
        Female
    		 383 392 775
        Male
    		 858 866 1724
    Subject analysis sets

    Subject analysis set title
    ITT comparison
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients, analysed according to the group to which they were randomised. This will be the population for the primary analysis.

    Subject analysis set title
    PP Population analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomised patients who received at least one dose of IMP, and have no major protocol deviations, analysed according to the group to which they were randomised. Patients with major protocol deviations will be identified before database lock and unblinding.

    Subject analysis sets values
    		 ITT comparison PP Population analysis
    Number of subjects
    2466
    2450
    Age categorical
    Units: Subjects
        From 65-84 years
    2466
    2450
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    765
    757
        Male
    1701
    1693

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Standard of Care
    Reporting group description
    		 Standard of care for secondary prevention carried out according to current ESC clinical guidelines

    Reporting group title
    Intervention Arm
    Reporting group description
    		 Patients randomized to Cardiovascular Combination Pill AAR ASA 100 mg, Atorvastatin (40) mg, Ramipril 2.5 / 5 / 10) mg. If considered necessary and per investigators’ judgment, the Cardiovascular Combination Polypill AAR 40 may be switched to Cardiovascular Combination Polypill AAR 20 (Atorvastatin 20 mg, ASA 100mg and Ramipril 2.5, 5 or 10 mg)

    Subject analysis set title
    ITT comparison
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients, analysed according to the group to which they were randomised. This will be the population for the primary analysis.

    Subject analysis set title
    PP Population analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All randomised patients who received at least one dose of IMP, and have no major protocol deviations, analysed according to the group to which they were randomised. Patients with major protocol deviations will be identified before database lock and unblinding.

    Primary: Major Cardiovascular Adverse Events (MACE)

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    End point title
    		 Major Cardiovascular Adverse Events (MACE)
    End point description
    The incidence of the first occurrence of any component of the following composite endpoint, as adjudicated by the Clinical Events Committee: - Cardiovascular death. - Any nonfatal type 1 myocardial infarction. - Any nonfatal ischemic stroke. - Any urgent coronary revascularization not resulting in death.
    End point type
    Primary
    End point timeframe
    After randomization during the trial, first occurence
    End point values
    		 Standard of Care Intervention Arm ITT comparison PP Population analysis
    Number of subjects analysed
    1241 [1]
    1258 [2]
    2466 [3]
    2450 [4]
    Units: number of adjudicated events
    156
    118
    274
    272
    Notes
    [1] - Stardard of Care
    [2] - ITT poluplation
    [3] - Total population included in the ITT analysis
    [4] - number of participants included in the PP analysis
    Statistical analysis title
    		 Non-inferiority test
    Statistical analysis description
    Non-inferiority hypotheshis will be tested using a univariable Cox PH regression model including treatment group as the only covariate and stratified by country.
    Comparison groups
    Intervention Arm v Standard of Care
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.025 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.96
    Notes
    [5] - One-sided non-inferiority test on the primary endpoint where the alpha level will be set to 2.5%. All statistical analyses will use 95% confidence intervals (CI). If the non-inferiority hypothesis is confirmed, it will be followed with a test of superiority using a log-rank test.
    [6] - One-sided test
    Statistical analysis title
    		 Superiority test
    Statistical analysis description
    If the non-inferiority hypothesis is confirmed, it will be followed with a test of superiority using a log-rank test.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval
    Notes
    [7] - Test of superiority using a log-rank test.

    Secondary: Efficacy endpoints

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    End point title
    		 Efficacy endpoints
    End point description
    a. The first occurrence of any component of the following composite endpoint: CV death, MI type 1, stroke. b. The first occurrence of the individual components of the primary endpoint - CV death. - Nonfatal type 1 myocardial infarction. - Nonfatal ischemic stroke. - Urgent coronary revascularization. c. Improvement in treatment adherence at 2 years, as measured by Morisky Medication Adherence Scale (MMAS-8). d. Change of risk factor control at 2 years - LDL-cholesterol level. - SBP. - DBP. e. Cost effectiveness of the polypill strategy. f. Performance of the polypill strategy across different socioeconomic and health settings. g. Treatment Satisfaction.
    End point type
    Secondary
    End point timeframe
    Anytime after the randomization
    End point values
    		 Standard of Care Intervention Arm ITT comparison PP Population analysis
    Number of subjects analysed
    1241
    1258
    2466
    2450
    Units: number of events
    1057
    1077
    1057
    1077
    Statistical analysis title
    		 Treatment adherence at 6 months
    Statistical analysis description
    Treatment adherence is measured at visit 1 (6 months) and visit 3 (24 months) using the Morisky- Medication Adherence Scale (8 item) Questionnaire (MMAS-8). The number and percentage of patients with low (0-5), medium (6-7) and high (8) adherence will be reported by treatment group. The distributions of the MMAS-8 score at 6 months and 24 months will be compared between treatment groups using an ordinal logistic regression model.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.005
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 1.2
    Statistical analysis title
    		 Treatment adherence at 24 months
    Statistical analysis description
    Treatment adherence is measured at visit 1 (6 months) and visit 3 (24 months) using the Morisky- Medication Adherence Scale (8 item) Questionnaire (MMAS-8). The number and percentage of patients with low (0-5), medium (6-7) and high (8) adherence will be reported by treatment group. The distributions of the MMAS-8 score at 6 months and 24 months will be compared between treatment groups using an ordinal logistic regression model.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.005
    Method
    		 Chi-squared
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.25
    Statistical analysis title
    		 SBP - 6 months
    Statistical analysis description
    The following three CV risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP) and low-density lipoprotein (LDL) cholesterol levels are measured at baseline, visit 1 (6 months), visit 2 (12 months) and visit 3 (24 months). For each of the three risk factors the frequency, mean and standard deviation at each visit will be reported by treatment group. The difference in mean change from baseline between groups will be compared using ANCOVA.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 1.2
    Notes
    [8] - The difference in mean change from baseline between groups will be compared using ANCOVA (adjusting for baseline levels) at 6 months, 12 months and 24 months. The difference in mean change adjusting for baseline and 95% CI will be reported.
    Statistical analysis title
    		 SBP - 12 months
    Statistical analysis description
    The following three CV risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP) and low-density lipoprotein (LDL) cholesterol levels are measured at baseline, visit 1 (6 months), visit 2 (12 months) and visit 3 (24 months). For each of the three risk factors the frequency, mean and standard deviation at each visit will be reported by treatment group. The difference in mean change from baseline between groups will be compared using ANCOVA.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 3
    Notes
    [9] - The difference in mean change from baseline between groups will be compared using ANCOVA (adjusting for baseline levels) at 6 months, 12 months and 24 months. The difference in mean change adjusting for baseline and 95% CI will be reported.
    Statistical analysis title
    		 SBP - 24 months
    Statistical analysis description
    The following three CV risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP) and low-density lipoprotein (LDL) cholesterol levels are measured at baseline, visit 1 (6 months), visit 2 (12 months) and visit 3 (24 months). For each of the three risk factors the frequency, mean and standard deviation at each visit will be reported by treatment group. The difference in mean change from baseline between groups will be compared using ANCOVA.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [10]
    P-value
    		 < 0.05 [11]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 1.4
    Notes
    [10] - The difference in mean change from baseline between groups will be compared using ANCOVA (adjusting for baseline levels) at 6 months, 12 months and 24 months. The difference in mean change adjusting for baseline and 95% CI will be reported.
    [11] - The difference in mean change from baseline between groups will be compared using ANCOVA (adjusting for baseline levels) at 6 months, 12 months and 24 months. The difference in mean change adjusting for baseline and 95% CI will be reported.
    Statistical analysis title
    		 DBP - 6 months
    Statistical analysis description
    The following three CV risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP) and low-density lipoprotein (LDL) cholesterol levels are measured at baseline, visit 1 (6 months), visit 2 (12 months) and visit 3 (24 months). For each of the three risk factors the frequency, mean and standard deviation at each visit will be reported by treatment group. The difference in mean change from baseline between groups will be compared using ANCOVA.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05 [12]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 1
    Notes
    [12] - The difference in mean change from baseline between groups will be compared using ANCOVA (adjusting for baseline levels) at 6 months, 12 months and 24 months. The difference in mean change adjusting for baseline and 95% CI will be reported.
    Statistical analysis title
    		 DBP - 12 months
    Statistical analysis description
    The following three CV risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP) and low-density lipoprotein (LDL) cholesterol levels are measured at baseline, visit 1 (6 months), visit 2 (12 months) and visit 3 (24 months). For each of the three risk factors the frequency, mean and standard deviation at each visit will be reported by treatment group. The difference in mean change from baseline between groups will be compared using ANCOVA.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05 [13]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 1.6
    Notes
    [13] - The difference in mean change from baseline between groups will be compared using ANCOVA (adjusting for baseline levels) at 6 months, 12 months and 24 months. The difference in mean change adjusting for baseline and 95% CI will be reported.
    Statistical analysis title
    		 DBP - 24 months
    Statistical analysis description
    The following three CV risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP) and low-density lipoprotein (LDL) cholesterol levels are measured at baseline, visit 1 (6 months), visit 2 (12 months) and visit 3 (24 months). For each of the three risk factors the frequency, mean and standard deviation at each visit will be reported by treatment group. The difference in mean change from baseline between groups will be compared using ANCOVA.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 1
    Notes
    [14] - The difference in mean change from baseline between groups will be compared using ANCOVA (adjusting for baseline levels) at 6 months, 12 months and 24 months. The difference in mean change adjusting for baseline and 95% CI will be reported.
    Statistical analysis title
    		 LDL cholesterol - 12 months
    Statistical analysis description
    The following three CV risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP) and low-density lipoprotein (LDL) cholesterol levels are measured at baseline, visit 1 (6 months), visit 2 (12 months) and visit 3 (24 months). For each of the three risk factors the frequency, mean and standard deviation at each visit will be reported by treatment group. The difference in mean change from baseline between groups will be compared using ANCOVA.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 4.4
    Statistical analysis title
    		 LDL cholesterol - 24 months
    Statistical analysis description
    The following three CV risk factors, systolic blood pressure (SBP), diastolic blood pressure (DBP) and low-density lipoprotein (LDL) cholesterol levels are measured at baseline, visit 1 (6 months), visit 2 (12 months) and visit 3 (24 months). For each of the three risk factors the frequency, mean and standard deviation at each visit will be reported by treatment group. The difference in mean change from baseline between groups will be compared using ANCOVA.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 2.4

    Secondary: Safety endpoints

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    End point title
    		 Safety endpoints
    End point description
    All-cause mortality. Non-cardiovascular death
    End point type
    Secondary
    End point timeframe
    Anytime after randomization
    End point values
    		 Standard of Care Intervention Arm ITT comparison PP Population analysis
    Number of subjects analysed
    1241
    1258
    2466
    2450
    Units: number of events
    326
    363
    345
    344
    Statistical analysis title
    		 All-cause death
    Statistical analysis description
    Time to first event will be investigated using Cox proportional hazards regression. Hazard ratios and 95% confidence intervals will be obtained from the Cox proportional hazards model. P-values will be obtained using the log-rank test.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.25
    Statistical analysis title
    		 Non-cardiovascular death
    Statistical analysis description
    Time to first event will be investigated using Cox proportional hazards regression. Hazard ratios and 95% confidence intervals will be obtained from the Cox proportional hazards model. P-values will be obtained using the log-rank test.
    Comparison groups
    Standard of Care v Intervention Arm
    Number of subjects included in analysis
    2499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 2.07

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    yearly after first patient
    Adverse event reporting additional description
    Aspirin, Atorvastatin, and Ramipril have been extensively studied in Phase 1 through Phase 4 clinical studies and their overall safety profile has been well characterized. Thus, appropriate information concerning adverse events were systematically collected and submitted to regulatory authorities
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Standard of Care
    Reporting group description
    		 Adverse Events are classified by body system according to MedDRA English V 4.0.0.97. Adverse events are displayed in absolute data and rate (%) of adverse events. In addition, adverse events are classified according to the study period (screening phase, treatment phase) and itemized by severity and relationship. The following adverse events or serious adverse events were collected and entered into the eCRF: • Adverse events leading to change of dose or permanent study drug discontinuation • All drug related adverse event: ADR, SADR and SUSAR • Bleeding: according to Bleeding Academic Research Consortium Definition • Renal dysfunction • Angioedema

    Reporting group title
    Intervention Arm
    Reporting group description
    		 -

    Serious adverse events
    		 Standard of Care Intervention Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    224 / 1229 (18.23%)
    237 / 1237 (19.16%)
         number of deaths (all causes)
    117
    115
         number of deaths resulting from adverse events
    Cardiac disorders
    Non fatal SAEs
         subjects affected / exposed
    224 / 1229 (18.23%)
    237 / 1237 (19.16%)
         occurrences causally related to treatment / all
    45 / 346
    41 / 339
         deaths causally related to treatment / all
    0 / 117
    0 / 115
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Standard of Care Intervention Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    388 / 1229 (31.57%)
    404 / 1237 (32.66%)
    Cardiac disorders
    BARC bleeding
         subjects affected / exposed
    49 / 1229 (3.99%)
    57 / 1237 (4.61%)
         occurrences all number
    49
    57
    Refractory cough
         subjects affected / exposed
    35 / 1229 (2.85%)
    40 / 1237 (3.23%)
         occurrences all number
    35
    40
    Drug Allergy
         subjects affected / exposed
    7 / 1229 (0.57%)
    14 / 1237 (1.13%)
         occurrences all number
    7
    14
    AEs of no interest
         subjects affected / exposed
    275 / 1229 (22.38%)
    269 / 1237 (21.75%)
         occurrences all number
    275
    269
    Renal and urinary disorders
    Renal
         subjects affected / exposed
    22 / 1229 (1.79%)
    24 / 1237 (1.94%)
         occurrences all number
    22
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Apr 2016
    - Added new exclusion criterion: “2. Inability to understand and comply with the protocol requirements and instructions.” - Section 4.3 and 4.4: Updated members of CEC and DSMB. - Section 7.8, 7.9, 7.11, and 8.6: Updated criteria - Section 8.3.1: Added specification of drug supply for Germany - Section 8.6: Added treatment compliance and missed dose procedure under 8.6.1. - Section 8.10.1: Updated definition of Resource Use and Costs - Section 9: patient follow-up for Germany and removed collection of Hb1Ac. - Section 10.2.4.1: Added “Definitely Related” to Assessment of Causality. - Annex 1: Name of Béla Merkely added for Hungary. - Annex 3: Definition of MI. - Annex 8: Corrected MMAS-8’s score assessment of question 5 and 8. - Annex 13: Helsinki 1996 version was added. - Annex 14: Added Withdrawal of Consent Checklist
    01 Jul 2017
    - Section 1.1: Visiting Schema updated to reflect protocol changes on data collection and inclusion criteria (time of MI increased) - Section 5, 6.1,7.2, 7.3, and 7.6: Inclusion Criteria on time of MI increased from 8 weeks to 6 months - Section 7.7: Clarified information on safety assessment and patient follow-up - Section 7.8-7.10: Reorganized, clarified, and condensed withdrawal of patient from treatment and trial discontinuation - Section 7.11: New section added to address patient follow up after site closure - Section 8.1: Updated storage conditions and added relabeling information - Section 8.3: Updated drug supply section to clarify dispensation - Section 9.1: Removed MMAS-8 from baseline, and transferred TSQM questionnaire from Baseline to six (6) month visit - Section 13.3.2. and 11.4.2: Health Economic Endpoints were further specified and definition of the data/variables to be collected were included - Section 10.3.4: Edited and updated the list of reportable Adverse Events - Annex 13.2: Helsinki 2013 version was added per the request of Hungarian authorities - Updated Investigators brochure to V4
    01 Oct 2018
    - Updated of Investigator's brochure V5 and V6
    07 Oct 2019
    - Change in the target number of patients from 3206 to 2514 with updated statistical analysis (different sections through the protocol). - Section 1.1 Visiting Schema. Updated schema including 60 months follow-up by telephone call. - Section 1.2 Study Flow chart including 60 months follow-up by telephone call. - Section 4.3 Data Safety and Monitoring Board update. - Section 4.4 Clinical Events Committee update. - Section 8.1 IMP Drug Supply - New Section 9.1.8 with telephone Follow-up 4. - Section 11.6.1 Determination of Sample Size. Updated calculations. - Annex 1: Participating Organization. Updated information of CNIC. - Updated informed consent - Updated Investigator's brochure to V7

    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.
    Although SECURE was not a blinded trial, the event adjudicators were blinded and endpoint assessment was unbiased. No adjustment was made for multiple comparisons of secondary endpoints

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36018037
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