Secondary Prevention of Cardiovascular Disease in the Elderly Trial
Phase: PHASE3
Conditions: Myocardial Infarction, Cardiovascular Disease
Sponsor: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III



 
Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
Version 5.0   25/09/2019 
CNIC Confidential 
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Site Principal Investigator Signature Page  
 
PROTOCOL TITLE: Secondary Prevention of Cardiovascular Disease in the Elderly Population 
(SECURE) 
 
 
PROTOCOL NUMBER:     633765 
  
EudraCT Number: 2015-002868-17 
 
 
 
 
 
CONFIDENTIALITY AND cGCP COMPLIANCE STATEMENT 
 
I have read the preceding clinical study protocol entitled: “Secondary Prevention of Cardiovascular 
Disease in the Elderly Population (SECURE)” and agree that it contains all necessary information for 
conducting the study. 
 
I hereby confirm that I have carefully read and understood this clinical study protocol, and I agree to 
that my staff and I will conduct the study according to the study protocol and will comply with its 
requirements, including ethical and safety considerations. 
I understand that, should the Sponsor decide to prematurely terminate or suspend the study for 
whatever reason such decision will be communicated to me in writing. Conversely, if I decide to 
withdraw from execution of the study I will immediately communicate such a decision to the Sponsor. 
I agree not to publish any part of the results of the study carried out under this clinical study protocol 
without the prior written consent of the Sponsor. 
 
Site Principal Investigator 
 
 
 
 
 
 
 
 
 
 
                              ______________________________________ 
 
                               Signature 
 
 
 
 
    
                                _____________________________________ 
 
                                Date 
 
 
 
 
 
 
 
 
Centro Nacional de Investigaciones Cardiovasculares (CNIC) 
Address: c/Melchor Fernandez Almagro 3, Madrid 28029, Spain 
Telephone: (34) 914531200 
Fax: (34) 914531265 
 
 
 

 
Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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CNIC Confidential 
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DOCUMENT HISTORY 
 
Document 
Version 
Version Date 
Original protocol- VHP Approved 
2.1 
14 December 2015 
Amendment 1 
3.0 
21 April 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 per the request of German Lead Ethics Committee to 
clarify compulsory discontinuation criteria of the trial, study, and withdrawal of patients. 
 
- 
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 Resource Use and Costs in order to clarify the definition and variables 
to be collected. 
 
- 
Section 9: Clarified 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: Added clarification on 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 
Amendment 2 
4.0 
1 July 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: 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 

 
Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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- 
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 
 
Amendment 3 
5.0 
11 June 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 
 
- 
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 
 
 

 
Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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CLINICAL TRIAL SUMMARY 
PRINCIPAL 
INVESTIGATOR/TRIAL 
LOCATION 
Dr. Valentin Fuster, MD, PhD 
Centro Nacional de Investigaciones Cardiovasculares 
Carlos III (CNIC) 
Calle del Melchor Fernández Almagro 3 
28029 Madrid, Spain 
INVESTIGATIONAL 
MEDICINAL PRODUCTS 
(IMPs): 
Cardiovascular Combination Polypill AAR (acetylsalicylic 
acid 100 mg, atorvastatin 40 mg or 20 mg, and ramipril 10, 5 
and 2.5 mg). 
STUDY OBJECTIVES 
Primary Objective 
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). 
 
The secondary objectives are to evaluate a polypill strategy 
as compared with standard of care for secondary 
cardiovascular prevention after MI in  an elderly population 
in: 
- 
reducing other clinical endpoints. 
- 
improving baseline adherence.  
- 
improving quality of life. 
- 
controlling 
cardiovascular 
risk 
factors. 
(LDL 
cholesterol, systolic and diastolic blood pressure). 
- 
Cost-effectiveness  
- 
safety and tolerability 
- 
patient satisfaction  
- 
performance across the different socioeconomic and 
health settings.  
STUDY DESIGN 
Multicenter, open-label, randomized, open-label, repeated-
dose, adaptive parallel two arms trial. 
STUDY POPULATION 
 
 
 
 
 
 
 
 
 
 
Main Selection Criteria 
Inclusion and Exclusion Criteria 
A total of N=2514 patients will participate in this study 
(n=1257 polypill group, n=1257 control group). 
 
Subjects will be recruited in seven European countries 
(Spain, Italy, Germany, France, Hungary, Poland, and Czech 
Republic) 
 
Approximately 115 active sites (i.e, sites with SIV 
performed) 
Inclusion Criteria 
1. Giving consent after information. 
2. Patients diagnosed with a type 1 myocardial infarction 
within the previous 6 months.  
3. Subjects must be ≥65 years old, presenting with at least 
one of the following additional conditions: 
i. 
Documented diabetes mellitus or previous 
treatment with oral hypoglycemic drugs or 

 
Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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insulin.  
ii. 
Mild to moderate renal dysfunction: creatinine 
clearance 60-30 mL/min/1.73 m2. 
iii. 
Prior myocardial infarction: defined as an AMI 
occurring before the index event documented in 
a medical report. 
iv. 
Prior coronary revascularization: coronary artery 
bypass grafting (CABG) or percutaneous 
coronary intervention (PCI). 
v. 
Prior stroke: history of a documented stroke, 
defined as an acute episode of focal cerebral, 
spinal, or retinal dysfunction caused by 
infarction of central nervous system tissue, not 
resulting in death. 
vi. 
Age ≥ 75 years. 
Exclusion Criteria 
 
1. Unable to sign informed consent. 
2. Inability to understand and comply with the 
protocol requirements and instructions. 
3. Contraindications to any of the components of 
the polypill. 
4. Living in a nursing home or committed to an 
institution by virtue of and order issued by the 
judicial or the administrative authorities. 
5. Mental illness limiting the capacity of self-care. 
6. Participating in another clinical trial. 
7. Severe congestive heart failure (NYHA III-IV). 
8. Severe renal disease (Creatinine Clearance 
(CrCl) <30ml/min/1.73 m2). 
9. Severe hepatic impairment. Liver cirrhosis 
transaminases exceeding 3 times the upper limit 
of the normal limit.  
10. Allergies to lactose, peanut, or soy. 
11. Need for oral anticoagulation at the time of 
randomization or planned in the future months. 
12. Any condition limiting life expectancy <2 years, 
including but not limited to active malignancy. 
13. Significant arrhythmias (including unresolved 
ventricular arrhythmias or atrial fibrillation). 
14. Scheduled coronary revascularization (patients 
can be randomized after final revascularization is 
completed within the pre-specified timeframe). 
15. Do not agree to the filing, forwarding and use of 
his/ her pseudonymised data. 
16. Individuals dependent from the sponsor, 
investigator or investigational site/institution. 
 
INVESTIGATIONAL 
PRODUCT 
 
Formulation(s): 
 
 
INTERVENTION ARM 
 
Patients randomized to Cardiovascular Combination Pill 
AAR arm will receive one of the following treatments: 
 
 

 
Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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Route(s) of administration: 
 
Dose Regimen: 
 
 
Cardiovascular Combination Polypill AAR 40  
ASA 100 mg, Atorvastatin 40 mg, Ramipril 2.5mg 
ASA 100 mg, Atorvastatin 40 mg, Ramipril 5 mg 
ASA 100 mg, Atorvastatin 40 mg, Ramipril 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) 
 
Oral 
 
Intervention Arm: once daily administration of one capsule 
(Cardiovascular Combination Polypill AAR). 
 
Usual Care: Standard of care for secondary prevention will 
be carried out according to current ESC clinical guidelines. 
STUDY PROCEDURES AND 
TREATMENT: 
Once the inclusion and exclusion criteria are confirmed, 
written consent will be obtained and patients will be included 
in the study. All patients will be assigned a unique study ID 
number.  
Randomization will occur within 6 months of the index event 
(AMI) in a 1:1 ratio to one of the two arms: 
 
Cardiovascular Combination Polypill AAR 40 
 
Usual care 
Patients randomized to the Cardiovascular Combination 
Polypill AAR arm will begin treatment within 6 months of 
the index event at the discretion of the physician. 
There will be 3 follow-up visits at month 6, 12 and 24 and 3 
telephone follow-up at month 18, 36 and 48. 
STUDY DURATION PER 
PATIENT 
Patients will be followed up for a minimum of 2 years and a 
maximum of 4 years. 
SAMPLE SIZE ESTIMATION 
AND INTERIM ANALYSIS 
The sample size of 2514 patients, with an accrual period of 
three years and a minimum follow-up of two years. Based on 
these assumptions and a primary event rate of 7.7% per year 
over a median 3.8 years follow-up and an estimated loss to 
follow-up of 1%, 2514 patients will provide 78% power to 
demonstrate a relative risk reduction of 21% with a two-
sided alpha of 0.05 
 
A total of 1257 will be assigned to each treatment arm.  
 
Non-inferiority will be tested first with the pre-specified non-
inferiority margin of HR = 1.373. If the non-inferiority 
hypothesis is confirmed, superiority testing will be 
conducted 

 
Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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Adaptive design: An unblinded interim analysis will be 
performed in order to check if the initial assumptions for 
sample size calculations (estimated event rate) are met with a 
possibility of the increase in the sample size and/or a long-
term follow up to.  
EVALUATION CRITERIA 
Primary Endpoint  
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. 
Secondary Endpoints 
1. Efficacy endpoints 
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.  
 
2. Safety endpoints 
a. All-cause mortality. 
b. Adverse Events 
i. Bleeding  
ii. Renal dysfunction. 
iii. Drug allergic reaction. 
iv. Refractory cough leading to drug 
discontinuation. 
c. Drug Discontinuation. 
EVENT REPORTING 
Study endpoints should be reported after collecting all 
relevant clinical information (medical records, death 
certificate, imaging techniques, etc.) in order to adjudicate 
clinical events.  

 
Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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1.2 Study Flow chart 
                                               
1Medication supply will be done every 3-6 months. 
2 Blood pressure and heart rate, a mean of two readings after 5 min sitting rest. 
 
 
 
Assessments1 
 
Study Visits 
Screening 
and 
baseline 
Visit 1    
(6m + 2 w) 
Visit 2  
(12m + 2 w) 
Phone 1  
(18m + 2 w) 
V3 
(24m + 2 w) 
Phone 2 
(36m + 4 w) 
Phone 3 
(48m + 4 w) 
Phone 4 
(60m + 4 w) 
Informed Consent 
x 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
 
 
 
 
 
 
 
Randomization (R) 
x 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
Physical 
examination 
including body 
weight 
x 
 
 
 
 
 
 
 
Vital signs and 
blood pressure2 
x 
x 
x 
 
x 
 
 
 
Previous/concomita
nt medications 
x 
x 
x 
x 
x 
x 
x 
x 
Non-fasting blood 
analysis 
x 
 
x 
 
x 
 
 
 
Adherence 
 
x 
 
 
x 
 
 
 
Quality of Life 
x 
 
 
 
x 
 
 
 
TSQM 
 
x 
 
 
x 
 
 
 
Resources 
Utilization 
 
x 
x 
 
x 
 
 
 
Outcomes  
 
x 
x 
x 
x 
x 
x 
x 
Adverse Event 
Reporting 
 
 

Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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TABLE OF CONTENTS 
CLINICAL TRIAL SUMMARY ..................................................................................................... 6 
 
VISITING SCHEMA .............................................................................................................. 10 
1.1 
Visiting Schema .................................................................................................................... 10 
1.2 
Study Flow chart ................................................................................................................... 11 
 
LIST OF ABBREVIATIONS ................................................................................................. 16 
 
INTRODUCTION ................................................................................................................... 18 
3.1 
Background Information ....................................................................................................... 18 
3.2 
Rationale ............................................................................................................................... 20 
3.3 
Hypothesis ............................................................................................................................. 20 
 
STUDY COMMITTEES ........................................................................................................ 21 
4.1 
Executive Committee ............................................................................................................ 21 
4.2 
Steering Committee ............................................................................................................... 21 
4.3 
Data Safety and Monitoring Board ....................................................................................... 21 
4.4 
Clinical Events Committee .................................................................................................... 21 
 
STUDY OBJECTIVES ........................................................................................................... 22 
5.1 
Primary Objective ................................................................................................................. 22 
5.2 
Secondary Objectives ............................................................................................................ 22 
 
STUDY DESIGN ..................................................................................................................... 22 
6.1 
Description of Study Design ................................................................................................. 22 
6.2 
Study Design ......................................................................................................................... 23 
6.3 
Duration of Study Participation ............................................................................................. 23 
6.4 
Interim Analysis .................................................................................................................... 23 
 
PATIENT SELECTION/ENROLLMENT ........................................................................... 24 
7.1 
Number of Patients ................................................................................................................ 24 
7.2 
Patient Screening ................................................................................................................... 24 
7.3 
Inclusion Criteria ................................................................................................................... 24 
7.4 
Exclusion Criteria .................................................................................................................. 24 
7.5 
Informed Consent .................................................................................................................. 25 
7.6 
Randomization ...................................................................................................................... 25 
7.7 
Post Randomization Safety Assessment................................................................................ 25 
7.8 
Withdrawal of Patients .......................................................................................................... 26 
7.8.1 
Withdrawal of Consent .................................................................................................. 26 
7.8.2 
Trial Discontinuation ..................................................................................................... 26 
7.8.3 
Investigator’s request .................................................................................................... 26 
7.9 
Lost to Follow-up .................................................................................................................. 27 
7.10 
Discontinuation of Study Treatment ................................................................................. 27 
 
 ............ 27 
7.10.1.1 
Temporary Discontinuation Definition ................................................................. 27 
7.10.1.2 
Temporary Discontinuation Criteria ..................................................................... 27 
 
 ....................................................................................... 28 
7.10.2.1 
Permanent Discontinuation Definition .................................................................. 28 
7.10.2.2 
Permanent Discontinuation Criteria ...................................................................... 28 
7.11 
Patient Follow up After Site Closure. ............................................................................... 29 

Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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7.12 
End of Trial Definition ...................................................................................................... 29 
7.13 
Criteria for Discontinuation of the Trial ............................................................................ 29 
 
TREATMENTS ....................................................................................................................... 29 
 
Identity of Investigational Medicinal Products (IMPs) ......................................................... 29 
 
 ................................................................................................................... 29 
8.1.2 
Contraindications to IMP .............................................................................................. 29 
 
 ................................................................................................................... 34 
 
 .................................................................................................................. 34 
8.1.5 
Storage conditions ......................................................................................................... 34 
 
 ............................................................................................... 34 
8.1.7 
IMPs administered ......................................................................................................... 34 
8.2 
Blinding ................................................................................................................................. 35 
8.3 
Drug Supply .......................................................................................................................... 35 
8.3.1 
Drug Supply in the Intervention Arm ............................................................................ 35 
8.3.2 
Drug Supply in the Usual Care Arm ............................................................................. 35 
8.3.3 
Receipt of Drug Supplies .............................................................................................. 36 
8.3.4 
Return or Destruction of Drug Supply .......................................................................... 36 
8.4 
Dose Regimen ....................................................................................................................... 36 
 
 ................................................................................................................... 36 
8.6 
Treatment Compliance .......................................................................................................... 38 
Study drug accountability will be performed at each visit. Intentional or unintentional stopping 
of study drug by either the patient or investigator or other physician must be documented. The 
following criteria will be used: .................................................................................................. 38 
8.6.1 
Missed dose ................................................................................................................... 38 
8.7 
Prior and Concomitant Therapy ............................................................................................ 38 
8.8 
Treatment Adherence ............................................................................................................ 38 
8.9 
Quality of Life ....................................................................................................................... 38 
8.10 
Health Economic Evaluation ............................................................................................. 38 
 
 ............................................................................................ 38 
 
STUDY PROCEDURES ......................................................................................................... 39 
9.1 
Visit Schedule ....................................................................................................................... 39 
9.1.1 
Screening and Baseline ................................................................................................. 39 
9.1.2 
Visit 1 (At 6 months Post Randomization ± 2 weeks) .................................................. 40 
9.1.3 
Visit 2 (At 12 months Post Randomization ± 2 weeks) ................................................ 40 
9.1.4 
Telephone Follow-up 1 (At 18 months Post Randomization ± 2 weeks) ...................... 40 
9.1.5 
Visit 3 (At 24 months Post Randomization ± 2 weeks) ................................................ 40 
9.1.6 
Telephone Follow-up 2 (At 36 months Post Randomization ± 4 weeks) ...................... 41 
9.1.7 
Telephone Follow-up 3 (48 months Post Randomization ± 4 weeks) ........................... 41 
9.1.8 
Telephone Follow-up 4 (60 months Post Randomization ± 4 weeks) ........................... 41 
9.1.9 
Treatment Duration ....................................................................................................... 41 
 
STUDY ASSESSMENTS .................................................................................................... 42 
10.1 
Assessment Schema .......................................................................................................... 42 
10.2 
Primary Endpoints ............................................................................................................. 42 
10.3 
Secondary Endpoints ......................................................................................................... 43 
10.3.1 
Efficacy Endpoints .................................................................................................... 43 
10.3.2 
Health Economic Endpoints ...................................................................................... 43 
10.3.3 
Safety Endpoints ....................................................................................................... 44 
10.3.4 
Adverse Events (AE) Assessment Guidelines ........................................................... 44 

Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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Figure 2. Clinical Events Flow Chart ........................................................................................ 44 
 
DATA MANAGEMENT AND STATISTICAL ANALYSIS .......................................... 50 
11.1 
Data Management and Coding .......................................................................................... 50 
11.2 
Statistical Methods ............................................................................................................ 50 
11.2.1 
Statistical and Analytical Plans ................................................................................. 50 
11.3 
Demographic and Other Baseline Characteristics ............................................................. 51 
11.4 
Variables ........................................................................................................................... 51 
11.4.1 
Definition of Primary Endpoint ................................................................................. 51 
11.4.2 
Definition of Secondary Endpoints............................................................................ 51 
11.5 
Methods of Analysis.......................................................................................................... 52 
11.6 
Safety Variables ................................................................................................................ 53 
11.6.1 
Determination of Sample Size ................................................................................... 54 
11.6.2 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan ......... 55 
 
INVESTIGATOR/SPONSOR RESPONSIBILITIES ..................................................... 55 
12.1 
Ethics ................................................................................................................................. 55 
12.1.1 
Ethics Committee ...................................................................................................... 55 
12.1.2 
Ethical Conduct of the Study..................................................................................... 55 
12.1.3 
Patient Information and Consent ............................................................................... 55 
12.2 
Patient Records and Source Data ...................................................................................... 56 
12.2.1 
Archiving ................................................................................................................... 56 
12.3 
Monitoring ......................................................................................................................... 56 
12.4 
Access to Source Data and Documentation ...................................................................... 57 
12.5 
Quality Assurance and Audit ............................................................................................ 57 
12.6 
Protocol Amendments ....................................................................................................... 57 
12.7 
Financing and Insurance .................................................................................................... 58 
12.8 
Report and Publication ...................................................................................................... 58 
 
ANNEXES TO CLINICAL PROTOCOL ........................................................................ 59 
Annex 1: Participating Organization .............................................................................................. 59 
Annex 2: The Data Safety and Monitoring Board (DSMB) ........................................................... 60 
Annex 3: Definition of Myocardial Infarction24, 25 ......................................................................... 62 
Annex 4: Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical 
Trials25 ............................................................................................................................................ 67 
13.1.1 
Definition of Cardiovascular Death .......................................................................... 67 
13.1.2 
Definition of Noncardiovascular Death .................................................................... 68 
13.1.3 
Definition of Undetermined Death ............................................................................ 68 
13.1.4 
Definition of Urgent Coronary Revascularization. ................................................... 69 
13.1.5 
Definition of Transient Ischemic Attack and Stroke ................................................. 69 
Annex 5: Safety Measures – Bleeding Definition22 ........................................................................ 70 
Annex 6: Notes on Use of Atorvastatin 40mg on the Elderly in a Post MI setting ........................ 71 
Annex 7: Drug Equivalence ........................................................................................................... 72 
Annex 8: The Morisky-Medication Adherence Scale (8 item) Questionnaire ............................... 73 
Annex 9: Treatment Satisfaction Questionnaire for Medication (TSQM) ..................................... 74 
Annex 10: European Quality of Life- 5 Dimensions (EQ-5D) Questionnaire ............................... 77 
Annex 11: Identification of a Protocol Deviation or Violation ...................................................... 78 
Annex 12: Management of Urgent Safety Measures (Clinical Trials) ........................................... 79 
Annex 13. DECLARATION OF HELSINKI 1996 ........................................................................ 80 
Annex 13.2. DECLARATION OF HELSINKI 2013 ..................................................................... 83 
Annex 14: Withdrawal of Consent Checklist ................................................................................. 89 

Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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LIST OF ABBREVIATIONS 
ACC 
American College of Cardiology 
ADR 
Adverse Drug Reaction 
AEs 
Adverse Events 
ACEI 
Angiotensin Converting Enzyme Inhibitors 
AMI 
Acute Myocardial Infarction 
ARBs 
Angiotensin II Receptor Blockers 
ASA 
Acetylsalicylic acid 
BP 
Blood Pressure 
CA 
Consortium Agreement 
CAD 
Coronary Artery Disease 
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
CHD 
Coronary Heart Disease 
CNIC 
Centro Nacional de Investigaciones Cardiovasculares 
CTA 
Clinical Trial Application 
CTU 
Clinical Trial Units 
CAD 
Coronary Artery Disease 
CVD 
Cardiovascular Disease 
DBP 
Diastolic Blood Pressure 
EMA 
European Medicines Agency 
ESC 
European Society of Cardiology 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EC 
Ethics Committee 
EU 
European Union 
EUROASPIRE 
III 
European Action on Secondary Prevention through Intervention to Reduce 
Events 
EQ-5D 
European Quality of Life-5 Dimensions 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
FRS 
Framingham Risk Score 
GA 
General Assembly 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
HRQoL 
Health Related Quality of Life 
ICER 
Incremental cost-effectiveness ratio 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IP 
Intellectual Property 
IPR 
Intellectual Property Rights 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LMIC 
Low and Middle Income Countries 
MACE 
Major Adverse Cardiovascular Events 
MI 
Myocardial Infarction 
MAQ 
Morisky-Green Questionnaire 
MMAS-8 
Eight Item Morisky Medication Adherence Scale 

Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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NCA 
National Competent Authorities 
PGEU 
Pharmaceutical Group of the European Union 
PURE 
Prospective Urban Rural Epidemiology 
QALY 
Quality-Adjusted Life Year 
RCT 
Randomized Clinical Trial 
SAEs 
Serious AEs 
SBP 
Systolic blood pressure 
SADR 
Serious Adverse Drug Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TSC 
Trial Steering Committee 
USA 
United States of America 
WHO 
World Health Organization 
 
 
 

Protocol Title: Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) 
Funded by H2020 Programme  
Protocol ID: 633765 
 
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INTRODUCTION 
3.1 Background Information 
Cardiovascular disease (CVD) has become the number one cause of death among men and women 
aged over 65 in Europe1, and the magnitude of the burden of CVD is expected to grow in parallel 
with the projected aging population.2 Moreover, the overall ageing of the European population 
(projected to almost double by 2060 – rising from 85 million in 2008 to 151 million in 2060 in the 
EU)2 and improving survival of patients with Coronary Heart Disease (CHD) has created a large 
population of older adults eligible for secondary prevention.  
There is ample evidence on the massive treatment gap and room for improvement in secondary 
prevention. The European Action on Secondary Prevention through Intervention to Reduce Events 
(EUROASPIRE III) demonstrated that 54% of patients with a previous myocardial infarction (MI) 
had not achieved target blood pressure (BP) levels and 51% of patients had not achieved target low-
density lipoprotein cholesterol (LDL-C) levels.3  
On a global scale, the scenario is even more worrisome and wide variations in the use of cardio 
protective drug therapies exist among countries. Data from the Prospective Urban Rural 
Epidemiology (PURE) study showed that among participants with a history of CHD or stroke, only 
25% were taking antiplatelet drugs, 17% were taking beta blockers, 20% were taking angiotensin 
converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) and 15% were 
taking statins 5 years after their event.4 In low and middle income countries (LMIC) within the 
same study, the use of these drugs was as low as 3%.  
Despite ground-breaking advances in therapeutic interventions, rates of CVD mortality remain high 
mainly because patients are not following ideal medical management. The administration of 
guideline recommended CV medications (i.e.: statins, antihypertensive, and antithrombotic agents) 
remains the most common medical intervention for secondary prevention of CVD. It has been 
estimated that these medications alone might be responsible for half of the overall 50% reduction in 
mortality from coronary artery disease (CAD) observed over the past 20 years in some western 
countries.1  
However, the efficacy of guideline recommended treatment is seriously hampered mainly due to 
non-adherence. Multiple registries have shown that CV treatments are nearly universally prescribed 
at discharge after a coronary event, shifting the focus from the prescribers adhering to clinical 
guidelines onto the multiple factors that impede adherence to medications by the patients. It is 
estimated that 20% to 30% of patients do not adhere to medication regimens that are curative or 
relieve symptoms, and 30% to 40% fail to follow regimens designed to prevent health problems. 
When long-term medication is prescribed, 50% of patients fail to adhere to the prescribed regimen. 
Unfortunately, and despite the established efficacy of CV medications, adherence in patients taking 
these medications for prevention of CVD has been estimated at only 57% in a recent meta-analysis 
of almost 400,000 patients.5  
Suboptimal adherence reduces the effectiveness of these essential medications and is the primary 
reason for suboptimal clinical benefit, contributing significantly to worsening of diseases and deaths 
at the population level.6 Absolute and relative risk assessments demonstrate that a considerable 
proportion of all CVD events (∼9% in Europe) could be attributed to poor adherence to vascular 
medications alone.7 Furthermore, medication non-adherence carries a huge medical and economic 
burden. According to the Pharmaceutical Group of the European Union (PGEU), it has been 
estimated that there are 194,500 deaths a year in the EU due to miss-dose and non-adherence to 
prescribed medication, resulting in an estimated cost of 125 billion € annually.8 The issue is 
particularly relevant in wealthier nations, where access to and use of healthcare systems are high, 
and where further increasing the effectiveness of a medication could rely largely on improving 
adherence levels. 

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Non adherence is a complex phenomenon and barriers to adherence include factors related to the 
patient, the prescriber, and the health care system.6 Certain characteristics inherent to the elderly 
population (such as treatment complexity, polypharmacy, poor accessibility to medical care and 
lack of treatment affordability) render this population especially vulnerable to CVD and preclude 
adequate CV prevention. Although medication non adherence in the elderly is not well described in 
the literature, increased frequency of dosing and treatment complexity have repeatedly been shown 
to decrease adherence.6 Therefore, a better understanding of the burden of non-adherence to CV 
medication in the elderly, where evidence is incomplete, as well as developing and scaling up 
interventions to improve levels of adherence in this population, seem reasonable in order to have a 
societal, economic and health impact.  
Ratified estimates of non-adherence in the older-aged with chronic conditions vary from 40% to 
75%.9 Non-adherence to medication regimens in the older-aged, regardless of disease state, is a 
common cause of residential care and hospital admissions. Eleven percent of hospital admissions in 
the ≥65-year age group are the result of non-adherence, and this increases to 26% in the ≥75-year 
age group. An even greater percentage (33%) of the older-aged undergoing hospitalization has a 
history of non-adherence.9 
In addition to hospitalizations, re-hospitalizations and residential care admissions resulting from 
non-adherence in the older-aged are responsible for direct costs to society. In many cases, it seems 
likely that improvements in health outcomes and/or savings in healthcare utilization will repay the 
costs of improving adherence.  
One of the barriers to adherence that has been consistently shown in registries, studies and trials is 
the number of pills and treatment complexity.10, 11 In this aspect, the last decade has seen a surge of 
technical innovation in order to propose a polypill strategy to effectively improve adherence at the 
same time that it serves as a therapeutic vehicle to improve accessibility in LMIC.12  
Recently a large body of data regarding the effects of the polypill on adherence has been published. 
Three important randomized clinical trials have recently tested the effect of such an approach of 
adherence, showing spectacular results. Kanyini GAP,13 IMPACT14 and UMPIRE15 found relative 
risks of being adherent on the polypill compared to usual care of 1.49 (95% CI; 1.30-1.72; 
p<0.001); 1.75 (95% CI; 1.52-2.03; p<0.001); and 1.33 (95% CI; 1.26-1.41; p<0.001) respectively.  
Beyond the results of these studies, the FOCUS (Fixed-dose Combination Drug for Secondary 
Cardiovascular Prevention) study, funded under the Seventh Framework Programme, has tried to 
answer the fundamental question of which factors impede adequate adherence to CV drugs in 
secondary prevention, as well as carrying out a RCT to study the impact of a polypill on adherence 
(measured through direct, pill count, as well as indirect self-reported methods) in a post MI 
population.16 The study consisted of a cross-sectional study (Phase 1) aimed to elucidate factors that 
interfere with appropriate adherence to CV medications for secondary prevention after an AMI. 
Additionally, 695 patients from phase 1 were randomized into a controlled clinical trial (Phase 2) to 
test the effect of a polypill (containing aspirin 100 mg, simvastatin 40mg and ramipril 2.5, 5 or 10 
mg) compared to the three drugs given separately on adherence, blood pressure (BP) and low 
density lipoprotein cholesterol (LDL-C), as well as safety and tolerability over a period of 9 months 
of follow-up. In phase 1, a 5-country cohort (Argentina, Brazil, Italy, Paraguay, and Spain) of 2118 
patients was analyzed. Patients were randomized to either the polypill or the three drugs separately 
for phase 2. Primary end-point was adherence to the treatment measured at the final visit by the 
self-reported Morisky-Green questionnaire (MAQ) and pill count (patients had to meet both criteria 
for adherence at the in-person visit in order to be considered adherent). 
In phase 1, overall CV medication adherence defined as a MAQ score of 20 was 45.5%. In a 
multivariable regression model, the risk of being non-adherent (MAQ<20) was associated with 
younger age, depression, being on a complex medication regimen, poorer health insurance 
coverage, and a lower level of social support, with consistent findings across countries.  

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In Phase 2, the polypill group showed improved adherence compared to the group receiving 
separate medications after 9 months follow up: 50.8% vs 41% (p=0.019; intention-to-treat 
population) and 65.7% vs 55.7% (p=0.012; per protocol population) when using the primary 
endpoint, attending the final visit with MAQ=20 and high pill count (80-110%) combined, to assess 
adherence. Adherence was also higher in the FDC group when measured by MAQ alone (68% vs. 
59%, p=0.049). No treatment difference was found at follow-up in mean SBP (129.6 vs 128.6 
mmHg), mean LDL-C levels (89.9 vs 91.7 mg/dL), serious adverse events (23 [6.6%] vs. 21 [6%]) 
or death (1, 0.2% in each group). 
The collective data from these four Randomized Clinical Trials (RCTs) has consistently shown a 
significant benefit of the polypill on the adherence of CV medications.  
 
3.2  Rationale 
Together with the rising costs of treating CVD, this complex problem calls for the use of 
innovative, simple and cost-effective interventions that will diminish the burden of CVD. In this 
complex setting, the polypill concept appears as an attractive and novel idea that can significantly 
improve CV prevention by lowering costs and improving patient adherence to treatment.17 
Moreover, improved adherence has been consistently shown to decrease MACE and improve 
survival.18  
Strategies addressing the issue of poor adherence and simplify treatment regimens but still provide 
the required interventions, such as the polypill, should improve elderly patients’ management and 
adherence, and ultimately improve outcomes. To date, however, no large RCT has been 
conducted to study the impact of a polypill strategy on outcomes for secondary CV 
prevention. This is a crucial piece of information that is currently lacking, and is needed, in order 
to prove such a strategy to be effective.  
 
3.3 Hypothesis 
The use of a polypill strategy including three components with proven efficacy as well as 
demonstrated positive impact on adherence will reduce major cardiovascular events in 
patients with myocardial infarction (MI) by reducing treatment complexity, lack of adherence 
and achieving better risk factor control, reducing the risk of recurrent disease and death in elderly 
patients with CVD, and thereby reducing the burden of CVD in Europe.   
 
In addition to the key question about clinical efficacy, a RCT comparing a polypill with standard of 
care in Europe should also allow to gather information on health and economic outcomes in 
different European countries and compare differences in the efficacy of a polypill strategy between 
Eastern and Western European countries. 
 
 
 

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  STUDY OBJECTIVES  
SECURE will test the efficacy of a polypill containing aspirin (100 mg), ramipril (2.5, 5, or 10 mg), 
and atorvastatin (40mg or 20mg), for secondary cardiovascular prevention in the elderly patients 
(≥65 years old) with a recent (within 6 months) myocardial infarction (MI).  
 
5.1 Primary Objective 
The primary objective of the SECURE study 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 (individual drugs with ad-hoc dosages) in secondary prevention of major 
cardiovascular events as defined by composite endpoint including: 
 
Cardiovascular death. 
 
Nonfatal myocardial infarction. 
 
Nonfatal ischemic stroke. 
 
Urgent coronary revascularization not leading to death.  
 
5.2 Secondary Objectives 
The secondary objectives of the study are: 
 
To evaluate all-cause mortality in both treatment arms. 
 
To evaluate whether a polypill strategy is effective in improving baseline adherence.  
 
To evaluate whether a polypill strategy is effective in improving baseline quality of life. 
 
To evaluate whether a polypill strategy is effective in controlling cardiovascular risk factors. 
(LDL cholesterol and systolic and diastolic blood pressure). 
 
To evaluate the costs and effectiveness of a polypill strategy vs standard therapy in the elderly 
population.  
 
To evaluate the performance of the polypill strategy in the elderly population across the 
different socioeconomic and health settings.  
 
To evaluate the safety and tolerability of the polypill strategy and the safety and tolerability 
of drugs prescribed in the usual care arm. 
 
To evaluate patient satisfaction on taking the polypill. 
 
 
STUDY DESIGN 
6.1 Description of Study Design 
SECURE is a multicenter, prospective, randomized, open-label, repeated-dose, parallel two arms 
study comparing the efficacy of a polypill strategy with the standard of care (usual care according to 
the local clinical practices at each participating country) in secondary prevention of major 
cardiovascular events in elderly patients with a recent MI.  
 
A total number of 2514 patients will be randomized (1:1) to treatment arms. Patients will be 
recruited across seven countries in Europe (Spain, Italy, Germany, France, Hungary, Poland, and 
Czech Republic). 
 
Patients will be ≥65 years old and diagnosed with a type 1 myocardial infarction within 6 months 
prior to study enrolment.  
 
Once the inclusion and exclusion criteria are confirmed, patients will be included in the study after 
signing informed consent.  

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PATIENT SELECTION/ENROLLMENT 
7.1  Number of Patients 
A total of 2514 patients will be randomized (1257 patients per study arm).  
 
7.2 Patient Screening 
Patients can be screened at any time within the first 6 months 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 or patients with atrial fibrillation should not be randomized. Patients scheduled for coronary 
revascularization (either PCI or CABG) cannot be randomized until the procedure is being 
performed provided that this happens within the first 6 months of index event.  
7.3  Inclusion Criteria 
To be eligible to enter the study candidates must satisfy all of the following criteria: 
1. Giving consent after information.  
2. Patients diagnosed with type 1 myocardial infarction within the previous 6 months.  
3. Subjects must be ≥65 years old, presenting with at least one of the following additional 
conditions: 
a. Documented diabetes mellitus or previous treatment with oral hypoglycemic drugs or 
insulin.  
b. Mild to moderate renal dysfunction: defined as creatinine clearance (CrCl) 60-30 
mL/min/1.73 m2. 
c. Prior myocardial infarction: defined as a myocardial infarction occurring before the 
index event reported in a medical record. 
d. Prior coronary revascularization: patients have previously undergone coronary artery 
bypass grafting (CABG) or percutaneous coronary intervention (PCI). 
Prior stroke: patients have previously suffered a stroke occurring before the index event 
reported in a medical record. 
e. Age ≥ 75 years. 
 
7.4  Exclusion Criteria 
1. Unable to sign informed consent. 
2. Inability to understand and comply with the protocol requirements and instructions. 
3. Contraindications to any of the components of the polypill. 
4. Living in a nursing home or committed to an institution by virtue of and order issued by the 
judicial or the administrative authorities. 
5. Mental illness limiting the capacity of self-care. 
6. Participating in another clinical trial. 
7. Severe congestive heart failure (NYHA III-IV). 
8. Severe renal disease (creatinine clearance (CrCl) < 30ml/min/1.73 m2). 
9. Severe hepatic impairment, liver cirrhosis transaminases exceeding 3 times the upper limit 
of the normal limit. 
10. Allergies to lactose, peanut or soy.  
11. Need for oral anticoagulation at the time of randomization or planned in the future months. 
12. Any condition limiting life expectancy < 2 years, including but not limited to active 
malignancy. 
13. Significant arrhythmias (including unresolved ventricular arrhythmias or atrial fibrillation) 
leading to hemodynamic instability. 

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14. Scheduled coronary revascularization (patients can be randomized after final 
revascularization is completed within the pre-specified timeframe). 
15. Do not agree to the filing, forwarding and use of his/ her pseudonymised data 
16. Individuals dependent from the sponsor, investigator or investigational site/institution. 
 
Patients fulfilling inclusion criteria and not presenting with any of the exclusion criteria at time of 
trial screening will be invited to participate in the SECURE clinical trial.  
Please refer to section 8.1.2 for further details on contraindications to the components of the 
cardiovascular combination polypill. 
7.5 Informed Consent 
It is the responsibility of the Investigator to obtain written informed consent from the patient. A 
Patient Information Sheet (PIS) will be provided to facilitate this process. Investigators must 
adequately explain the aim, trial treatment, anticipated benefits and potential risks of taking part in 
the trial to the participant. The investigator should also emphasize that the patient is completely free 
to refuse to take part or withdraw from the trial at any time. Time should be given for patient to read 
the Information Sheet and ask questions, which should be answered to patient satisfaction. Once 
patient express continued interest in participating in the trial, patient will be asked to sign and date 
the latest version of the Informed Consent Form (ICF). The Investigator will also sign and date the 
ICF. A copy of the ICF will be provided to the patient, another copy of the ICF will be filed in the 
hospital notes (if applicable), and the original placed in the Investigator Site File (ISF).  
7.6  Randomization 
After signing the informed consent form (ICF), patients will be randomized (1:1) stratified by 
center to Cardiovascular combination pill AAR or standard therapy for cardiovascular prevention 
within 6 months of the index event (AMI type I). A centralized online system will be used to 
generate randomization. 
7.7 Post Randomization Safety Assessment 
In order to maximize monitoring adverse effects of therapy and to comply with current guidelines, a 
4-6 week laboratory analysis (for safety and efficacy of statins and ACEI) will be performed. It is 
expected that a large proportion of patients will already be on chronic statin and ACEI treatment prior 
to the index event and may therefore not need further analysis at 4-6 weeks to check for efficacy or 
safety. Alternatively, for those patients requiring close monitoring due to initiation of statins and/or 
ACE (i.e. naïve patients), patients may be enrolled either before the 4-6 weeks lab analysis or after. 
For patients being enrolled after the 4-6 week analysis, the PIs will titrate statins and ACEI according 
to CPK, LFTs, creatinine clearance, ionogram and cholesterol levels. For patients enrolled before the 
analysis, each clinical coordinating center will coordinate lab analysis 4-6 week post event period (to 
be carried out either by GP or in hospital following standard follow up procedure for each center) to 
ensure patients undergo analysis. Once lab results are available, titrate accordingly.  
The following algorithm describes the monitoring of patients in the subacute phase: 

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If the 4-6 week lab results indicate patient will not tolerate treatment, IMP  will be discontinued, but 
patient follow-up will be continued as planned. For patients in the SOC, allowed medication and 
follow-up will be continued. 
 
This lab assessment is mandatory. If lab assessment is not carried out, further assessment of the 
Sponsor will be required, which may result in patient withdrawal from the study. 
 
 
7.8 Withdrawal of Patients 
 
7.8.1 Withdrawal of Consent 
Patients are free to withdraw from the study at any time without providing reason for withdrawal 
and with the assurance that their decision will not influence ensuing medical care. Patient 
withdrawal should be documented in writing in the electronic case report form (eCRF) and if 
available, reason for withdrawal should be documented in the electronic case report form (eCRF).  
 
Patients withdrawing from the study will be encouraged to continue follow-up and appropriately 
complete the evaluations as patients completing the study according to the protocol, particularly 
efficacy and safety endpoints (see Annex 14: Withdrawal of Consent Checklist). Reasonable efforts 
will be made to contact patients who are lost to follow-up.  
 
Although patients may withdraw from the study drug or study at any time and for any reason, 
patient withdrawal should be avoided as much as possible.  
 
7.8.2 Trial Discontinuation  
Please refer to Section “7.12 Criteria for Discontinuation of the Trial” 
 
7.8.3 Investigator’s request 
Patients who withdraw or are withdrawn from the study or study treatment will not be replaced. 

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7.9 Lost to Follow-up 
In case a subject fails to come to scheduled follow-up visits, every reasonable effort will be made to 
contact the subject to determine (A) the endpoint status; (B) reason for discontinuation; and (C) 
vital status, as local law permits. A subject will be considered lost to follow-up only after patient 
has not been confirmed alive or dead in more than 18 means AND all means of all subsequent 
contact have been exhausted. 
 
7.10 Discontinuation of Study Treatment 
The study medication AAR 20 and AAR40 contain standard medical compounds that are part of the 
regular state of the art treatment regimen of the respective patients. Therefore, any discontinuation 
of the study medication may occur only if one of its components should be discontinued according 
to the clinical condition of the patients and in accordance with state of the art medical therapy 
standards. This decision for discontinuation has to be made by the study physician in accordance 
with state of the art clinical treatment recommendations. 
All drug discontinuations have to be reported in the electronic Case Report Form (eCRF), 
together with time and reasons for discontinuation. Drug discontinuation will be classified as 
either (A) Temporary or (B) Permanent, refer to section 7.10.1 and 7.10.2 respectively. 
 
If a subject’s treatment has been interrupted for more than 14 days due to toxicity or to reasons 
other than toxicity (unplanned travel or vacation, or lack of transportation to the site), the 
Investigator must review the subject’s condition in order to restart the treatment. 
 
All randomized patients must be followed up according to the study flowchart until study end 
date or death, regardless of whether they discontinued study drug prematurely or not. Unless 
patient decides to withdraw consent and not take further participation in the study. 
 
 
7.10.1.1 Temporary Discontinuation Definition 
 
Brief Temporary Discontinuation of polypill is defined as a period of 1 to 5 days. 
 
Temporary Discontinuation of polypill is defined as a period of 6 to 30 days. 
 
For patients allocated to the intervention group (AAR), during the Temporary Discontinuation of 
the study drug, if applicable and safe, patients will be given the separate components (ASA, statin, 
and Ace-I) until intervention drug can be resumed. 
 
After brief temporary and temporary discontinuation, patients can continue treatment with 
 
7.10.1.2 Temporary Discontinuation Criteria 
Study drug should be temporarily discontinued if subject: 
1. Undergoes PCI, CABG, or any other surgical procedure or medical condition that may 
require temporary interruption of study drug, or use of prohibited therapy due to bleeding 
risk. 
2. Experiences a significant bleeding event. 
3. Presents any serious adverse event possibly related or exacerbated by study drug 
administration 

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4. Requires a therapy on a temporary basis that may react or is contraindicated with study drug 
 
 
7.10.2.1 Permanent Discontinuation Definition 
Permanent Discontinuation of polypill is defined as any period longer than 30 days will be 
considered permanent discontinuation. Patients will be followed up according to regular protocol 
until the end of the follow up period. 
7.10.2.2 Permanent Discontinuation Criteria 
Study drug should be permanently discontinued for the following reasons: 
1. Patient Safety: 
a. If labs indicate treatment is not safe for patient 
 
Creatinine Clearance < 30 ml/ min/ 1.73m²;  
 
ALT/AST >3x the laboratory upper normal limit 
 
Creatine Kinase (CK) ≥ 10x the laboratory upper normal limit  
 
b. Occurrence of SUSARs or SAEs not compatible with the continuation of patient 
participation in the study treatment, in the investigator’s opinion, which may include 
but are not limited to:  
 
Results in death. 
 
Is life-threatening. 
 
Requires inpatient hospitalization or prolongs existing hospitalization. 
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital anomaly or birth defect. 
 
Is any other medically important event that may jeopardize the patient’s 
well-being or may require intervention to prevent one of the other above 
outcomes. 
 
c. Adverse Drug Reaction: if patient presents an adverse reaction that given its 
seriousness or nature, justifies study discontinuation. To minimize the risk of adverse 
reaction, the study protocol includes a substantial list of medical conditions that 
contraindicate treatment with the IMP (section 8.1.2). Furthermore, the clinical 
protocol includes adverse effects that have been described by the manufacturer of the 
individual components of the IMP. 
  
d. Drug allergic reaction 
 
e. Bleeding greater or equal to type 2 according to Bleeding Academic Research 
Consortium Definition for Bleeding (Annex 5)  
 
2. Subject requests to discontinue study drug permanently. 
 
The study investigator will document reason for study discontinuation in the eCRF. Patients 
permanently discontinued from study drug treatment should be treated with guideline-directed 
medical therapy in accordance with ESC guidelines. 
 

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7.11 Patient Follow up After Site Closure.  
In the event of site closure due to low recruitment, if applicable and allowed by regulatory 
authorities, the follow-up of randomized patients from that site might be transferred to nearby 
participating sites in order to avoid patient lost to follow-up. 
 
7.12 End of Trial Definition 
End of trial is defined as the last visit of the last patient, which will take place on October 30th 2019. 
7.13 Criteria for Discontinuation of the Trial 
The Data and Safety Monitoring Board (DSMB) may recommend stopping for reasons of safety, if 
there is excess mortality in the polypill arm with p<0.01. At the main interim analysis, the DSMB 
may recommend stopping for efficacy if the primary event rate is lower in the polypill arm with 
p<0.001.  
In making any recommendation, the DSMB will weigh up the totality of the evidence for both efficacy 
and harm. 
If persistently low recruitment, poor protocol adherence, low event rates or other problems with the 
conduct of the trial are likely to limit its ability to provide a clear answer to the primary research 
question, then consideration will be given to terminate the trial early. Such a decision will only be 
made once all measures to improve the limiting problems have been exhausted. 
Early termination of the trial will take place in the following instances:  
 
The primary endpoint is reached during interim analysis 
 
Due to safety issues.  
 
If persistent low recruitment, poor protocol adherence, low event rates or other problems with 
the conduct of the trial that are likely to limit its ability to provide a clear answer to the 
primary research question. Decision based on these criteria will only be made after all 
measures to improve the limiting problems are exhausted. 
 
 
 TREATMENTS 
 Identity of Investigational Medicinal Products (IMPs)
 
The Cardiovascular Combination Polypill AAR 40 contains 100 mg acetylsalicylic acid, 40 mg 
atorvastatin, and 2.5, 5 or 10 mg ramipril. 
Cardiovascular Combination Polypill AAR 20 contains 100 mg acetylsalicylic acid, 20 mg 
atorvastatin, and 2.5, 5 or 10 mg ramipril. 
8.1.2 Contraindications to IMP 
 
Hypersensitivity to the active substances, to any of the excipients, to other salicylates, to 
nonsteroidal anti-inflammatory drugs (NSAIDs), to any other ACE (Angiotensin Converting 
Enzyme) inhibitors or to tartrazine. 
 
Hypersensitity to soya or peanut. 
 
In case of history of previous asthma attacks or other allergic reactions to salicylic acid or 
other non-steroidal analgesics / anti-imflamatories. 
 
Acute gastric and enteric ulcers. 

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 
Haemophilia and other bleeding disorders. 
 
Severe kidney and liver impairment. 
 
Patients in hemodialysis. 
 
Severe heart failure. 
 
Concomitant treatment with methotrexate at a dosage of 15 mg or more per week. 
 
Patients with nasal polyps associated to asthma induced or exacerbated by acetylsalicylic 
acid. 
 
Active liver disease or unexplained persistent elevations of serum transaminases exceeding 
3 times the upper limit of normal. 
 
Due to the risk of rhabdomyolysis concomitant treatment with tipranavir or ritonavir. 
 
Due to the risk of rhabdomyolysis concomitant treatment with ciclosporin. 
 
History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE 
inhibitors or Angiotensin II receptor antagonists (AIIRAs). 
 
Extracorporeal treatments leading to contact of blood with negatively charged. 
 
Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning 
kidney. 
 
Ramipril must not be used in patients with hypotensive or haemodinamically unstable states. 
 
Existing contraindication to Aliskiren containing products.  
 
Acetylsalicylic Acid is a salicylate drug with the chemical name 2-ethanoylhydroxybenzoic acid.  
The adverse effects of aspirin have been well studied and characterized. Gastrointestinal tract 
perforation, ulceration, and bleeding are adverse effects associated with long-term aspirin therapy. 
Because inhibition of prostaglandin synthesis is the common mechanism for both the beneficial 
thrombo-prophylactic effects and the adverse effects on the gastrointestinal tract, it is unlikely that 
the benefits can be achieved without some degree of risk. 
The major risk of aspirin, as with other nonsteroidal anti-inflammatory drugs (NSAIDs), is bleeding. 
Although the antiplatelet effects of aspirin likely contribute to an increase in the risk of bleeding, as 
highlighted by an increased risk of hemorrhagic stroke of 0.2 events per 1000 patients-year19, the 
majority of the increased risk of bleeding has a gastrointestinal tract etiology. A relationship between 
aspirin dosage and bleeding as well as chronic gastric ulcer has been demonstrated in clinical trials. 
Unfortunately, enteric-coated or buffered aspirin preparations do not appear to influence the risk of 
major bleeding in the upper gastrointestinal tract. In fact, no differences have been found in the 
frequency of gastrointestinal complications with the use of low doses of aspirin either as entericcoated 
or plain tablets.20 
While gastrointestinal bleeding is increased with the use of aspirin, in the secondary prevention 
studies this outcome is rare, manageable, and does not use to cause deaths. Furthermore, the potential 
for this adverse outcome must be compared with the highly significant and clinically meaningful 
finding of a reduction in all-causes of mortality (the gold standard for drug effectiveness). This 
benefit, together with substantial and comparable reductions in nonfatal vascular events, leads to the 
conclusion that the benefit-to-risk ratio for aspirin in the secondary prevention of cardiovascular and 
cerebrovascular events is highly favourable.21  
Acetylsalicylic Acid Contraindications 
Hypersensitivity to salicylates or NSAIDs; hemophilia, bleeding ulcers, or hemorrhagic states. 

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Ramipril is an angiotensin-converting enzyme (ACE) inhibitor with the chemical name  
(2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-
carboxylic acid, 1-ethyl ester 
The safety profile of ramipril appears to be consistent with that of other ACE-I. Adverse effects 
associated with these agents in clinical trial settings were generally mild and rarely required 
discontinuation of therapy. Known adverse effects include cough, hyperkalemia, renal dysfunction, 
and angioedema. Overall, ramipril has a good safety profile and is generally well tolerated. 
Renal: Treatment with Ramipril may impair renal function and in isolated cases progression to acute 
renal failure may occur. 
Allergic: Hypersensitivity reactions accompanied by pruritus, rash, shortness of breath and sometimes 
fever may occur, but usually resolve spontaneously after withdrawal of Ramipril. In addition, the 
following cutaneous and mucosal reactions may occur: reddening of skin areas with accompanying 
heat sensation, conjunctivitis, itching, urticaria, other skin or mucosal eruptions (maculo-papular and 
lichenoid exanthema and enanthema, erythema multiforme), sometimes pronounced hair loss, 
exacerbation of perfusion disturbances due to vascular stenoses and precipitation or intensification of 
Raynaud's phenomenon. In isolated cases, pemphigus, exacerbation of psoriasis, psoriasiform and 
pemphigoid exanthema and enanthema, Stevens- Johnson syndrome, toxic epidermal necrolysis, 
hypersensitivity of the skin to light, and onycholysis have been observed. 
Haematological reactions: Rarely, a mild - in isolated cases severe – reduction in the red blood cell 
count and haemoglobin content, white blood cell or blood platelet count may develop. In isolated 
cases, agranulocytosis, pancytopenia and bone marrow depression may occur. In isolated cases 
haemolytic anaemia may develop. Vasculitis, muscle and joint pains, fever, or eosinophilia may 
occur. Raised titres of antinuclear antibodies have been seen with other ACE inhibitors. Respiratory 
tract: A dry tickling cough may occur. This is possibly due to the desired ACE inhibition as are the 
following adverse effects: rhinitis, sinusitis, bronchitis and, especially in patients with tickling cough, 
bronchospasm. Other adverse reactions: Disturbances of balance, headache, nervousness, 
restlessness, tremor, sleep disorders, confusion, loss of appetite, depressed mood, feeling of anxiety, 
paraesthesiae, uncommonly, disturbances of smell and taste or partial, sometimes complete loss of 
taste, muscle cramps, erectile impotence and reduced sexual desire may occur. 
Laboratory test findings: Increases in blood urea nitrogen and serum creatinine may occur, in 
particular with renal insufficiency or in patients pre-treated with a diuretic. Pre-existing proteinuria 
may deteriorate (though ACE inhibitors usually reduce proteinuria), or there may be an increase in 
urinary output. 
Ramipril Contraindications 
 Ramipril capsules are contraindicated in patients who are hypersensitive to this product or any 
other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other 
ACE inhibitor). 
Atorvastatin is a completely synthetic hypolipidemic drug belonging to the class of 
pharmaceuticals named statins. Atorvastatin has the chemical name [R-(R*, R*)]-2-(4-
fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1Hpyrrole-1-
heptanoic acid, calcium salt (2:1) trihydrate. 
 

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Atorvastatin Side Effects 
Most common adverse reactions in patients treated with Atorvastatin that led to treatment 
discontinuation and occurred at a greater rate than placebo were in data from RCT were: 
 
Myalgia (0.7%) 
 
Diarrhea (0.5%) 
 
Nausea (0.4%) 
 
Alanine aminotransferase increase (0.4%) 
 
Hepatic enzyme increase (0.4%). 
Extensive data are available on the safety of atorvastatin from randomized clinical trials, 
postmarketing analyses and reports to regulatory agencies. Atorvastatin is generally well tolerated 
across the range of therapeutic dosages, with the exception of a slightly higher rate of liver enzyme 
elevations with atorvastatin 80 mg/day which does not appear to confer an increased risk of clinically 
important adverse events. Atorvastatin is associated with a low incidence of muscular toxicity. It is 
not associated with neurological, cognitive or renal adverse effects and does not require dosage 
adjustment in patients with renal dysfunction, due to its favourable pharmacokinetic profile.  
In patients aged ≥65 years, atorvastatin is well tolerated with no dose-dependent increase in adverse 
events up to the maximum daily dosage of 80 mg/day. Thus, atorvastatin is a safe and well tolerated 
statin for use in a wide range of patients. The following adverse events are described (extracted from 
the respective SmPC). 
Skeletal Muscle: Myopathy is the most concerning adverse effect of statins. The most common 
symptom of statin myotoxicity is myalgia (muscle pain, weakness or cramps) with normal creatine 
phosphokinase (CK) levels. Fortunately, myopathy and rhabdomyolysis are very rare with 
monotherapy. The risk of myopathy during treatment with statins is increased with concurrent 
administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C 
protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir plus 
ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, 
and fosamprenavir plus ritonavir, niacin, or azole antifungals.  
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported 
with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor 
for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle 
effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or 
muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times 
ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine 
and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) 
increases the risk of myopathy/rhabdomyolysis. There have been rare reports of immunemediated 
necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. 
IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which 
persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy 
without significant inflammation; improvement with immunosuppressive agents.  
Liver Dysfunction: Statins, like some other lipid-lowering therapies, have been associated with 
biochemical abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal 
[ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who 
received LIPITOR in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 
2.3% for 10, 20, 40, and 80 mg, respectively. 

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Endocrine Function: Increases in HbA1c and fasting serum glucose levels have been reported with 
HMG-CoA reductase inhibitors, including atorvastatin. Statins interfere with cholesterol synthesis 
and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown 
that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. The 
effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, 
if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be 
exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity 
of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.  
Other adverse reactions reported in placebo-controlled studies include: 
Body as a whole: malaise, pyrexia; 
Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; 
Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; 
Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline 
phosphatase increase, creatine phosphokinase increase, hyperglycemia; 
Nervous system: nightmare; 
Respiratory system: epistaxis; 
Skin and appendages: urticaria; 
Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive.The 
adverse events of atorvastatin are summarized below (extracted from the correspondingSmPC): 
Common side effects (affects 1 to 10 users in 100) include:inflammation of the nasal passages, pain 
in the throat, nose bleed allergic reactions increases in blood sugar levels (if you have diabetes 
continue careful monitoring of your bloodsugar levels), increase in blood creatine kinase headache 
nausea, constipation, wind, indigestion, diarrhea joint pain, muscle pain and back pain blood test 
results that show your liver function can become abnormal 
Uncommon side effects (affects 1 to 10 users in 1000) include: anorexia (loss of appetite), weight 
gain, decreases in blood sugar levels (if you have diabetes you should continue careful monitoring of 
your blood sugar levels) having nightmares, insomnia dizziness, numbness or tingling in the fingers 
and toes, reductions of sensation to pain or touch, change in sense of taste, loss of memory blurred 
vision ringing in the ears and/or head vomiting, belching, abdominal pain upper and lower, 
pancreatitis (inflammation of the pancreas leading to stomach pain) hepatitis (liver inflammation) 
rash, skin rash and itching, hives, hair loss neck pain, muscle fatigue fatigue, feeling unwell, 
weakness, chest pain, swelling especially in the ankles (oedema), raised temperature urine tests that 
are positive for white blood cells 
Rare side effects (affects 1 to 10 users in 10,000) include: visual disturbance unexpected bleeding or 
bruising cholestasis (yellowing of the skin and whites of the eyes) tendon injury 
Very rare side effects (affects less than 1 user in 10,000) include: an allergic reaction - symptoms 
may include sudden wheezing and chest pain or tightness, swelling of the eyelids, face, lips, mouth, 

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tongue or throat, difficulty breathing, collapse hearing loss gynecomastia (breast enlargement in men 
and women). 
Possible side effects reported with some statins (medicines of the same type): Sexual difficulties, 
depression, breathing problems including persistent cough and/or shortness of breath or fever, 
cholestasis (yellowing of the skin and whites of the eyes), tendon injury 
Very rare side effects (affects less than 1 user in 10,000) include: an allergic reaction - symptoms 
may include sudden wheezing and chest pain or tightness, swelling of the eyelids, face, lips, mouth, 
tongue or throat, difficulty breathing, collapse hearing loss gynecomastia (breast enlargement in men 
and women). 
Atorvastatin Contraindications 
 
Active liver disease, which may include unexplained persistent elevations in hepatic 
transaminase levels. 
 
Hypersensitivity to any component of this medication 
 
The Cardiovascular Combination Polypill AAR 40 and 20 are supplied as hard gelatin capsules.  
 
The Cardiovascular Combination Polypill AAR will be manufactured by Ferrer S.A. (Sant Cugat, 
Barcelona, Spain) according to the current regulatory requirements (Directive EU 2001/20/EC and 
subsequent versions combined with communication from the Commission – detailed guidance “CT-
3”). Medications in the usual care arm are commercially available in all participating countries.   
8.1.5 Storage conditions 
All investigational drug supplies in the study will be stored in a secure, safe place, under the 
responsibility of the Investigator or other authorized individual. 
 
Medication packaging and labeling will be performed by a specialized company for the 
Cardiovascular Combination Polypill AAR, in accordance with Good Manufacturing Practice for 
Medicinal Products. 
Relabeling of IMP will be performed according to extension of expiration date production and 
supply needs of recruiting centers. 
8.1.7 IMPs administered 
Patients allocated to polypill will start treatment with Cardiovascular Combination Polypill AAR 40 
by default, so they will receive one of the following polypills: 
 
ASA 100 mg, atorvastatin 40 mg, ramipril 2.5mg 
 
ASA 100 mg, atorvastatin 40 mg, ramipril 5 mg 
 
ASA 100 mg, atorvastatin 40 mg, ramipril 10 mg 
 
If considered necessary and per investigators judgment polypill Cardiovascular Combination Polypill 
AAR 40 may be switched to Cardiovascular Combination Polypill AAR 20 (ASA 100mg, atorvastatin 
20 mg, and ramipril 2.5, 5 or 10 mg). 

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Patients randomized to receive usual care will follow standard therapy (which will be initiated at 
admission), according to clinical guidelines and local clinical practice.  
 
8.2 Blinding 
Study treatments are not blinded. 
The main objective of SECURE is to test the efficacy of simple treatment strategy of bioequivalent 
active principals in an easy to use, once daily capsule versus the multi-pill treatment regimen. In 
order to test this hypothesis, the design does not allow for blinding the treatments.  
 
8.3 Drug Supply  
8.3.1 Drug Supply in the Intervention Arm 
 
Drug will be shipped to each participating site by a specialized company 
 
Medication supply will be provided to all patients in the polypill arm in all countries.  
 
Participants will be provided with IMP to cover the treatment period and will take the 
assigned dose at home (a total of 105 doses to cover 3 months + two weeks of polypill supply 
or a total of 210 doses to cover 6 months + two weeks of polypill supply). 
 
Patients will be provided with a prescription refill date at 90 days. If patients do not comply 
after 104 days they will be contacted by telephone. 
 
If needed and allowed by regulatory authorities of the corresponding country, drug supply/ies 
will be shipped to patients. 
8.3.2 Drug Supply in the Usual Care Arm 
 
Prescriptions to elderly patients following AMI (hence chronic medication) are usually 
renewed every 1 to 3 months in the participating countries.   
 
According to the national regulations, dispensing of standard therapy is carried out as the following: 
 
Spain, Italy, Germany, France, and Czech Republic: 
 
Patients randomized to usual care arm in the countries listed above will be treated at the 
discretion of their physician following clinical guidelines.  
 
Patients will receive free or heavily subsidized medication (Co-payment of less than 2EUR 
per month). 
 
These patients will follow the standard care at their country, both medication prescription 
and dispensing. Patients will collect their prescriptions at their local pharmacy or study 
site.  
 
Germany 
 
After discharge from hospital /rehabilitation clinic it may be more suitable for logistical 
reasons (patient travel) that study visits are performed at the central study site Charité – 
Universitätsmedizin Berlin, Virchow Klinikum in Berlin. This transfer will be done only 
after patient’s consent. 
 
 
If the pick-up of the Polypill every three months is unfeasible for the study participant, e.g. 
due to long distances, it may be considered to send the study medication via mail to patient 
after patient submits the request by phone. 
 
Hungary and Poland 
 
Pharmacological therapy is only partially subsidized for patients after an MI. Buying 
medicine in standard pharmacy by patients randomized to usual care may have a significant 

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impact on adherence compared to patients randomized to Polypill Cardiovascular 
Combination Polypill AAR.  
 
 
Patients will receive a 3 or a 6-month prescription for usual care treatment (to be chosen 
by the physician) and will be asked to return to the research pharmacy or site before the 
end of medication supply. Therefore, patients will collect study medication at their 
research pharmacy or site every 12-24 weeks.  
 
8.3.3 Receipt of Drug Supplies 
Upon receipt of the Cardiovascular Combination Polypill AAR 40 and 20, an inventory must be 
performed and signed by the person receiving the shipment. The following will be checked: 
 
Medication quantity corresponds with the shipment inventory 
 
Damage or unusable study drug 
 
A copy of the appropriate form should be retained in the site file and another copy sent to the 
Sponsor. 
 
8.3.4 Return or Destruction of Drug Supply 
At the completion of the study, final reconciliation of study drug (shipped, consumed, and 
remaining) must be performed. The final drug reconciliation will be recorded on the correspondent 
form, signed, and dated. Any discrepancies will be investigated, resolved, and documented prior to 
return or drug destruction. For drugs destroyed on site, a dug destruction certificate will be issued 
and provided to the Sponsor and a copy retained in the study files. 
 
8.4 Dose Regimen 
A total of 1257 patients will receive a once daily oral dose of the Cardiovascular Combination 
Polypill AAR for the whole duration of the study. 
 
A total of 1257 patients randomized to the usual care arm will follow standard therapy for 
secondary CV prevention, according to the ESC clinical practice guidelines. 
 
 
Dose adjustment must be done with caution in both groups.  
General guidelines are provided for patients already receiving statins and ACEI prior to inclusion 
and for naive patients:  
1. Patients already taking statins or ramipril before enrollment: Replacement of previous 
medication by the study drugs should be undertaken taking into account differences in potency, 
pharmacodynamic and pharmacokinetic properties of different drugs. 
a. Statin treatment:  
Patients randomized to the polypill arm: start in with Cardiovascular Combination Polypill 
AAR 40 (40mg of atorvastatin) dose unless contraindicated. 
Patients randomized to control arm: physicians must individualize statin dosage according to 
individual patient risk factor profile, cholesterol level, and history of side effects 
 
 

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b. ACEI treatment:  
Patients randomized to the polypill arm: Patients with prior ACEI treatment should be 
treated with bioequivalent doses of ramipril 
Patients randomized to control arm: continue treatment as previously prescribed unless 
contraindicated by patient’s current hemodynamic conditions.  
2. Naive patients:  ESC guidelines clearly state the following recommendations:  
a. Statin treatment:  
ESC guidelines recommend high-intensity statin therapy regardless of the baseline LDL-C level 
and to continue it indefinitely. “This treatment should be started early during admission, as this 
increases patient adherence after discharge, and given at high doses, as this is associated with 
early and sustained clinical benefits.. The treatment goal is an LDL-cholesterol concentration of 
1.8 mmol/L (70 mg/dL). The use of lower-intensity statin therapy should be considered in 
patients at increased risk of side-effects from statins (e.g. the elderly, patients with hepatic 
or renal impairment, with previous side-effects of statins or the potential for interaction 
with essential concomitant therapy).”1 
Therefore, patients receiving the polypill should start in with Cardiovascular Combination 
Polypill AAR 40 (40mg of atorvastatin) dose unless contraindicated.  
Important: ESC Guidelines clearly state that “Lipids should be re-evaluated 4–6 weeks 
after the ACS, to determine whether the target levels have been reached and regarding 
safety issues; the statin dose can then be adjusted accordingly.”1 Taking into account the 
high risk elderly population of the trial, participating centers must comply with this 
recommendation in order to achieve an efficacious and safe titration.  
If dose adjustment for atorvastatin is necessary, it can be switched to Cardiovascular 
Combination Polypill AAR 20, containing 20mg of Atorvastatin. 
 
b. ACEI treatment  
ACEI reduce total mortality, MI, stroke and heart failure among specific subgroups of patients, 
including those with heart failure, previous vascular disease alone, or high-risk diabetes. Hence, 
it is appropriate to consider ACE inhibitors for the treatment of patients with SCAD, especially 
with co-existing hypertension, LVEF ≤40%, diabetes, CKD, unless contra-indicated. 1 
For naive patients, the recommended starting dose of Ramipril capsules is 2.5 mg daily. 
Clinical benefit of use of Ramipril has been shown to increase with increased dose (if tolerated) 
toward a target dose of 10 mg daily, with dosage increases being about 3 weeks apart. 
If down titration is necessary for ramipril, two dose reductions are permitted in a stepwise 
fashion (initially to 5 mg and subsequently to 2.5 mg, if necessary). The dose can then be 
increased step-wise back to 5 mg and 10 mg in the next scheduled or unscheduled visits after 
monitoring for 3 weeks at each step if side effects do not recur or worsen. 
The ramipril dose in the polypill arm will be adjusted by the investigator and adapted to 
patients’ needs throughout the study period.  
Supplementary medication to achieve adequate secondary prevention targets is allowed and left 
to the investigators’ discretion. This includes blood pressure and lipid lowering drugs. 
For drug equivalences: see annex 7 

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8.6 Treatment Compliance 
Study drug accountability will be performed at each visit. Intentional or unintentional 
stopping of study drug by either the patient or investigator or other physician must be 
documented. The following criteria will be used:  
 
Brief Temporary Discontinuation of polypill is defined as a period of 1 to 5 days. 
 
 
Temporary Discontinuation of polypill is defined as a period of 6 to 30 days. 
 
 
Permanent Discontinuation of polypill is defined as any period longer than 30 days 
will be considered permanent discontinuation. Patients will be followed up according 
to regular protocol until the end of the follow up period. 
 
After brief temporary and temporary discontinuation, patients can continue treatment with 
Cardiovascular Combination Polypill AAR, if advised by investigator. 
 
8.6.1 Missed dose 
A missed dose from a previous calendar day should not be taken with the current dose. 
 
8.7 Prior and Concomitant Therapy 
Details of all prior and concomitant medications and therapies administered before randomization 
will be recorded in the eCRF. 
8.8 Treatment Adherence 
Adherence to all treatments will be assessed by the self-reported eight-item Morisky-Medication 
Adherence Scale (MMAS-8), which has been validated in various CV treatment scenarios as an 
indirect, self-reported measure of adherence. (87) 
8.9  Quality of Life 
Quality of Life will be assessed with the validated EQ-5D scale. (Annex 10) 
8.10 Health Economic Evaluation 
A within-trial health economic evaluation will be conducted comparing Cardiovascular 
Combination Polypill AAR  with usual care using a third party payer perspective.
 
Within-trial data collection will inform of significant health service resource inputs following the 
index event. The individual costs associated with the following secondary clinical events and 
procedures will be considered including: death from CV causes, nonfatal MI, nonfatal ischemic 
stroke, and urgent revascularization. The latter includes the identification and quantification of the 
number of hospitalizations due to CV causes, the number of revascularization procedures, and the 
follow-up emergency room, outpatient and rehabilitation visits due to CV causes beyond the study 
visits. The number of days per hospitalization due to CV causes will also be collected.  
 
Information on health service resource usage will be obtained through the eCRF.  
 

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Costs for secondary clinical events and procedures associated with hospitalization including death 
from CV causes, nonfatal MI, nonfatal ischemic stroke, and urgent revascularization will be 
calculated. Costs for emergency room, outpatient and rehabilitation visits for CV causes in the 
follow up period not requiring hospitalization will also be calculated. 
The costs for the use of resources for secondary clinical events and procedures in the follow up 
period associated with hospitalization and visits for CV causes not requiring hospitalization will be 
valued according to national or regional health tariffs, and on the collection of costs from the 
participating study centers.  
The costs for the use of resources for secondary clinical events and procedures in the follow up 
period associated with hospitalisation and visits for CV causes not requiring hospitalisation will be 
valued according to national or regional health tariffs, and when available on the collection of costs 
from the participating study centers. Costs for emergency room visits, rehabilitation visits and 
outpatient visits beyond study visits for CV causes in the follow up period not requiring 
hospitalisation will also be calculated.  
 
 
STUDY PROCEDURES 
9.1 Visit Schedule 
See Section 3. Study Flowchart at the beginning of the protocol.  
See Section 10.1. Assessment schema and descriptions. 
For Germany, after discharge from hospital /rehabilitation clinic it may be more suitable for logistical 
reasons (patient travel) that study visits are performed at the central study site Charité – 
Universitätsmedizin Berlin, Virchow Klinikum in Berlin. This transfer will be done only after 
patient’s consent. 
9.1.1 Screening and Baseline 
At the screening and baseline visit, written informed consent will be obtained before any 
assessments are made. All patients will be assessed for eligibility against the inclusion and 
exclusion criteria.   
The patient’s full medical history, baseline ECG, and previous labs*: full blood count, full lipid 
profile, haemoglobin, serum creatinine, creatinine clearance, creatine kinase (CK), liver function 
tests (ALT, AST, and alkaline phosphatase), and ionogram; concomitant illnesses and medication 
use will be documented. Demographic data, such as race, age and sex, and historical disease data 
and diagnostic information will be recorded in the eCRF.).   
 
*Most recent lab values from date of qualifying MI up-to randomization date. 
 
Following ESC guidelines, patients will undergo laboratory analysis (full blood count, full lipid 
profile, haemoglobin., serum creatinine and creatinine clearance, CK, liver function tests, and 
ionogram) 4-6 weeks post ACS to monitor drug response and potential toxicity to drug therapy.  
Patients included before that first analysis will be followed by the PI of each participating site to 
ensure access to lab results and determine dose regimen accordingly. For patients enrolled after the 
4-6 week analysis, results will be made available to the PI to monitor that dose modification has 
been undertaken appropriately. 
 
Once the eligibility criteria are confirmed patients will be randomized to one of the treatment arms. 
Medication supply will be provided to the patients randomized to the Cardiovascular Combination 

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Polypill AAR arm and prescription to collect the medication at the local pharmacy will be given to 
usual care arm. 
Questionnaires regarding quality of life (EQ-5D) will be run at inclusion to have a baseline measure.  
9.1.2 Visit 1 (At 6 months Post Randomization ± 2 weeks) 
 
Information on outcomes (MACE). 
 
Changes in concomitant diseases/illnesses and medication since Baseline visit. 
 
Adverse Events. 
 
Vital signs (blood pressure and heart rate after 5 min sitting rest). 
 
Medication Self-Adherence Questionnaire, MMAS-8. 
 
Treatment satisfaction questionnaire, TSQM. 
9.1.3 Visit 2 (At 12 months Post Randomization ± 2 weeks) 
 
Information on outcomes (MACE). 
 
Changes in concomitant diseases/illnesses and medication since Visit 1. 
 
Adverse Events. 
 
Vital signs (blood pressure and heart rate after 5 min sitting rest). 
 
Blood Sample will be collected and analyzed by the local laboratory linked with each trial 
center: 
o Full Blood Count. 
o Full Lipid Profile (total cholesterol, LDL-cholesterol, and HDL-cholesterol). 
o Haemoglobin. 
o Serum Creatinine and Creatinine Clearance. 
o Creatine Kinase 
o Liver Function Tests 
 
Alanine aminotransferase (ALT) 
 
Aspartate aminotransferase (AST) 
 
Alkaline phosphatase 
o Ionogram  
9.1.4 Telephone Follow-up 1 (At 18 months Post Randomization ± 2 weeks)  
 
Information on outcomes (MACE). 
 
Changes in concomitant diseases/illnesses and medication since Visit 2. 
 
Adverse Events. 
 
9.1.5 Visit 3 (At 24 months Post Randomization ± 2 weeks) 
 
Information on outcomes (MACE). 
 
Changes in concomitant diseases/illnesses and medication since Telephone Follow-up 1. 
 
Adverse Events. 
 
Vital signs (blood pressure and heart rate after 5 min sitting rest). 
 
Blood Sample will be collected and analyzed by the local laboratory linked with each trial 
center (Section 9.1.3). 
 
Medication Self-Adherence Questionnaire, MMAS-8. 
 
Quality of Life Questionnaire, EQ-5D. 
 
Patient Preference, Treatment Satisfaction Questionnaire for Medication (TSQM). 
 

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9.1.6 Telephone Follow-up 2 (At 36 months Post Randomization ± 4 weeks) 
 
Information on outcomes (MACE). 
 
Changes in concomitant diseases/illnesses and medication since Visit 3. 
 
Adverse Events. 
 
9.1.7 Telephone Follow-up 3 (48 months Post Randomization ± 4 weeks) 
 
Information on outcomes (MACE). 
 
Changes in concomitant diseases/illnesses and medication since Telephone Follow-up 3. 
 
Adverse Events. 
 
9.1.8 Telephone Follow-up 4 (60 months Post Randomization ± 4 weeks) 
 
Information on outcomes (MACE). 
 
Changes in concomitant diseases/illnesses and medication since Telephone Follow-up 3. 
 
Adverse Events. 
 
9.1.9 Treatment Duration 
The duration of the treatment will be a minimum of 2 years and a maximum of 5 years. 
Treatment with the components of the polypill is considered long term, and thus clinical guidelines 
recommend chronic treatment with statins, ASA and ACEI unless adverse effects present.  
 
 
 

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 STUDY ASSESSMENTS 
10.1 Assessment Schema 
Assessments planned to be conducted throughout the course of the study: 
 
10.2 Primary Endpoints 
Major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal 
myocardial infarction, nonfatal ischemic stroke, and urgent revascularization) will be monitored as 
the primary outcome and include the following: 
 
Cardiovascular death: includes any death resulting from acute myocardial infarction, 
sudden cardiac death, heart failure, stroke, or any other cardiovascular causes. 
 
 
Nonfatal myocardial infarction: Evidence of spontaneous myocardial necrosis related to 
atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting 
intraluminal thrombus in one or more of the coronary arteries leading to decreased 
myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis in a clinical 
setting consistent with acute myocardial ischaemia with a rise and/or fall of cardiac biomarker 
values [preferably cardiac troponin with at least one value above the 99th percentile upper 
reference limit (URL) and with at least one of the following: 
- 
Symptoms of ischaemia. 
- 
New or presumed new significant ST-segment or T wave changes or new left bundle 
branch block (LBBB). 
- 
Development of pathological Q waves in the ECG. 
- 
Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality. 
 
Nonfatal ischemic stroke: Acute episode of focal or global neurological dysfunction 
caused by brain, spinal cord, or retinal vascular injury as a result of infarction documented 
by imaging technique (CT or MRI). 
 
 
Urgent coronary revascularization: Coronary revascularization (either PCI or CABG) of a 
lesion or lesions with diameter stenosis >50% by QCA triggered by the presence of clinical 

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or functional ischemia with severe ischemic signs and symptoms leading to urgent 
hospitalization and intervention. 
 
10.3 Secondary Endpoints 
10.3.1 Efficacy Endpoints 
1. Incidence of the first occurrence of any component of the following composite endpoint: 
CV death, MI, stroke.  
 
2. The first occurrence of the individual components of the primary endpoint  
 
CV death. 
 
Nonfatal type 1 myocardial infarction.  
 
Nonfatal ischemic stroke.  
 
Urgent coronary revascularization. 
 
3. Treatment Adherence: Changes in Treatment Adherence at two years will be measured by 
the Eight-Item Morisky-Medication Adherence Scale (MMAS-8), which has been validated 
in various CV treatment scenarios as an indirect, self-reported measure of adherence (8). 
 
4. Patient Satisfaction: Assessed with the validated Treatment Satisfaction Questionnaire for 
Medication (TSQM) version 1.4 (Annex 9) 
 
5. Change in Risk Factors at Two Years 
a. Systolic and Diastolic Blood Pressure (SBP and DBP): BP will be measured using a 
sphygmomanometer. A mean of two readings will be taken after 5 min sitting rest. 
Patients are required to avoid drinking coffee or beverages containing caffeine for at 
least one hour before study visits. Patients are also required to refrain from smoking for 
at least one hour before study visits. 
b. LDL cholesterol level will be collected and analyzed by the local laboratory linked 
with each trial center. 
6. Regional differences in performance of the polypill in the previous endpoints. 
 
10.3.2 Health Economic Endpoints 
1. Quality of Life will be assessed with the validated EuroQol EQ-5D (3L) scale. EQ-5D 
scores will be transformed into quality adjusted life years (QALYs). Annex 10. 
 
2. Cost differences and Incremental Cost-Effectiveness Ratio (ICER), expressed as the 
costs per QALY gained, of the Cardiovascular Combination Polypill AAR versus usual 
care. 
 
3. Occurrence of the following events (section 11.4.2): 
 
Scheduled Revascularization (non-urgent) 
 
Angina 
 
Atherosclerosis 
 
Other Cardiovascular Hospitalizations or Interventions 
 
Emergency Room Visits 
 

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10.3.3 Safety Endpoints 
1. All-cause mortality: Any death not covered by the above definitions, such as death caused 
by infection, malignancy, sepsis, pulmonary causes, accident, suicide, or trauma. 
2. Adverse Events 
a. Bleeding: according to Bleeding Academic Research Consortium Definition22 
(Annex 5).  
b. Renal dysfunction (increase in creatinine by 0.5 mg/dl or more) or hyperkalemia (K 
5.5 mEq/L) reported by physician in charge and leading to a change in doses or 
drug interruption. 
c. Drug allergies. 
d. Refractory cough leading to drug discontinuation. 
 
10.3.4 Adverse Events (AE) Assessment Guidelines 
 
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 in 
the past. For the purposes of this study (and after discussion with appropriate pharmacovigilance 
experts) certain not serious adverse events will not be collected, while certain events will be collected 
as endpoints and therefore not reported as serious adverse events. 
 
 
The investigator will closely monitor the AE and will adopt the necessary clinical measures to 
ensure the safety of the patients, following the proposed Event Flow Chart on figure 2. 
 
Figure 2. Clinical Events Flow Chart 
 
 
 

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10.3.4.1.1 Definitions and Classifications 
Adverse Event  
An AE is any untoward medical occurrence in a patient or clinical study patient administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended medical occurrence in a study patient, 
including an abnormal value in a laboratory assessment, an ECG abnormality or an abnormal 
finding in the physical examination.  
Criteria to assess an abnormal result in a complementary test as an AE are the following (one is 
enough): is associated to signs or symptoms, requires diagnostic tests, medical or surgical 
intervention, requires modification of the IMP dosage or its discontinuation, requires the 
administration of medication or other type of treatment or when the investigator or the sponsor 
consider it as clinically significant. 
Planned surgical interventions or planned hospitalizations scheduled prior to signing the informed 
consent but performed during the study should not be considered as AEs. 
Adverse Drug Reaction (ADR) 
An ADR is an untoward and unintended response to an IMP related to any dose administered. 
Therefore, it is an AE assessed as being related to the IMP administered. 
Serious Adverse Event and Serious ADR 
An SAE is any AE or ADR that: 
 
Results in death. 
 
Is life-threatening. 
 
Requires inpatient hospitalization or prolongs existing hospitalization. 
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital anomaly or birth defect. 
 
Is any other medically important event that may jeopardize the patient’s well-being or may 
require intervention to prevent one of the other above outcomes. 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe. 
Hospitalization is defined as an overnight stay at the hospital or emergency room.  
Prolongation of hospitalization is defined as any extension of an in-patient hospitalization beyond 
the stay anticipated/required in relation to the original reason for the initial admission, as 
determined by the investigator or treating physician. 
 
Assessment of Expectedness 
An AE is defined as expected or unexpected according to the list of AEs in the valid Investigator’s 
Brochure (or the Reference Product Information) and not on the basis of what might be anticipated 
from its pharmacological properties. 

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An unexpected AE relates to an event the nature or severity of which is not consistent with the 
reference product information for the IMP (Investigator's Brochure/Reference Product information). 
 
Assessment of Intensity 
For grading the intensity of an AE the following 3 categories will be considered: 
 
Mild: means awareness of symptoms or signs, but easily tolerated (acceptable). 
 
Moderate: means enough discomfort to interfere with usual activity (disturbing). 
 
Severe: means incapacity to work or to perform usual activities (unacceptable). 
 
Assessment of Causality 
Causality of an AE to the IMP or study procedures will be assessed in 5 categories according to the 
information provided below: 
 
Probable: To be applied when there is a plausible temporal relationship, a biological 
plausibility and additional explanations such as concomitant medications, drug interactions, 
or intercurrent diseases are lacking. In addition, the event should follow a clinically 
reasonable response on product withdrawal.  
 
Possible: To be applied when there is a plausible temporal relationship and a biological 
plausibility but the event could have been due to another equally likely cause such as 
concomitant medications, drug interactions, or intercurrent diseases. 
 
Unlikely: To be applied when the temporal relationship is plausible but the event is likely to 
be explained by another cause which can, by itself, explain the occurrence of the event. 
 
Not related: To be applied when the temporal relationship is not plausible or another cause 
can by itself explain the occurrence of the event. 
 
Definitely related: The adverse event is clearly related to the investigational 
agent/procedure – i.e. an event that follows a reasonable temporal sequence from 
administration of the study intervention, follows a known or expected response pattern to 
the suspected intervention, that is confirmed by improvement on stopping and reappearance 
of the event on repeated exposure and that could not be reasonably explained by the known 
characteristics of the subject’s clinical state. 
10.3.4.1.2 Reporting Adverse Events 
Study endpoints or suggestive study endpoints will not be reported as adverse events. These events 
will be captured on an event page in the eCRF and final event assessment will be performed by the 
CEC. All other events that are serious such as SAE, SUSARs, ADR, or events that lead to 
permanent discontinuation will be collected in the AE/SAE eCRF page. As stated in section 10.2 
and 10.3, the study endpoints/events include, but are not limited to: 
 
 
Cardiovascular Death 
 
All-cause Mortality 
 
Non-fatal Myocardial Infarction 
 
Non-fatal Ischemic Stroke 
 
Urgent Coronary Revascularization 

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 
Scheduled Revascularization (non-urgent) 
 
Angina 
 
Atherosclerosis (definition Section 11.4.2) 
 
Other Cardiovascular Hospitalizations or Interventions (definition Section 11.4.2) 
 
Emergency Room Visits (definition Section 11.4.2) 
 
The following adverse events or serious adverse events will be 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 (Annex 5) 
 
Renal dysfunction 
 
Angioedema  
 
Although not required, any nonserious adverse events, of particular concern to the investigator may 
be recorded in the eCRF to bring them to the attention of the sponsor. All other non-serious adverse 
events not fulfilling the above mentioned criteria will not be reported as adverse events in the 
eCRF. 
Reported AEs will be coded using MedDRA, classified by system organ class and preferred term 
and tabulated by intensity and causal relationship for each treatment. 
The AEs listed in the investigator’s brochure would, by definition not be considered unexpected and 
thus would not be unanticipated problems. Possible exceptions would include situations in which 
the specificity or severity of the event is not consistent with the description in the investigator’s 
brochure, or it can be determined that the observed rate of occurrence for a serious, expected AE in 
the clinical trial represents a clinically important increase in the expected rate of occurrence. 
The above mentioned adverse events should be reported from the time a signed and dated ICF is 
obtained, to the completion of the clinical study (including the Follow-up Visit); or premature 
patient withdrawal from the study; and until 30 days after the last dose of study drug was taken by 
the subject. The sponsor will evaluate any safety information that is spontaneously reported by an 
investigator beyond the timeframe specified in the protocol. 
 
AE information will be collected through in-person visits, telephone follow-up, physical 
examination, laboratory assessments, medical records, and/or other complementary tests results. 
Assessment will be based on the seriousness, intensity, causal relationship to the IMP, and 
according to the definitions provided above. 
10.3.4.1.3 Follow Up of Adverse Events 
As a general rule all patients with reported AEs will be followed up until the complete resolution of 
the AE or until the stabilization of its progression is confirmed. 
Reported AEs that are still present after the last patient’s scheduled visit will be followed up within 
30 days of receiving the last IMP by phone call or in-person visit, as considered appropriate. After 
that time point, the need for additional follow-up of ongoing AEs/SAEs will be discussed between 
the investigator and the sponsor, although in the event of discrepancies, the investigator’s criteria 
will prevail.  

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All reported and unresolved non-serious AEs beyond this date will be considered as ongoing and 
recorded on the AE eCRF page with an outcome of “recovering” (if the event improved compared 
with the previous observation), “not recovered” (if the event did not vary or worsened compared 
with the previous observation) or “unknown” (if the patient is lost to follow-up and no previous 
information is available). 
10.3.4.2 Serious Adverse Events (SAEs) 
10.3.4.2.1 Reporting Requirements of Serious Adverse Events 
Reporting During the Study  
In the event of a reportable SAE the investigator or a delegate will: 
1. FILL IN immediately the SAE form in English.  
2. The MINIMUM INFORMATION that must be included in the initial report is: 
 
An event meeting the criteria of SAE. 
 
A qualified reporter, defined as an investigator of this study or his/her delegate. 
 
A qualified patient, defined as a patient who has consented to this study. 
 
Suspected medicinal product (test or reference), if initiated. 
 
The investigator’s or delegate’s causality assessment. 
3. SUBMIT information immediately in the eCRF (within 24 hours of the moment the 
investigator or delegate first learnt of it) and notify CNIC and the CRO responsible for 
pharmacovigilance.  
4. CONTACT immediately by phone all pharmacovigilance contacts in case of SUSAR 
CNIC Safety Contact Details 
Phone numbers and email addresses will be provided directly to 
the investigator and research staff prior or during site initiation 
 
5. ARCHIVE the original documents in the investigator’s file.  
6. FOLLOW-UP information. Unless the SAE has been sufficiently documented in the initial 
report, the investigator has to provide all available additional information in follow up reports 
by using a new form and adhering to the same routing and timeframes as defined by the initial 
report. This will be continued until the event has been fully documented and reported 
7. NULLIFICATION. An event reported to the sponsor that does not meet the SAE criteria shall 
be nullified by the investigator by forwarding a follow-up report. 
Reporting after Completion or Premature Discontinuation of the Study 

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Any reportable SAE coming to the knowledge of the investigator that has occurred to a patient after 
his/her participation in the study will be collected and reported up to 30 days after the last IMP 
administration, but only if the investigator judges that is related to the IMP or the study procedures.  
The same reporting procedure and timeframes apply as during the study. 
Expedited Submission to the Competent Authorities, ECs and Investigators 
CNIC will submit the regulatory report to the Competent Authorities and the Ethics Committees as 
soon as possible but no later than 7 calendar days (fatal or life-threatening SUSARs) or 15 calendar 
days (other SUSARs), after becoming aware of the information. All investigators will also be 
informed. 
Other Safety Findings 
In addition, the CNIC will promptly notify the Competent Authorities and the Ethics Committees of 
findings that could adversely affect the safety of patients, impact on the conduct of the study or alter 
the EC approval/favorable opinion of the study, as well as the investigators. 
 
10.3.4.3 Suspected Unexpected Serious Adverse Reaction (SUSARs) 
A SUSAR is an adverse reaction that is both unexpected (not consistent with the applicable product 
information) and also meets the definition of a Serious Adverse Reaction and must meet the 
following criteria: 
1. The event must be serious, that is to say irrespective of the dose the event: 
 
is fatal, and/or 
 
is life-threatening for the patient, and/or; 
 
makes hospital admission or an extension of the admission necessary, and/or 
 
causes persistent or significant invalidity or work disability. 
 
 2.  There must be a certain degree of probability that the event is harmful, and an undesirable, reaction 
to the medicinal product being research, regardless of the administered dosage. In other words, there 
is an adverse reaction. 
3. The adverse reaction must be unexpected. That is to say, the nature and severity of the adverse 
reaction are not in agreement with the product information as recorded in: 
 
for an authorized medicinal product: the IMPD text.  
 
for an unauthorized medicinal product: the Investigator’s Brochure. 
10.3.4.3.1 Definition of SUSAR 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For the CV polypill, the expectedness of an adverse event will 
be determined by whether or not it is listed in the Investigator's Brochure. For comparator agent and 
background/combination therapy agents with a marketing authorization, ie, ASA, ramipril, 
atorvastatin, the expectedness of an adverse event will be determined by whether or not it is listed in 
the package insert. 
10.3.4.3.2 Reporting SUSAR 

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In the event of an SUSAR the investigator or a delegate will inform the sponsor or delegated party 
immediately of every event in the study that ‘takes a course that is significantly more unfavorable to 
study participants than foreseen in the research protocol’. The same applies to all undesirable effects 
that are both serious and unexpected and/or form a risk to the research subject. The investigator or a 
delegate are required to report all relevant information on SUSARs, including SUSARs relating to 
the comparative product which have occurred in a control group. 
 
SUSARs within the study that are life-threatening or have had fatal consequences must be reported, 
at the latest, within 7 days after the sponsor has become aware of them. All relevant information on 
the aftermath of this must be reported within a time period of a further 8 days. Other reports of 
SUSARs must be made within 15 days after the sponsor has become aware of them. SUSARs from 
another study with the same product will be submitted within the 6 monthly line-listings, unless 
there are direct consequences for the subject within the study. In that case expedited reporting 
within the same terms as noted above is required. 
  DATA MANAGEMENT AND STATISTICAL ANALYSIS 
11.1 Data Management and Coding 
Data will be captured in an eCRF and the Investigator is responsible for ensuring the prompt and 
accurate reporting of study data into the eCRF. Data management documentation will be prepared 
by CNIC.  
Previous and concomitant medications (including rescue medication) will be coded using the latest 
available WHO Drug Reference Dictionary. Coexistent diseases and AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
When the database has been declared to be complete and accurate, the database will be locked. Any 
changes to the database after that time can only be made by written agreement between Ferrer, S.A. 
and the CNIC project team. 
11.2 Statistical Methods 
Statistical Analysis will be performed by London School of Hygiene and Tropical Medicine, under 
the supervision of 
 
In general terms, categorical data will be presented as absolute and relative frequencies and 
continuous variables will be presented as mean, median, standard deviation (SD), minimum, 
maximum, and number of patients with an observation (n). In general, minima and maxima will be 
recorded to the number of decimal places as recorded in the CRF; means, medians, and SDs will be 
recorded to one further decimal place. Percentages will be rounded to one decimal place.  
The inferential analysis will be limited to the primary endpoint incidence of combined endpoint 
(occurrence of MACE). Other analysis will include change in blood pressure (SBP and DBP), lipid 
profile variables (LDL-cholesterol, HDL-cholesterol, total cholesterol and triglycerides) and 
adherence (MMAS-8). Other variables will be analyzed descriptively. All statistical tests will be 
2-sided and will be performed using a 5% significance level if not stated otherwise.  
All individual patient data will be listed. 
11.2.1 Statistical and Analytical Plans 
The following datasets will be defined: 

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Safety dataset:  All patients who have given informed consent. 
Intent-to-treat (ITT) dataset: All randomized patients who received at least one dose of IMP. This 
will be the population for the primary analysis. 
Per protocol (PP) dataset: All randomized patients who received at least one dose of IMP have 
baseline and final time point measurement, and have no major protocol deviations.   
11.3 Demographic and Other Baseline Characteristics 
The following demographic variables will be summarized by treatment group:  age, sex, race, 
height, weight, and BMI. Smoking history will also be summarized by treatment group. No 
statistical hypothesis testing of demographic or baseline data will be performed. 
History of disease and other diagnostic information will be summarized. Other baseline 
characteristics collected in the eCRF will be summarized as appropriate. 
Concomitant medications taken during the study will be summarized. 
11.4 Variables 
 
11.4.1 Definition of Primary Endpoint 
The first occurrence of any component of the following composite endpoint, as adjudicated by the 
Clinical Events Committee: 
 
Any nonfatal type 1 myocardial infarction  
 
Any nonfatal ischemic stroke  
 
Any urgent coronary revascularization 
 
Cardiovascular death 
 
Nonfatal myocardial infarction: defined by the presence of electrocardiographic changes or at 
least 1 elevated biomarker measurement of a troponin T level ≥ 0.1 ng/mL 
 
Nonfatal ischemic stroke. Acute episode of focal cerebral, spinal, or retinal dysfunction caused by 
infarction of central nervous system tissue, not resulting in death.  
 
Urgent coronary revascularization: Episode/s of persisting or increasing chest pain (with or 
without ST-T changes or elevated biomarkers) requiring urgent hospitalization and urgent coronary 
revascularization (PCI or CABG), during the same hospitalization. 
 
Cardiovascular death: includes any death resulting from acute myocardial infarction, sudden 
cardiac death, heart failure, stroke, or any other cardiovascular causes 
 
11.4.2 Definition of Secondary Endpoints 
Efficacy Endpoints 
1. The first occurrence of any component of the following composite endpoint: CV death, MI, 
stroke 
2. The first occurrence of the individual components of the primary endpoint CV death: 
 
Nonfatal type 1 myocardial infarction.  
 
Nonfatal ischemic stroke.  

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 
Urgent coronary revascularization 
3. Treatment adherence, measured by MMAS-8. 
4. Patient satisfaction measured by TSQM. 
5. Risk factor control at 2 years defined as LDL-cholesterol and blood pressure values (SBP and 
DBP) 
6. Regional differences in performance 
Safety Endpoints 
All-cause mortality: Any death not covered by the above definitions, such as death caused by 
infection, malignancy, sepsis, pulmonary causes, accident, suicide, or trauma. 
Safety and tolerability of the treatments, defined by adverse events and percentage of the patients 
who discontinue the treatment in both arms. 
 
Health Economic Endpoints 
1. Costs  
2. QALYs 
3. Incremental cost-effectiveness ratios (ICERs) 
4. Occurrence of the following events: 
 
Scheduled Revascularization (non-urgent): defined as Coronary revascularization 
(either PCI or CABG) of a lesion or lesions with diameter stenosis >50% by QCA 
triggered by the presence of clinical or functional ischemia with severe ischemic signs 
and symptoms not being an urgent hospitalization and intervention 
 
Angina 
 
Atherosclerosis: defined as Hospitalization for atherosclerosis of the coronary arteries, 
including: atherosclerosis heart disease of native coronary artery, atherosclerosis of 
coronary artery bypass graft(s), atherosclerosis of bypass graft of coronary artery of 
transplanted heart, old myocardial infarction, ischemic cardiomyopathy, silent 
myocardial ischemia, chronic total occlusion of coronary artery, coronary 
atherosclerosis due to lipid rich plaque, chronic ischemic heart disease, cardiomegaly, 
heart disease (unspecified), abnormal findings on diagnostic imaging of heart and 
coronary circulation; excluding angina, myocardial infarction or surgical intervention. 
 
Other Cardiovascular Hospitalizations or Cardiovascular interventions (excluding 
myocardial infarction, stroke, urgent revascularization, scheduled revascularization, 
hospitalization for ischemic heart disease or atherosclerosis of the coronary arteries or 
angina.) 
 
Emergency room visits for cardiac atherosclerosis-related causes without hospital 
admission. 
 
 
11.5  Methods of Analysis 
For the primary endpoint first the non-inferiority will be tested using Cox proportional hazards 
regression with the pre-specified non-inferiority margin of HR = 1.373. If this non-inferiority 
hypothesis is confirmed, it will be preceded with the superiority testing using a log-rank test.  
 
Secondary endpoints defined as time to event will be analyzed using a log-rank test. 
Treatment adherence between groups will be compared by a Mann-Whitney test. 
 
Between-group differences in SBP, DBP and lipid profile variables after treatment will be analyzed 
by ANCOVA, including fixed terms for treatment, center and baseline SBP or LDL-cholesterol 

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accordingly as covariate. A point estimate will be constructed using the error variance obtained 
from the ANCOVA.  
 
Adaptive Design 
The trial will use an adaptive sample size re-estimation23. In brief, an unblinded interim analysis of 
the primary endpoint will take place after 70% of the initial sample size have been recruited and 
followed for a minimum of 6 months. If the conditional power lies in a “promising zone” then the 
sample size and length of follow-up will be increased.  
Full details of the adaptive sample size re-estimation design, including definition of the favorable, 
promising and unfavorable zones and rules regarding the sample size inflation, will be provided in 
an Adaptive Charter and in the Statistical Analysis Plan (SAP), both of which will be agreed and 
signed off before the trial data are unblinded. 
 
Health Economic Analysis 
As part of a sub study a within-trial health economic evaluation will be conducted comparing 
Cardiovascular Combination Pill AAR with usual care using a third party payer perspective. For 
this purpose data on health service resource use alongside the clinical trial will be collected. 
The sub study will include the following analyses:  
1. An intention-to-treat comparison of health service resource use and costs associated with 
Cardiovascular Combination Polypill AAR and usual care at different time points. Costs will 
be compared using nonparametric bootstrapping.  
2. A cost-effectiveness analysis will be conducted using the third party payer perspective to 
estimate the incremental cost-effectiveness ratio (ICER), expressed as the cost per QALY 
gained of the Cardiovascular Combination Polypill AAR versus usual care. Different time 
horizons will be explored using discount rates for costs and benefits applicable for each 
country. Costs and outcomes will be discounted at rates appropriate for country level 
analyses. Cost-effectiveness analyses will be performed for each country separately to 
incorporate differences in cost data.  
3. Several sensitivity analyses will be carried out to investigate the robustness of the results with 
respect to parameter uncertainty. In addition, the effect of different cost-effectiveness ratio 
thresholds for the willingness-to-pay will be explored to show the probability the 
Cardiovascular Combination Polypill AAR has to be cost-effective relative to standard care. 
 
A detailed description of the statistical analysis in used in the cost comparisons and cost-
effectiveness analysis will be provided in the Statistical Analysis Plan. 
 
11.6  Safety Variables 
Exposure and compliance to IMP will be summarized. 
Reported AEs will be coded by the pharmocovigilance company using the MedDRA dictionary 
(most recent version), by system organ class and preferred term. Only treatment emergent AEs (ie 
commencing after dosing with the IMP) will be included in the summary tables. Treatment 
emergent AEs will be assigned to the treatment received preceding event onset. All reported AEs, 
whether treatment emergent or not will be included in the data listings. 
IMP-related AEs will be defined as events considered to have a probable, possible, or unlikely 
causal relationship to the IMP. AEs leading to withdrawal will be defined as events where the IMP 

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was withdrawn as a result of the AE. If the intensity or causal relationship to the IMP of an AE is 
missing, a worst-case scenario will be assumed (ie it will be set to severe or probably related). 
The denominator used for the calculation of percentages will be the number of patients in the safety 
dataset (N) for the treatment group. 
The following summary of treatment emergent AEs will be provided. 
The number and percentage of patients reporting AEs, serious AEs, IMP-related AEs, AEs leading 
to withdrawal and AEs leading to death will be presented. 
In addition, the following summary tables will be presented. 
Summary of AEs by system organ class and preferred term. 
Summary of AEs by intensity of event. 
Summary of AEs by seriousness 
Summary of IMP-related AEs. 
Summary of AEs by causal relationship to the IMP. 
Laboratory variables (hematology and clinical chemistry) will be summarized at baseline and final 
timepoint including changes from baseline. Shift tables from baseline to final timepoint (with 
respect to the number and percentage of patients with values below, within, or above the reference 
range) will also be presented. Values outside the reference ranges will be flagged in the data 
listings. 
Vital signs data will be summarized at each timepoint, including changes from baseline (i.e. 
predose). 
Physical examination data will be summarized over the course of the study. 
 
11.6.1 Determination of Sample Size 
The planned total sample size in this study is 2514 patients (1257 per group). The initial 
assumptions for the determination of sample size are as following: 
 
A composite primary endpoint event rate of 7.7% per year in the population to be 
recruited 
 
A true hazard ratio of 1 
 
A planned accrual period for the study of 3 years 
 
A minimum follow-up and treatment period of 2 years  
 
An estimated loss to follow-up of 1% 
 
Based on these assumptions, it is anticipated that 420 composite primary events will be accrued 
during the follow-up period.  
A non-inferiority margin of 1.373 for the upper limit of the 95% confidence interval for the hazard 
ratio is set for this study. With the total sample size of 2514 patients (1257 per group) a non-
inferiority test at 0.025 one-sided significance level with have a 90% power to reject the null 
hypothesis of inferiority. 
With this sample size, the study will have 78% power at a two-sided alpha of 0.05 to demonstrate a 
relative risk reduction of 21%, which corresponds to a hazard ratio 0.79. 

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11.6.2 Procedures for Reporting any Deviation(s) from the Original Statistical Plan 
Any deviation(s) from the original statistical plan will be described and justified in a protocol 
amendment and/or in a statistical analysis plan and/or in the final report, as appropriate. 
 
 INVESTIGATOR/SPONSOR RESPONSIBILITIES 
12.1 Ethics 
12.1.1 Ethics Committee 
Before initiating the study, the investigator must have written and dated approval from the Ethics 
Committee (EC) for the study protocol, written informed consent form, patient recruitment 
procedures (e.g. advertisements), and any other written information to be provided to patients.  
Approval from the EC must be documented in a letter to the investigator specifying the protocol 
number, protocol version, documents reviewed, date on which the EC met, date the EC granted the 
approval, the date of approval expiration and the EC membership list.  A list of all ECs will be 
included in the Trial Master File. 
In the event the EC approval/favorable opinion requires a change(s) in any aspect of the study (e.g. 
modification to the protocol), the sponsor must be provided with a copy of all requested 
modification(s). If the sponsor is in agreement with the requested modification(s), the sponsor will 
provide an investigator-specific protocol amendment to the investigator for submission to the 
reviewing EC.  Dated documentation must then be provided to the sponsor upon approval/favorable 
opinion of the protocol based upon the investigator-specific protocol amendment by the EC. 
12.1.2 Ethical Conduct of the Study 
The study will be conducted in compliance with the protocol, regulatory requirements, good clinical 
practice (GCP) and the ethical principles of the Declaration of Helsinki as adopted by the World 
Medical Assembly, 1996 (and subsequent revisions). 
12.1.3 Patient Information and Consent 
The investigator is responsible for ensuring that no patient undergoes any study-related examination 
or activity before that patient has given written informed consent to participate in the study.  The 
written consent must be given by the patient of the patient, after detailed information about the study 
has been given as in accordance with any national provisions on the protection of clinical study 
patients.  The verbal explanation will cover all the elements specified in the written information 
provided for the patient.   
The investigator or designated personnel will inform the patient of the objectives, methods, 
anticipated benefits and potential risks and inconveniences of the study. The patient must be given 
every opportunity to clarify any points he/she does not understand and, if necessary, ask for more 
information. At the end of the interview, the patient will be given time to consider the study if this is 
required, or if the patient requests more time.  Patients will be required to sign and date the informed 
consent form.  After signatures are obtained, the informed consent form will be kept and archived by 
the investigator in the investigator’s study file for possible inspection by regulatory authorities, the 
EC and sponsor.   
It should be emphasized to the patient that he/she is at liberty to withdraw from the study at any time, 
without penalty or loss of benefits to which the patient is otherwise entitled.  Patients who refuse to 
give or who withdraw written informed consent should not be included or continue in the study. 

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12.2 Patient Records and Source Data 
There may be data that are recorded only in the eCRF. In these circumstances, the Investigator 
would not be expected to duplicate information. With information of this type, in which the clinical 
data are associated with protocol-specific procedures and not with clinical care practice, the eCRFs 
will stand as the source documents. 
The origin of source data in the study will be further specified in a separate document (“Origin of 
Source Data”).  
It is the responsibility of the Investigator to record essential information in the medical records in 
accordance with national regulations and requirements. The following information should be 
included as a minimum: 
 
Study code 
 
Patient screening number and/or patient number 
 
Date when informed consent was obtained 
 
Diagnosis 
 
All visits during the study period 
 
All reportable AEs 
 
Treatments and medications (including dosage) 
 
Date of study termination 
 
Patient health service identification number 
The Investigator is responsible for ensuring the accuracy, completeness, legibility and timeliness of 
the data recorded in the eCRFs. 
 
12.2.1 Archiving 
All documents compiled in the Trial Master File (TMF) and Investigator Site File (ISF) will abide 
to the principles and guidelines of good clinical practice and with the applicable requirements and, 
in particular with Annex I of Directive 2001/83/EC.  
The sponsor and each investigator (participating sites) shall retain the essential documents relating 
to a clinical trial for at least fifteen years after the completion or discontinuation of the clinical trial. 
Investigator must also obtain approval from Sponsor prior to destroying any study essential 
documents within the fifteen year period after the completion or discontinuation of the clinical trial. 
Retention of documents for a longer period shall occur, if so required by other applicable 
requirements. 
Essential documents shall be archived in a way that ensures they are readily available, upon request 
to the competent authorities. 
The medical files of trial subjects shall be retained in accordance with national legislation and 
accordance with the maximum period of time permitted by the hospital, institution, or private practice. 
Access to archives shall be restricted to the named individuals responsible for the archives. 
Any alteration to records shall be traceable. 
12.3 Monitoring 
The study sites will be visited on a regular basis to ensure that the study is conducted and documented 
in accordance with this protocol, ICH GCP guidelines, regulatory requirements and any study specific 
documents such as eCRF completion guidelines. 

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Monitoring visits will be conducted to confirm e.g. that: 
 
The investigational team is adhering to this study protocol 
 
Informed consent has been obtained for all participants 
 
AEs have been collected and reported according to the protocol requirements 
 
Data are being accurately recorded in the eCRFs 
 
Investigational products have been stored correctly and that drug accountability has been 
performed 
 
Facilities are and remain acceptable 
 
The Investigator and the site receive sufficient information and support 
Moreover, during monitoring visits the data recorded in the CRFs, source documents and other study-
related records will be compared against each other in order to ensure accurate data that reflects the 
actual existence of the patient in the study i.e. source data verification. 
Deviations to the study protocol will be documented in the Protocol Deviation Log.  
12.4  Access to Source Data and Documentation 
All personnel involved in the study at the site are bound to professional secrecy under the national 
official secrecy act. 
An individual secrecy agreement will be established for all Sponsor and CRO representatives 
(including study monitors), independent auditors, and representatives from Competent Authorities (if 
applicable) that will have access to the information in the medical records for the participating 
patients. 
The Investigator should guarantee access to source documents for the monitor and auditors, as well 
as for inspection by appropriate regulatory agencies. 
12.5 Quality Assurance and Audit 
A quality assurance system has been implemented to ensure that the study is performed and the data 
are generated, documented (recorded), and reported in compliance with GCP as defined in ICH E6 
guidelines and the applicable regulatory requirement(s). 
SOPs have been created to ensure that clinical studies are conducted in compliance with regulatory 
requirements and GCP. Quality control will be applied to each stage of data handling to ensure that 
data are accurate, reliable and processed correctly. 
Authorized representatives of CNIC, the Sponsor and/or a Competent Authority and/or the EC may 
visit the center to perform audits/inspections, including source data verification. 
12.6 Protocol Amendments 
Unless otherwise agreed, substantial protocol amendments will be approved by the same persons 
that approved the study protocol. All substantial protocol amendments to the protocol will be 
submitted to the EC and Competent Authorities. Substantial protocol amendments become effective 
first when the Competent Authorities and/or EC have provided written approval. Non-substantial 
amendments will be approved by appropriate persons. 
 

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12.7 Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement. 
12.8 Report and Publication 
After completion of the study, a clinical study report will be prepared according to the ICH Guideline 
for Structure and Content of Clinical Study Reports (ICH E3) by CNIC in collaboration with the 
SECURE consortium. 
The results of the study will be published in a peer review journal.  
All publications and presentations must be based upon the clinical study report.  
All information supplied by the Sponsor in connection with this study will remain the sole property 
of the Sponsor and is to be considered confidential information. No confidential information will be 
disclosed to others without obtaining prior written consent from the Sponsor and will not be used 
except in the performance of this study. 
If an Investigator wishes to publish results from this clinical study, written permission to publish must 
be obtained from the Sponsor in advance. As some of the information regarding the investigational 
product and development activities at the Sponsor may be of a strictly confidential nature, the Sponsor 
must first review any publication manuscript prior to their submission to journals, meetings or 
conferences. 
The Sponsor will publish and present data from this study. If an Investigator is offered first authorship, 
he/she will be asked to comment and approve the publication.  
 

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Annex 2: The Data Safety and Monitoring Board (DSMB) 
 
Purpose Overview 
The purpose of an independent Data and Safety Monitoring Board (DSMB) has been convened to 
safeguard the interests of trial participants and to safeguard the scientific integrity of the trial. The 
DSMB will review accumulating safety and efficacy data throughout the trial as well as other data 
related to the overall conduct of the trial. The DSMB will make recommendations concerning 
continuation, modification or termination of the trial to the Executive Committee. 
 
Independence of the DSMB 
The DSMB will be independent of the sponsor, national competent authorities, ethics committees, 
and investigators. Such independence of the DSMB is essential to maintain subject’s safety, 
preserve the integrity of the study, and ensure members are objective and capable of an unbiased 
assessment of the study’s safety and efficacy data. A set of strict criteria will be used in evaluating 
the independence of the DSMB. 
 
Responsibilities of the DSMB 
All DSMB members will review the study protocol, amendments, planned analysis, investigator 
brochure (IB), and summary of product characteristics (SmPC) to ensure a complete understanding 
of the study’s objective and its design in order to anticipate interim safety review and possible early 
stopping rules. The responsibilities of the DSMB and its members are: 
 
To evaluate, on an ongoing basis, the accumulating safety assessments to ensure the ongoing 
safety of study subjects 
 
To consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants 
or the ethics of the study 
 
To review all documents provided in the DSMB data review packets upon receipt 
 
To review the conduct of the study, including protocol violations 
 
To review data on participant recruitment, accrual, and retention, as well as assessments of data 
quality, completeness, and timeliness 
 
Protect the confidentiality of the study data and the DSMB discussions 
 
Review specific interim analyses for efficacy  
 
To make recommendations to continue, modify, or terminate the study depending upon these 
analyses 
 
Operate according to the procedures described in the DSMB charter  
 
Follow conflict of interest guidelines as detailed in the charter 
 
Maintain documentation and records of all activities. 
 
Responsibilities of the Sponsor 
 
Ensuring resources are available to the DSMB as required to perform its designated functions  
 
Promptly reviewing and responding to the DSMB recommendations 
 
Deciding whether to continue or terminate the trial, and determining whether amendments to 
the protocol or changes in study conduct are necessary 

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 
Communication of all pertinent DSMB information to Regulatory Authorities 
 
Forward special requests from any national regulatory authority requiring input from the DSMB 
 
Recommendations from the DSMB 
The DSMB will transmit the recommendations in writing, to the Executive Committee. At each of 
their meetings, one of the following will be recommended: 
 
continue the trial until the next meeting  
 
continue the trial with recommendations (e.g., modify the informed consent form, disseminate 
information to study Investigators, seek additional expert review/analysis) 
 
modify the trial (amend the protocol)  
 
temporarily suspend subject enrollment or dosing to obtain additional data or resolve an issue, 
or  
 
stop the trial early because of undue safety risks to subjects or compelling benefits to the 
subjects   
Recommendations to modify or terminate the trial will be accompanied by the DSMB’s justification 
for the recommendation.  The Executive Committee will review the recommendations made by the 
DSMB, discuss them as appropriate with the DSMB, and accept or reject the DSMB’s 
recommendations in writing together with some members of the Executive Committee. In the event 
that the DSMB’s recommendations are not agreed upon by the TSC and DSMB, the TSC will 
discuss this further with the DSMB; however, the final decision for study continuation, 
modification, suspension or discontinuation rests solely with the TSC and Executive Committee. 
The recommendations and final decision will be disseminated to all study Investigators. 
Confidentiality 
DSMB members are bound by confidentiality disclosure agreements to refrain from disclosing 
study-related material to any person without prior approval from CNIC. The DSMB members must 
ensure that no other individuals involved with the conduct, editing, entry, or analysis of data are 
informed of study results.  
 
 
 
 
 
 
 
 

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Annex 3: Definition of Myocardial Infarction24, 25 
 
All myocardial infarctions (MIs) will be counted as events whether they represent the reason for the 
hospitalization or occurred during a hospitalization.  In addition, they will be counted as events 
whether they occurred spontaneously or as the direct consequences of an investigation/procedure or 
operation.  The definition of MI as an endpoint will take into account whether a subject had a recent 
MI or has undergone revascularization with PCI or CABG surgery. In cases where both cardiac 
troponin and CK-MB are available (drawn at similar time points) and are discordant, biomarker 
criteria will be applied using cardiac Troponin except in cases of peri-procedural infarction.  The 
definitions of MI are as follows for the 4 clinical settings in which it may occur: 
 
1. Spontaneous MI (normal biomarkers)- For patients with no recent revascularization 
in whom biomarkers were never elevated or have been documented to return to normal 
after a qualifying (or recent) MI, criteria a & b or criterion c or criterion d must be met: 
 
a) Typical cardiac biomarker rise and/or fall with the following degrees of elevation accepted 
as biochemical evidence of myocardial necrosis (either one or both): 
 
 
Troponin T or I: maximal concentration greater than the MI decision limit 
 
CK-MB: maximal concentration greater than the ULN 
 
AND 
 
b) At least 1 of the following additional supportive criteria: 
 
 
Ischemic discomfort at rest lasting >10 minutes or 
 
ECG changes indicative of ischemia (ST elevation > 0.1 mV or ST depression > 0.05 
mV, or new T-wave inversions) 
 
OR 
 
c) Development of new, abnormal Q waves (>30 msec in duration and >1 mm in depth) in >2 
contiguous precordial leads or >2 adjacent limb leads; or increase R amplitude in V1-V3 
consistent with posterior infarction 
 
OR 
 
d) Pathologic findings of an acute MI. 
 
2. Spontaneous MI (Elevated biomarkers) - For patients with no recent revascularization in 
whom biomarkers from a qualifying (or recent) MI remain elevated, criteria a and b, or criterion 
c, or criterion d must be met: 
 
a) Cardiac biomarker re-elevation defined as: 
i. 
Increase by at least 20% of the previous value; and 
ii. 
Documentation that the biomarker assayed was decreasing prior to the suspected 
new MI 
 
AND 

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b) At least 1 of the following additional supportive criteria: 
i. 
Ischemic discomfort at rest lasting >10 minutes; or 
ii. 
ECG changes indicative of ischemia (ST elevation > 0.1 mV or ST depression > 0.05 mV, 
or new T-wave inversions) 
 
OR 
 
c) Development of new, abnormal Q waves (>30 msec in duration and >1 mm in depth) in >2 
contiguous precordial leads or >2 adjacent limb leads; or increase R amplitude in V1-V3 
consistent with posterior infarction 
 
OR 
 
d) New elevation of ST-segments > 0.1 mV in > 2 contiguous precordial or adjacent limb leads 
 
AND 
 
i. 
Ischemic discomfort at rest lasting > 20 minutes; or 
ii. 
Ischemia-mediated new hemodynamic decompensation requiring pharmacologic or 
mechanical support; or 
iii. 
Angiographic evidence of acute coronary occlusion 
 
3. Within 24 hours after PCI a patient must have EITHER: 
 
a) 
CK-MB >3× ULN and, if the pre-PCI CK-MB was >ULN, both an increase by at least 50% 
over the previous value and documentation that CK-MB was decreasing prior to the 
suspected recurrent MI; 
 
OR 
 
a) 
Pathologic findings of an acute MI. 
 
Note: symptoms are not required. 
 
4. Within 24 hours after CABG a patient must have EITHER: 
 
a) 
CK-MB >5× ULN and, if the pre-CABG CK-MB was >ULN, both an increase by at least 
50% over the previous value and documentation that CK-MB was decreasing prior to the 
suspected recurrent MI; 
 
AND 
 
b) 
At least one of the following supportive criteria: 
i. 
Development of new, abnormal Q waves (>30 msec in duration and >1 mm in depth) in 
>2 contiguous precordial leads or >2 adjacent limb leads; or increase R amplitude in V1-
V3 consistent with posterior infarction, or 
ii. 
Angiographically documented new graft or native coronary occlusion, or 
iii. 
Imaging evidence of new loss of viable myocardium 

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OR 
 
c) 
Pathologic findings of an acute MI. 
 
Note: symptoms are not required. 
 
5. Sudden Cardiac Death - Sudden cardiac death may represent an acute MI, but typically occurs 
before blood samples can be obtained.  In the absence of cardiac biomarkers, a patient who 
experiences sudden death will be considered to have had an acute MI if either of the following 2 
criteria is met: 
 
a) 
Pathologic findings of an acute MI (if no recent prior MI), or 
b) 
Presence of at least 2 of the following 3 criteria: 
i. 
Ischemic discomfort 
ii. 
New ST segment elevation at the J point in ≥2 anatomically contiguous leads with the cut-
off points: ≥ 0.2 mV in men (>0.25 mV in men < 40 years) or ≥ 0.15 mV in women in 
leads V2-V3 and/or ≥ 0.1 mV in other leads, new left bundle branch block, or new, 
abnormal Q waves (>30 msec in duration and ≥0.1 mV in depth) in 2 contiguous leads 
or new abnormal R waves (≥30 msec in duration and > depth of the S wave) in V1 and V2 
consistent with posterior infarction 
iii. 
Angiography with evidence of fresh coronary thrombus 
 
6. Silent MI - A patient must meet one of the following 3 criteria to qualify for a silent MI: 
 
a)     New, abnormal Q waves (>30 msec in duration and ≥0.1 mV in depth) in 2 contiguous 
leads, or new abnormal R waves (≥30 msec in duration and > depth of the S wave) in V1 and 
V2 consistent with posterior infarction, or 
b) 
Imaging evidence of a new (post-randomization) region (ie, must have a prior study) of loss 
of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic 
cause 
c) 
Pathological findings of acute MI (eg acute myocardial necrosis or fresh coronary 
thrombosis) that are clearly distinct from prior known MIs and which does not otherwise 
meet the criteria for any other category as described above 
Note: If cardiac troponin measurements are the only cardiac biomarker data available, they may be 
used by the CEC, along with the ECG and clinical scenario, in the adjudication of suspected MI 
after revascularization (PCI or CABG). 
 
The reviewers should also consider the clinical features (e.g., renal insufficiency), possible 
alternative diagnoses (e.g., pericarditis), pattern of marker release (e.g., absence of a rise and/or 
fall), and known sensitivity/specificity of the various cardiac markers in the adjudication of 
infarction, particularly when there is discordance in the results of multiple markers. 
Universal Definitions of MI Criteria 
Myocardial infarctions will be also be classified according to the following universal definition of 
MI criteria: 
 

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Type 1: Spontaneous Myocardial Infarction 
Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, 
erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries 
leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. 
The patient may have underlying severe Coronary Artery Disease (CAD) but on occasion non-
obstructive or no CAD. 
 
Other definitions of myocardial infarction not encompassed in the inclusion criteria 
 
Type 2: Myocardial infarction secondary to ischemia due to either increased oxygen demand or 
decreased supply, e.g., coronary artery spasm, coronary embolism, anemia, arrhythmias, 
hypertension, or hypotension. 
 
Type 3: Sudden unexpected cardiac death, including cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, accompanied by presumably new ST elevation, or new 
LBBB, or evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy, 
but death occurring before blood samples could be obtained, or at a time before the appearance 
of cardiac biomarkers in the blood. 
 
Type 4a: Myocardial infarction related to percutaneous coronary intervention (PCI) 
 
Type 4b: Myocardial infarction related to stent thrombosis as documented by angiography or at 
autopsy. 
 
Type 5: Myocardial infarction related to coronary artery bypass grafting (CABG). 
 
ST-Segment Elevation MI versus Non-ST-segment Elevation MI 
All events meeting criteria for MI* will also be classified as either ST-segment elevation MI 
(STEMI), non-ST-segment elevation MI (NSTEMI), or unknown. 
 
 
STEMI – To be classified as a STEMI the event must meet all of the above criteria for 
myocardial infarction and one of the four criteria below.  
o New ST segment elevation at the J point in 2 contiguous leads, defined as: ≥ 0.2 mV in 
men (> 0.25 mV in men < 40 years) or ≥ 0.15 mV in women in leads V2-V3 and/or ≥ 0.1 
mV in other leads. Subjects must have an interpretable ECG (i.e., without evidence of left 
ventricular hypertrophy or pre-existing left bundle branch block), or 
o New left bundle branch block 
 
NSTEMI – To be classified as a NSTEMI the event must meet all of the above criteria for 
myocardial infarction and not meet criteria for classification as STEMI. In order to be classified 
as NSTEMI there must be adequate interpretable ECG documentation associated with the event. 
 
Unknown – Events which meet criteria as specified above for MI but do not meet criteria for 
STEMI or NSTEMI. All cases where ECG documentation of the acute event is missing, 
inadequate, or uninterpretable should be classified as Unknown. 

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*All events adjudicated as MI will be classified as STEMI, NSTEM, or Unknown; however, it is 
acknowledged that a significant proportion of peri-procedural (PCI or CABG) events may have 
missing, inadequate or uninterpretable ECG documentation. 
 
 

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Annex 4: Standardized Definitions for Cardiovascular and Stroke End Point Events in 
Clinical Trials25  
13.1.1 Definition of Cardiovascular Death 
1. Death due to Acute Myocardial Infarction 
Refers to a death by any cardiovascular mechanism (e.g., arrhythmia, sudden death, heart 
failure, stroke, pulmonary embolus, peripheral arterial disease) ≤ 30 days1 after a MI related to 
the immediate consequences of the MI, such as progressive heart failure or recalcitrant 
arrhythmia. We note that there may be assessable mechanisms of cardiovascular death during 
this time period, but for simplicity, if the cardiovascular death occurs ≤ 30 days of the 
myocardial infarction, it will be considered a death due to myocardial infarction.  
 
Acute MI should be verified to the extent possible by the diagnostic criteria outlined for acute 
MI or by autopsy findings showing recent MI or recent coronary thrombosis.  
 
Death resulting from a procedure to treat a MI (percutaneous coronary intervention (PCI), 
coronary artery bypass graft surgery (CABG)), or to treat a complication resulting from MI, 
should also be considered death due to acute MI.  
 
Death resulting from an elective coronary procedure to treat myocardial ischemia (i.e., chronic 
stable angina) or death due to a MI that occurs as a direct consequence of a CV 
investigation/procedure/operation should be considered as a death due to a CV procedure. 
 
2. Sudden Cardiac Death 
Refers to a death that occurs unexpectedly, not following an acute MI, and includes the 
following deaths:  
 
Death witnessed and occurring without new or worsening symptoms. 
 
Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, 
unless the symptoms suggest acute MI. 
 
Death witnessed and attributed to an identified arrhythmia (e.g., captured on an 
electrocardiographic (ECG) recording, witnessed on a monitor, or unwitnessed but found on 
implantable cardioverter-defibrillator review). 
 
Death after unsuccessful resuscitation from cardiac arrest (e.g., implantable cardioverter- 
defibrillator (ICD) unresponsive sudden cardiac death, pulseless electrical activity arrest). 
 
Death after successful resuscitation from cardiac arrest and without identification of a specific 
cardiac or non-cardiac etiology. 
 
Unwitnessed death in a subject seen alive and clinically stable ≤ 24 hours prior to being found 
dead without any evidence supporting a specific non-cardiovascular cause of death  
(information regarding the patient’s clinical status preceding death should be provided, if 
available). 
 
3. Death due to Heart Failure 
Refers to a death in association with clinically worsening symptoms and/or signs of heart 
failure regardless of HF etiology. Deaths due to heart failure can have various etiologies, 
including single or recurrent myocardial infarctions, ischemic or non-ischemic cardiomyopathy, 
hypertension, or valvular disease.  
 
 
 

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4. Death due to Stroke 
Refers to death after a stroke that is either a direct consequence of the stroke or a complication 
of the stroke. Acute stroke should be verified to the extent possible by the diagnostic criteria 
outlined for stroke. 
 
5. Death due to Cardiovascular Procedures  
Refers to death caused by the immediate complications of a cardiac procedure. 
 
6. Death due to Cardiovascular Hemorrhage 
Refers to death related to hemorrhage such as a non-stroke intracranial hemorrhage, non-
procedural or non-traumatic vascular rupture (e.g., aortic aneurysm), or hemorrhage causing 
cardiac tamponade.  
 
7. Death due to Other Cardiovascular Causes  
Refers to a CV death not included in the above categories but with a specific, known cause 
(e.g., pulmonary embolism or peripheral arterial disease). 
 
13.1.2 Definition of Noncardiovascular Death 
Non-cardiovascular death is defined as any death with a specific cause that is not thought to be 
cardiovascular in nature, as listed above. Detailed recommendations on the classification of non-CV 
causes of death are beyond the scope of this document. The level of detail required and the optimum 
classification will depend on the nature of the study population and the anticipated number and type 
of non-CV deaths. Any specific anticipated safety concern should be included as a separate cause of 
death. The following is a suggested list of non-CV causes of death: 
 
Pulmonary 
 
Renal 
 
Gastrointestinal 
 
Hepatobiliary 
 
Pancreatic 
 
Infection (includes sepsis) 
 
Inflammatory (e.g., Systemic Inflammatory Response Syndrome (SIRS) / Immune 
(including autoimmune) (may include anaphylaxis from environmental (e.g., food) 
allergies) 
 
Hemorrhage that is neither cardiovascular bleeding or a stroke (see Chapter 1, Section 6, 
and Chapter 6) 
 
Non-CV procedure or surgery 
 
Trauma 
 
Suicide 
 
Non-prescription drug reaction or overdose 
 
Prescription drug reaction or overdose (may include anaphylaxis) 
 
Neurological (non-cardiovascular) 
 
Malignancy 
 
Other non-CV, specify: _________________ 
13.1.3 Definition of Undetermined Death 
Undetermined Cause of Death: refers to a death not attributable to one of the above categories of 
CV death or to a non-CV cause. Inability to classify the cause of death may be due to lack of 
information (e.g., the only available information is “patient died”) or when there is insufficient 

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supporting information or detail to assign the cause of death. In general, most deaths should be 
classifiable as CV or non-CV, and the use of this category of death; therefore, should be 
discouraged and should apply to few patients in well-run clinical trials.  
A common analytic approach for cause of death analyses is to assume that all undetermined cases 
are included in the CV category (e.g., presumed CV death, specifically “death due to other CV 
causes”). Nevertheless, the appropriate classification and analysis of undetermined causes of death 
depends on the population, the intervention under investigation, and the disease process. The 
approach should be prespecified and described in the protocol and other trial documentation such as 
the endpoint adjudication procedures and/or the statistical analysis plan. 
 
13.1.4 Definition of Urgent Coronary Revascularization.  
Coronary revascularization (either PCI or CABG) of a lesion or lesions with diameter stenosis 
>50% by QCA triggered by the presence of clinical or functional ischemia with severe ischemic 
signs and symptoms leading to urgent hospitalization and intervention. 
 
13.1.5 Definition of Transient Ischemic Attack and Stroke 
Transient Ischemic Attack  
Transient ischemic attack (TIA) is defined as a transient episode of focal neurological dysfunction 
caused by brain, spinal cord, or retinal ischemia, without acute infarction.  
 
Stroke  
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by brain, 
spinal cord, or retinal vascular injury as a result of hemorrhage or infarction, documented by 
imaging technique (CT or MRI). 
 
Stroke Classification 
A. Ischemic Stroke  
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused 
by infarction of central nervous system tissue.  
Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an ischemic 
stroke with hemorrhagic transformation and not a hemorrhagic stroke.  
 
B. Hemorrhagic Stroke  
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal dysfunction 
caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage.  
 
C. Undetermined Stroke  
Undetermined stroke is defined as an acute episode of focal or global neurological dysfunction 
caused by presumed brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction, but with insufficient information to allow categorization as A or B. 
 
 
 

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Annex 5: Safety Measures – Bleeding Definition22 
 
BLEEDING ACADEMIC RESEARCH CONSORTIUM DEFINITION FOR BLEEDING 
 
Type 0: no bleeding 
 
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional; may include 
episodes leading to self-discontinuation of medical therapy by the patient without consulting a 
healthcare professional. 
 
Type 2: any overt, actionable sign of hemorrhage (eg, more bleeding than would be expected for a 
clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for 
type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, medical 
intervention by a healthcare professional, (2) leading to hospitalization or increased level of care, or 
(3) prompting evaluation. 
 
Type 3 
Type 3a:  
Overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided hemoglobin drop is related to 
bleed) Any transfusion with overt bleeding. 
Type 3b:  
Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided haemoglobin drop is related to bleed).  
Cardiac tamponade. 
Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid).  
Bleeding requiring intravenous vasoactive agents. 
Type 3c:  
Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include 
intraspinal).  
Subcategories confirmed by autopsy or imaging or lumbar puncture.  
Intraocular bleed compromising vision. 
 
Type 4: CABG-related bleeding 
Perioperative intracranial bleeding within 48 h 
Reoperation after closure of sternotomy for the purpose of controlling bleeding 
Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
Chest tube output ≥2L within a 24-h period 
 
Type 5: fatal bleeding 
Type 5a 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious. 
Type 5b 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation. 
 
 
 
 
 

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Annex 6: Notes on Use of Atorvastatin 40mg on the Elderly in a Post MI setting 
Standard care for post-acute MI recommends high doses of statin to be use (Atorvastatin 80mgs, 
Rosuvastatin 40mg) which could potentially throw back investigators from enrolling patients in 
SECURE.  
 
However, according to the European Society of Cardiology (ESC) Guidelines for Management of 
STEMI, “the use of lower intensity statin should be considered in patients at increased risk of side 
effects (e.g. the elderly, patients with hepatic or renal impairment, with previous side effects to 
statins or the potential for interaction with essential concomitant therapy).”26    
 
Furthermore, the recently published 2013 guidelines on the treatment of blood cholesterol to reduce 
atherosclerotic cardiovascular risk in adults,27 Atorvastatin 40 mgs, is indeed considered high 
intensity treatment. (Table 1). 
 
Table 3. High- Moderate- and Low-Intensity Statin Therapy  
 
High- Intensity Statin 
Therapy  
Moderate-Intensity 
Statin 
Therapy  
Low-Intensity 
Statin 
Therapy  
Daily dose lowers LDL–C on 
average, by approximately 
≥50%  
Daily dose lowers LDL–C on 
average, by approximately 
30% to <50%  
Daily dose lowers LDL–C on 
average, by <30%  
Atorvastatin 40–80 mg  
Rosuvastatin 20 (40) mg  
Atorvastatin 10 (20) mg  
Rosuvastatin (5) 10 mg  
Simvastatin 20–40 mg‡  
Pravastatin 40 (80) mg  
Lovastatin 40 mg  
Fluvastatin XL 80 mg  
Fluvastatin 40 mg bid  
Pitavastatin 2–4 mg  
Simvastatin 10 mg  
Pravastatin 10–20 mg  
Lovastatin 20 mg  
Fluvastatin 20–40 mg  
Pitavastatin 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Annex 7: Drug Equivalence 
No differences in efficacy have been demonstrated between different doses of AAS from 75 to 325 
mg. So, the FDC (100mg) could replace any preparation of AAS within that range. In addition, the 
100mg AAS preparation provided by the study (control group) can replace other AAS previously 
prescribed to the patient. 
 
Atorvastatin 40 mg, the dose included in Cardiovascular Combination Polypill AAR, is equivalent 
Rosuvastatin 10mg. Atorvastatin 20mgs is equivalent to Lovastatin 80, Pitavastatin 4, Pravastatin 
80, Rosuvastatin 5, Simvastatin 40 in LDL lowering.  
 
Ramipril 10 mg, the maximal dose included in Cardiovascular Combination Polypill AAR is 
equivalent to Perindopril 8 mg, Trandolapril 4 mg, Enalapril 20 mg and Captopril 150 mg/day. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Annex 8: The Morisky-Medication Adherence Scale (8 item) Questionnaire  
 
MMAS – 8 
Points 
Do you sometimes forget to take your heart attack medication(s)? 
1 
People sometimes miss taking their medications for reasons other than forgetting. 
Thinking over the past two weeks, were there any days when you did not take your 
heart attack medication(s)? 
1 
Have you ever cut back or stopped taking your heart attack medication(s) without 
telling your doctor, because you felt worse when you took it? 
1 
When you travel or leave home, do you sometimes forget to bring along your heart 
attack medication(s)? 
1 
Did you take your heart attack medication(s) yesterday? 
1 
When you feel like your heart attack is under control, do you sometimes stop taking 
your medication(s)?  
1 
Taking medication(s) every day is a real inconvenience for some people. Do you ever 
feel hassled about sticking to your heart attack treatment plan?  
1 
How often do you have difficulty remembering to take all you medicine?* 
___A. Never/rarely 
___B. Once in a while 
___C. Sometimes 
___D. Usually 
___E. All the time 
1 
 
Adherence Score 
High adherence 8 
Medium adherence 6-7 
Low adherence 0-5 
 
*Each response carries a score: yes=0 and no=1, except for question 5, where yes=1 and no=0; 
and question 8, where never/rarely= 1, once in a while= 0.75, sometimes= 0.50, usually= 0.25, all 
the time= 0. 
 

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Annex 9: Treatment Satisfaction Questionnaire for Medication (TSQM) 
 

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Annex 10: European Quality of Life- 5 Dimensions (EQ-5D) Questionnaire 
 
 

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Annex 11: Identification of a Protocol Deviation or Violation 
The Chief Investigator of a research project is responsible for ensuring their appropriate oversight 
systems in place to monitor research activity and identify any deviations from the study protocol. 
This responsibility may be shared with other members of the research team, e.g. a Trial Steering 
Committee.  
 
1. All deviations identified must be reviewed by the Chief Investigator (CI) to assess whether 
participant safety or study integrity has been affected by the deviation and to what extent 
the deviation has affected the project.  
2. The CI will notify the sponsor if a deviation has an impact on safety or research integrity. 
The sponsor will advise whether the event is a protocol violation and take appropriate 
measures to address the occurrence which may include audit of the research project and 
defining a corrective action plan to be implemented by the CI.  
3. Where a protocol deviation is not judged to impact on safety or research integrity, a file 
note should be added to the Trial Master File and/or CRF and source documents explaining 
the action taken and its justification.  
4. If the CI is unsure whether an occurrence is a deviation or violation they should seek advice 
from the sponsor to ensure appropriate action is taken.  
 
Reporting a Protocol Violation 
When a protocol violation is identified it is essential to inform the appropriate parties of the 
occurrence and any corrective actions that have been implemented.  
 
1. The CI must notify the sponsor of the violation immediately upon identifying the issue. The 
sponsor will advise on what action is required and may initiate a triggered audit of research 
activity to assess the extent of the violation and its relation to any other protocol compliance 
issues.  
 
2. If the sponsor identifies a protocol violation during routine audit the process described in the 
Audit SOP will be followed. For IMP trials requiring MHRA approval, should the violation be 
identified as a serious breach of good clinical practice or the trial protocol, the sponsor will 
follow the procedure by SOP – Notification of Serious Breaches of GCP or the Trial Protocol, 
and inform the Regulatory Authorities of the incident within seven day of being notified of the 
event.  
 
3. Once a violation has been identified it may be necessary to inform the ethics committee and/or 
regulator of the incident and any corrective actions. The sponsor will inform the CI of reporting 
requirements and direct them to submit a report explaining the event. Key areas to include in a 
report are:  
a) An overview of the incident and its cause  
b) Description of corrective action  
c) An assessment of likelihood of reoccurrence  
d) Outline of any changes to the protocol that may be required  
e) Time line for corrective action and amendment approval (if applicable) 
 
4. If the protocol violation is deemed to be of a serious nature the sponsor will suspend the 
research project until all necessary corrective actions have been taken.  

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Annex 12: Management of Urgent Safety Measures (Clinical Trials) 
 
Under the Medicine for Human Use (Clinical Trials) Regulations the sponsor, Chief Investigator or 
Principal Investigator may carry out urgent safety measures (USM) to protect trial subject from 
immediate harm.  
 
1. Any urgent safety measure relating to an IMP trial must be notified to the sponsor, ethics 
committee and RA (Regulatory Authorities) within three days of the action being taken. The 
notification should describe the event, the measures taken and justification for the measures 
taken. The ethics committee will need to be informed in writing with a copy to the sponsor,  
 
2. The sponsor must be notified of the USM before submitting to the RA and ethics to advise on 
content and process, and to ensure the sponsor is aware of the event should the ethics committee 
or regulator contact for further information.  
 
 
 

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Annex 13. DECLARATION OF HELSINKI 1996 
 
 

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Annex 13.2. DECLARATION OF HELSINKI 2013 
 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
World Medical Association 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research on 
identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
The WMA encourages others who are involved in medical research involving human subjects to 
adopt these principles.  
 
General Principles 
 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when providing medical care.” 
 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects.  
 
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 

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7. Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects. The responsibility for the protection of research subjects must always rest with 
the physician or other health care professionals and never with the research subjects, even though 
they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this Declaration. 
 
11. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating 
in research must be ensured.  
 
Risks, Burdens and Benefits 
 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation.  
 
Measures to minimize the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher. 

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18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood 
of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the
health needs or priorities of this group and the research cannot be carried out in a nonvulnerable
group. In addition, this group should stand to benefit from the knowledge, practices or interventions 
that result from the research. 
 
Scientific Requirements and Research Protocols 
 
21. Medical research involving human subjects must conform to generally accepted scientific
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of
animals used for research must be respected. 
 
22. The design and performance of each research study involving human subjects must be clearly
described and justified in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved and should indicate
how the principles in this Declaration have been addressed. The protocol should include information
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for
subjects and information regarding provisions for treating and/or compensating subjects who are
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to
the concerned research ethics committee before the study begins. This committee must be transparent
in its functioning, must be independent of the researcher, the sponsor and any other undue influence
and must be duly qualified. It must take into consideration the laws and regulations of the country or
countries in which the research is to be performed as well as applicable international norms and
standards but these must not be allowed to reduce or eliminate any of the protections for research
subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide
monitoring information to the committee, especially information about any serious adverse events.
No amendment to the protocol may be made without consideration and approval by the committee.
After the end of the study, the researchers must submit a final report to the committee containing a
summary of the study’s findings and conclusions. 

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Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality
of their personal information.  
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in medical research
must be voluntary. Although it may be appropriate to consult family members or community leaders, 
no individual capable of giving informed consent may be enrolled in a research study unless he or 
she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of
the study and the discomfort it may entail, post-study provisions and any other relevant aspects of the
study. The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent
must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general outcome 
and results of the study. 
27. When seeking informed consent for participation in a research study the physician must be
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote
the health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and
minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to
give assent to decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorized representative. The potential subject’s dissent should be 
respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research group. In such circumstances 
the physician must seek informed consent from the legally authorized representative. If no such  

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representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the study
has been approved by a research ethics committee. Consent to remain in the research must be obtained 
as soon as possible from the subject or a legally authorized representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research.
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
Use of Placebo 
 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those
of the best proven intervention (s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention
less effective than the best proven one, the use of placebo, or no intervention is necessary to determine 
the efficacy or safety of an intervention and the patients who receive any intervention less effective 
than the best proven one, placebo, or no intervention will not be subject to additional risks of serious 
or irreversible harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed
consent process. 
Research Registration and Publication and Dissemination of Results 
 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in  

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the publication. Reports of research not in accordance with the principles of this Declaration should
not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known
interventions have been ineffective, the physician, after seeking expert advice, with informed consent
from the patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This
intervention should subsequently be made the object of research, designed to evaluate its safety and
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly
available. 

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Annex 14: Withdrawal of Consent Checklist 
 
 
  
 
 

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