Clinical trial NCT02525939
Conditions: Acute Coronary Syndrome
Sponsor: DalCor Pharmaceuticals
Start date: 2016-04-01; Completion date: 2021-10-01
Enrollment: 6147 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A placebo-controlled, randomized, double-blind, parallel group, phase III multicenter study in subjects recently hospitalized for ACS and with the appropriate genetic profile. Subjects will provide informed consent before any study-specific procedures are performed. Subject enrollment may begin in the hospital and will continue following release from the hospital. Screening procedures may be performed at the time of the index ACS event or anytime thereafter, with the condition that randomization must occur within the mandated window (4-12 weeks after the index event). Subjects will be assessed based on their medical history. Those who are likely to qualify will undergo Genotype Assay testing to evaluate genetic determination for the presence of AA genotype.

Detailed description:
This is an event driven study to reach statistical power given all other assumptions. Subjects will visit the clinic 1 month after randomization and at regular intervals thereafter. Additionally, for any subject prematurely discontinuing study medication, assessments will be conducted every 6 months for the collection of study endpoints.

Those who are likely to qualify will undergo Genotype Assay Testing to evaluate genetic determination or the presence of the AA genotype. The test is investigational and test procedures are Roche Molecular Diagnostics protocol ADCY9-COB-389.

Arms: arm 1: Participants received dalcetrapib 600 mg (two 300 mg tablets) orally once daily.

dalcetrapib: Cholesterol Ester Transfer Protein inhibitor, 300 mg tablets arm 2: Participants received dalcetrapib placebo tablets matching dalcetrapib orally once daily.

Placebo: dalcetrapib matching placebo tablets
Interventions: intervention 1: dalcetrapib intervention 2: Placebo
Intervention descriptions: intervention 1: Cholesterol Ester Transfer Protein inhibitor intervention 2: matching placebo tablets

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL DAL-301 v.5- Page 1 
 
CLINICAL STUDY PROTOCOL  
PROTOCOL NUMBER DAL-301 
DALCETRAPIB  
 
 
 
 
Protocol Number / Version 5: 11 Feb 2021 
EudraCT # 2015-003895-65 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
 
The information contained in this document, especially unpublished data, is the property 
of DalCor and therefore provided to you in confidence as an investigator, potential 
investigator or consultant, for review by you, your staff and an applicable Independent 
Ethics Committee/Institutional Review Board. It is understood that this information will 
not be disclosed to others without written authorization from DalCor except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be 
administered. 


CONFIDENTIAL DAL-301 v.5- Page 2 
 
SYNOPSIS OF PROTOCOL NUMBER DAL-301 
 
TITLE 
A phase III, double-blind, randomized placebo-controlled study to evaluate the effects of 
dalcetrapib on cardiovascular (CV) risk in a genetically defined population with a recent Acute 
Coronary Syndrome (ACS): The dal-GenE trial 
 
SPONSOR 
 
DalCor Pharma UK Ltd 
Altrincham, Swiss Branch Zug 
Baarerstrasse 2, CH-6304 Zug 
Switzerland 
Tel: +41 41 727 67 89 
 
INDICATION 
Reduction of cardiovascular mortality and morbidity in subjects with a documented recent Acute 
Coronary Syndrome (ACS) and the AA genotype at variant rs1967309 in the adenylate cyclase type 
9 (ADCY9) gene  
 
OBJECTIVES 
 
The primary objective of this trial is to evaluate the potential of dalcetrapib to reduce 
cardiovascular morbidity and mortality (cardiovascular death, resuscitated cardiac arrest, non-
fatal myocardial infarction (MI) and non-fatal stroke) in subjects with a documented recent ACS 
and the AA genotype at variant rs1967309 in the ADCY9 gene.  
 
Key secondary objectives of this trial are as listed below:  
 
 
Time to first occurrence of:  
• 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, or 
hospitalization for ACS (with ECG abnormalities) requiring coronary revascularization 
• 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
hospitalization for ACS (with ECG abnormalities), or unanticipated coronary 
revascularization 
• 
The composite of all cause death, resuscitated cardiac arrest, non-fatal MI, or non-fatal 
stroke  
 
Other secondary objectives of this trial are as listed below: 
• 
Assessment of the long-term safety profile of dalcetrapib in this population 
• 
Evaluation of the effects of dalcetrapib on lipids and hsCRP in this population 
• 
Evaluation of the effects of dalcetrapib on :  
o 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal 
stroke, or hospitalization for new or worsening heart failure 
o 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal 
stroke, hospitalization for ACS (with ECG abnormalities) requiring coronary 
revascularization, or hospitalization for new or worsening heart failure 
o 
The composite of all-cause death, resuscitated cardiac arrest, non-fatal MI, 
non-fatal stroke, or hospitalization for new or worsening heart failure 
o 
Fatal or non-fatal MI 
o 
All-cause death 
 
 
 
TRIAL DESIGN 
 
This is a placebo-controlled, randomized, double-blind, parallel group, phase III multicenter study 
in subjects recently hospitalized for ACS and with the appropriate genetic profile.  Subjects will 
provide informed consent before any study-specific procedures are performed.  Subject 
enrollment may begin in the hospital and will continue following release from the hospital.  
Screening procedures may be performed at the time of the index ACS event or anytime 
thereafter, with the condition that randomization must occur within the mandated window (1-3 
months after the index event). Subjects will be assessed based on their medical history.  Those 
who are likely to qualify will undergo cobas® ADCY9 Genotype CTA (Clinical Trial Assay) testing to 
evaluate genetic determination for the presence of AA genotype at variant rs 1967309 in the 
ADCY9 gene.  Those meeting the genetic testing criteria, all other inclusion criteria, and none of 
the exclusion criteria will be eligible for randomization.  Eligible subjects must be stabilized on 
statin and/or other medical therapy and have completed all planned revascularization procedures 
prior to randomization. Subjects must be randomized between 1 and 3 months after the index 
event. Eligible subjects in stable condition will be randomized to 600 mg of dalcetrapib or placebo 


CONFIDENTIAL DAL-301 v.5- Page 3 
 
in a 1:1 ratio. Subjects will receive study medication or placebo on a background of contemporary, 
evidence-based medical care for ACS. 
This is an event driven study and approximately 582 primary events are needed to reach 85% 
statistical power given all other assumptions. Subjects will visit the clinic 1 and 6 months after 
randomization. Thereafter visits will be approximately every 6 months for efficacy and safety 
assessments until completion of the trial.  Phone assessments will be performed 3 months after 
randomization and at the end of the study for subjects remaining on IP.  Additionally, for any 
subject prematurely discontinuing study medication, assessments will be conducted every 6 
months for the collection of study endpoints and concomitant medication.  
NUMBER OF 
SUBJECTS 
Approximately 50,000 screened and 6000 randomized 
 
TARGET 
POPULATION 
 
In order to be included in the trial, subjects must fulfill all of the inclusion criteria and none of the 
exclusion criteria listed below.  
 
Inclusion Criteria 
Subjects with the appropriate genetic background and recently hospitalized for ACS (between 1 
and 3 months following the index event), will be enrolled in this trial. ACS is defined as the 
occurrence of at least one of the following events: 
 
Myocardial Infarction (MI) 
 
Spontaneous MI 
 
A diagnosis of a qualifying MI event will be defined by a rise and/or fall of cardiac biomarkers 
(preferably cardiac troponin) with at least one determination greater than the 99th percentile 
upper reference limit (URL)  plus at least one of the following described below: 
 
• 
Symptoms of myocardial ischemia, or 
• 
New or presumed new significant ST-segment-T wave (ST-T) changes or new left bundle 
branch block, or  
• 
Development of pathological Q waves in the ECG, or  
• 
Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality, or 
• 
Identification of an intracoronary thrombus by angiography 
 
Procedure-Related MI after Percutaneous Coronary Intervention (PCI) 
 
A procedure-related MI after PCI is defined as an increase of cardiac troponin values  with at least 
one determination greater than 5 times the 99th percentile URL in patients with normal baseline 
values (less than or equal to 99th percentile URL) or a rise of cardiac troponin values > 20% if the 
baseline values are elevated and are stable or falling;  plus at least one of the following described 
below: 
 
• 
Symptoms suggestive of myocardial ischemia 
• 
New ischemic ECG changes  
• 
Imaging demonstration of new loss of viable myocardium or new regional wall motion 
abnormality 
• 
Angiographic findings consistent with a procedural complication  
 
 
Hospitalization for ACS (ECG Abnormalities without Biomarkers): 
 
A diagnosis of a qualifying ACS event without increases in cardiac biomarkers will require 
admission to hospital or emergency room (exceeding 23 hrs) with symptoms presumed to be 
caused by myocardial ischemia with an accelerating tempo in the prior 48 hrs and/or prolonged 
(at least 20 min) rest chest discomfort and new ECG findings (or presumed new if no prior ECG 
available) as described below and at least one of the following: 
 
• 
at least 50% stenosis of an epicardial coronary artery  


CONFIDENTIAL DAL-301 v.5- Page 4 
 
• 
positive exercise or pharmacologic stress indicating reversible ischemia 
• 
presence of pathologic Q-waves on ECG 
 
Examples of New ECG findings include: 
• 
New or presumed new ST depression of at least 0.5mm in at least 2 contiguous leads or 
T wave inversion of at least 1mm in leads with predominant R wave or R/S >1 in at least 
2 contiguous leads 
• 
New or presumed new ST elevation at the J point in ≥ 2 contiguous leads with the 
following cut-off points: ≥ 0.2mV in men or ≥ 0.15mV in women in leads V2-V3 and/or 
≥0.1 mV in other leads or new or presumed new left bundle branch block (LBBB)  
• 
New tall R wave of at least 40ms in V1 and/or V2 and R/S ≥ 1 in V1 with concordant 
positive T-wave in the absence of a conduction defect  
• 
New Q waves ≥ 30 ms wide and at least 1mm deep in any 2 leads of a contiguous lead 
grouping or Q wave >20ms or QS complex in leads V2 and V3 (these criteria also apply 
to silent MI detected during a routine follow-up visit) 
  
In addition, the following inclusion criteria apply:  
 
1.  Both male and female subjects age 45 years and over at screening visit (V1) 
2.  Signed informed consent (approved by Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC]) obtained prior to any study specific screening procedures  
3.  AA genotype at variant rs 1967309 in the ADCY9 gene as determined by cobas® ADCY9 
Genotype CTA testing, conducted at a designated investigational testing site (ITS) 
4.  Clinically stable, ie, free of ischemic symptoms at rest or with minimal exertion for at least 1 
week prior to randomization  
5.  Prior to randomization, subject must have evidence of guidelines-based management of LDL-C, 
at a minimum to include medical and dietary treatment to a target level of LDL-C <100 mg/dl 
(<2.6 mmol/L). Subjects with an LDL-C level ≥100 mg/dL (≥ 2.6 mmol/L) may be randomized if 
they cannot reach the target goal of less than 100 mg/dL despite lipid-lowering regimen, or 
are unable to tolerate lipid-lowering regimen.  
  
Exclusion Criteria 
 
1.  Females who are pregnant (negative pregnancy test required for all women of child-bearing 
potential at Visit 2, Day 0) or breast-feeding  
2.  Women of childbearing potential (women who are not surgically sterile or postmenopausal 
defined as amenorrhea for >12 months) who are not using at least one method of 
contraception  
3.  New York Heart Association (NYHA) Class III or IV heart failure  
4.  Last known hemoglobin <10 g/dL  
5.  Index ACS event presumed due to uncontrolled hypertension  
6.  Systolic blood pressure (BP) >180 mmHg and/or diastolic blood pressure >110 mmHg by the 
time of randomization despite anti-hypertensive therapy 
7.  Last known serum triglyceride level > 500 mg/dL (> 5.65 mmol/L) as assessed within 6 months 
prior to randomization 
8.  Last known hemoglobin A1c (HbA1c) >10% as assessed within 6 months prior to randomization 
9.  Subjects with clinically apparent liver disease, eg, jaundice, cholestasis, hepatic synthetic 
impairment, or active hepatitis  
10.  Last known ALT or AST level > 3 times the upper limit of normal (ULN) or last known alkaline 
phosphatase level > 2 times the ULN as assessed within 6 months prior to randomization 
(excluding index event) 
11.  History of persistent and unexplained creatine phosphokinase (CPK) levels > 3 times the ULN 
as assessed within 6 months prior to randomization (excluding index event) 
12. Last known serum creatinine > 2.2 mg/dL (195 μmol/l) as assessed within 6 months prior to 
randomization  
13. Previous exposure to anacetrapib or evacetrapib or documented allergic reaction to any CETP 
inhibitor 
14. History of malignancy (except for curatively treated basal cell or squamous cell carcinoma of 
the skin) during the 1 year prior to the screening  


CONFIDENTIAL DAL-301 v.5- Page 5 
 
15. Any clinically significant medical condition that according to the investigator could interfere 
with the conduct of the study 
16. Subjects whose life expectancy is shorter than 3 years 
17. Presence of any last known laboratory value as evaluated prior to randomization that is 
considered by the investigator to potentially limit the patient’s successful participation in the 
study 
18. Current alcohol or drug abuse or history thereof within 2 years prior to screening that would 
likely interfere with compliance, based on investigator assessment 
19. Subjects who have received any investigational drug within 1 month of randomization, or who 
expect to participate in any other investigational drug or device study during the conduct of 
this trial  
20. Subjects unable or unwilling to comply with protocol requirements, or deemed by the 
investigator to be unfit for the study 
21. Subjects who have undergone coronary artery bypass graft (CABG) surgery between the index 
event and randomization 
 
LENGTH OF 
STUDY 
 
This study is an event-driven study and will last until approximately 582 primary events have 
occurred.  The estimated total duration is approximately 54 months including enrollment and 
follow-up. 
 
INVESTIGATIONAL 
MEDICINAL 
PRODUCT(S) 
DOSE/ ROUTE/ 
REGIMEN 
Dalcetrapib and matching placebo will be provided as 300 mg film-coated tablets. Subject will take 
600 mg of dalcetrapib (2 tablets) once daily, preferably with the largest meal of the day. 
 
Dalcetrapib and matching placebo are to be taken on a background of contemporary evidence-
based medical care for status post-ACS, as individually prescribed by the treating physician.   
 
STANDARD OF 
CARE 
 
All co-existing medical conditions should be treated with optimized usual care and any 
concomitant medication prescribed as per the prescribing information. 
 
ASSESSMENTS 
OF:  
 
EFFICACY 
 
Primary Study Endpoint 
The primary endpoint of this study is the time to first occurrence of any component of the 
composite endpoint, as adjudicated by the Clinical Endpoint Committee (CEC). Components of the 
primary endpoint are: 
• 
Cardiovascular (CV) death  
• 
Resuscitated cardiac arrest 
• 
Non-fatal MI  
• 
Non-fatal stroke  
 
Secondary Study Endpoints 
The key secondary endpoints of this study are listed below. 
 
Time to first occurrence of:  
• 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, or 
hospitalization for ACS (with ECG abnormalities) requiring coronary revascularization 
• 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
hospitalization for ACS (with ECG abnormalities), or unanticipated coronary revascularization 
• 
The composite of all cause death, resuscitated cardiac arrest, non-fatal MI, or non-fatal 
stroke  
 
Other secondary endpoints are listed below: 
 
Time to first occurrence of 
• 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, or 
hospitalization for new or worsening heart failure 
• 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
hospitalization for ACS (with ECG abnormalities) requiring coronary revascularization, or 
hospitalization for new or worsening heart failure 
• 
The composite of all-cause death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
or hospitalization for new or worsening heart failure 
• 
Fatal or non-fatal MI 


CONFIDENTIAL DAL-301 v.5- Page 6 
 
• 
All-cause death 
 
Exploratory Study Endpoints are listed below 
 
Healthcare resource utilization information  
Change from baseline for:  
• 
Blood levels of TC, TG, LDL-C, and HDL-C 
• 
Blood levels of hsCRP 
 
SAFETY 
 
Safety Endpoints 
Safety evaluation will include the following:  
• 
Adverse event assessments 
• 
Vital signs  
 
An independent Data Safety Monitoring Board (DSMB) will monitor the unblinded safety data 
during the study. 
 
PROCEDURES (summary): 
 
A table of assessment is shown below 
 
STATISTICAL ANALYSES 
Sample Size: 
The sample size calculation is based on the primary endpoint. Under the following assumptions:  
 
• 
an expected relative risk reduction of 22% and 
• 
a statistical significance defined as a two-sided alpha of 0.05 
 
the trial would have 85% power if it continues until approximately 582 primary positively CEC adjudicated events occur in 
the combined treatment groups. 
 
The total number of subjects to randomize, 6000, is chosen so that the expected number of events is approximately 582. It 
is based on the following assumptions, which were reviewed according to actual and planned recruitment rate: 
 
• 
a 2.8-year recruitment period; 
• 
a 1% yearly lost to follow-up rate; and 
• 
a 7% event rate at 2 years following randomization in the placebo group. 
 
Primary and Secondary Efficacy Analyses: 
 
A stratified Cox proportional hazards model will be used to analyze the primary endpoint. Time to event will start at 
randomization and subjects who are lost to follow-up (while event free) will be censored at the time that they are last 
known to be event free. The strata will be defined by the region (Eastern Europe, Western Europe, North America, South 
America, and other) and the ACS index event (MI or ACS [ECG abnormalities without biomarkers]). 
 
In order to control the Type I error that results from the multiplicity of endpoints, a closed test procedure will be used for 
testing the significance of the three key secondary endpoints of main interest. This will be done if the primary analysis 
results in significant treatment effects at p < 0.048. In that event, these three endpoints will be tested using the 
Hochberg’s step-up procedure again testing against a p < 0.048. 
 
For the secondary endpoints that are expressed as time to event, an analysis similar to that for the primary endpoint will 
be conducted.  
 
Exploratory Analyses: 
 
The changes from baseline in lipid levels and hsCRP will be compared between treatment groups using an analysis of 
covariance (ANCOVA) adjusting for baseline value and for the two stratification factors, ACS index event type and region.  
 


CONFIDENTIAL DAL-301 v.5- Page 7 
 
In addition to the above, exploratory analyses will be performed to evaluate risk reduction as it relates to changes or 
actual lipid and hsCRP values while subjects are on randomized treatment and to explore potential treatment effects 
beyond those attributable to changes in lipid levels. Exploratory analyses will also evaluate the effect of prognostic factors. 
 
In addition, if significant treatment effect is demonstrated in the analysis of the primary endpoint, sensitivity analyses will 
be performed to establish the robustness of the results with respect to any potential dependence on the analysis 
assumptions. 
 
Subgroup analyses may be performed in subgroups such as those defined by: geographic location, gender, race, age, body 
mass index (BMI), and diabetes.  Details are provided in the Statistical Analysis Plan. 
 
Interim analyses: 
 
When approximately 70% (408) of the primary study endpoints have occurred and have been positively adjudicated, an 
interim analysis will be conducted by the independent Data Safety Monitoring Board (DSMB).  The DSMB will determine if 
there is sufficient evidence of efficacy benefit to justify continuation of the trial to its completion. This futility assessment 
will be based on the conditional power of the trial derived under various relative risk reduction assumptions. Following this 
assessment, the DSMB may recommend terminating the trial.   
 
Full details will be described in the DSMB charter and Statistical Analysis Plan. 
 
 


CONFIDENTIAL DAL-301 v.5- Page 8 
 
Schedule of Assessments  
Subjects who will be in the study for more than 3 years will continue to visit the clinic every 6 months and have the same 
assessments performed as during the second and third year. 
 
 
 
V1 
Screening 
V2 
Day 0 
(randomization) 
V3 
 
1M 
V4 
 
3M 
phone 
V5 
 
6M 
V6 
 
12M 
V7 
 
18M 
V8 
 
24M 
V9 
 
30M 
V10 
 
36M 
End of 
Study  
Phone 
14 days after 
end of study 
Visit windows (weeks) 
 
 
 
± 1 
± 3 
± 3 
± 3 
± 4 
± 4 
± 4 
± 4 
 
+ 1 
Informed Consent for 
Study Protocol 
X 
 
 
 
 
 
 
 
 
 
 
 
ACDY9 genetic 
determinant (blood 
draw) 
X 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographic 
Information 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Query subjects for 
new/changes in contact 
information 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Pregnancy Test (local) 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam and 
Medical History 
 
X 
 
 
 
 
 
 
 
 
X 
 
Blood Pressure, Pulse, 
Weight 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood draw for serum 
creatinine, HbA1c, 
fasting lipids and hsCRP 
(central lab) 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Informed consent for 
optional genetic and 
biomarker evaluations 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood draw for 
optional genetic and 
biomarker evaluations 
 
X 
 
 
X 
 
 
 
 
 
 
 
Prev/Conc Med 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study 
medication 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Return unused Study 
medication 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
*Optional phone calls by the site to the patient may be conducted between 6 month visit intervals 
** Procedures that require physical contact with patients such as obtaining, blood pressure, pulse, weight, and 
an End of Study physical exam are to be performed whenever possible, but may be considered as optional in 
situations where direct physical contact with the patient is not locally allowed or determined to be hazardous 
to the patient and/or staff due to the COVID-19 pandemic. 
 
 
 


CONFIDENTIAL DAL-301 v.5- Page 9 
 
TABLE OF CONTENTS 
GLOSSARY OF ABBREVIATIONS ....................................................................................... 12 
PART I: STUDY DESIGN AND CONDUCT .......................................................................... 14 
1. BACKGROUND AND RATIONALE ................................................................................ 14 
1.1 Background ..................................................................................................................... 14 
1.2 Rationale ......................................................................................................................... 14 
2. OBJECTIVES ............................................................................................................... 15 
2.1 Primary Objective ........................................................................................................... 15 
2.2 Secondary Objectives ...................................................................................................... 15 
3. STUDY DESIGN .......................................................................................................... 16 
3.1 Overview of Study Design and Dosing Regimen ............................................................... 16 
3.1.1 Rationale for Study Design .............................................................................................. 17 
3.1.2 Rationale for Dose Selection ........................................................................................... 17 
3.1.3 End of Study .................................................................................................................... 18 
3.2 Number of Subjects/ Assignment to Treatment Groups ................................................... 18 
3.3 Clinical Trial Centers ........................................................................................................ 18 
4. STUDY POPULATION ................................................................................................. 18 
4.1 Inclusion Criteria ............................................................................................................. 18 
4.2 Exclusion Criteria ............................................................................................................. 20 
4.3 Concomitant Medication and Treatment ......................................................................... 21 
4.4 Criteria for Premature Study Withdrawal ........................................................................ 22 
4.5 Criteria for Premature Study Medication Discontinuation ............................................... 22 
5. SCHEDULE OF ASSESSMENTS AND PROCEDURES ....................................................... 23 
5.1 Screening Assessments and Procedures (Visit 1) .............................................................. 23 
5.2 Randomization Procedures (Visit 2) ................................................................................. 24 
5.3 Assessments and Procedures During the Double-blind Treatment Period ........................ 24 
5.3.1 Assessments and Procedures in Response to COVID-19 ................................................. 25 
5.4 End of Treatment and Safety Follow-Up .......................................................................... 25 
5.5 Assessments and Procedures for Subjects Who Prematurely Discontinue Study 
medication. ............................................................................................................................. 26 
5.6 Assessments and Procedures at Occurrence of Efficacy Endpoints ................................... 26 
5.7 Efficacy Assessments and Procedures .............................................................................. 27 
5.7.1 Primary Efficacy Assessment ........................................................................................... 27 
5.7.2 Secondary Efficacy Assessments ..................................................................................... 28 
5.7.3 Exploratory Assessments ................................................................................................ 28 
5.8 Safety Assessments and Procedures ................................................................................ 29 
5.8.1 Adverse Events ................................................................................................................ 29 
5.8.2 Vital signs ........................................................................................................................ 29 
5.8.3 Physical examination and medical history ...................................................................... 29 
5.8.4 Laboratory Assessments ................................................................................................. 29 
5.8.4.1  Serum Creatinine and HbA1c ................................................................................................. 29 
5.8.4.2  Pregnancy Test ....................................................................................................................... 29 
6. INVESTIGATIONAL MEDICINAL PRODUCT .................................................................. 30 
6.1 Dose and Schedule of Study medication and Placebo ...................................................... 30 


CONFIDENTIAL DAL-301 v.5- Page 10 
 
6.1.1 Dose Modifications and Delays ....................................................................................... 30 
6.2 Formulation, Packaging and Labeling .............................................................................. 30 
6.3 Randomization ................................................................................................................ 31 
6.4 Blinding and Unblinding .................................................................................................. 31 
6.5 Assessment of Compliance .............................................................................................. 32 
6.6 Destruction of Study Medication ..................................................................................... 32 
7.  SAFETY INSTRUCTIONS AND GUIDANCE ................................................................... 32 
7.1 Adverse Events (AEs) and Laboratory Abnormalities ....................................................... 32 
7.1.1 Clinical AEs ...................................................................................................................... 32 
7.1.1.1  Intensity ................................................................................................................................. 33 
7.1.1.2  Drug - Adverse Event Relationship ........................................................................................ 33 
7.1.1.3  Serious Adverse Events .......................................................................................................... 33 
7.1.1.4  Project-Specific Definition of SAEs ......................................................................................... 34 
7.1.2 Treatment and Follow-up of AEs ..................................................................................... 34 
7.1.3 Laboratory Test Abnormalities ........................................................................................ 34 
7.1.4 Follow-up of Abnormal Laboratory Test Values .............................................................. 35 
7.2 Handling of Safety Parameters ........................................................................................ 35 
7.2.1 Reporting of AEs .............................................................................................................. 35 
7.2.2 Reporting of Serious Adverse Events .............................................................................. 35 
7.2.3 Pregnancy ........................................................................................................................ 35 
7.3 Warnings and Precautions ............................................................................................... 35 
8. STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ............................................ 36 
8.1 Primary and Secondary Study Endpoints ......................................................................... 36 
8.1.1 Primary Endpoint ............................................................................................................ 36 
8.1.2 Secondary and Exploratory Endpoints ............................................................................ 36 
8.1.3 Safety .............................................................................................................................. 37 
8.2 Statistical and Analytical Methods .................................................................................. 37 
8.2.1 Sample Size ..................................................................................................................... 37 
8.2.2  Analysis Populations ....................................................................................................... 37 
8.2.2.1  Exclusion of Data from Analysis ............................................................................................. 37 
8.2.2.2  Intent to Treat (ITT) Population ............................................................................................. 37 
8.2.2.3  Per-Protocol Population ........................................................................................................ 38 
8.2.2.4  Safety Analysis Population ..................................................................................................... 38 
8.2.2.5  Co-Diagnostic Analysis: Intent-to-Diagnose (ITD) .................................................................. 38 
8.2.3 Efficacy Analysis .............................................................................................................. 38 
8.2.3.1  Primary Analysis ..................................................................................................................... 38 
8.2.3.2  Secondary and Exploratory Analysis ...................................................................................... 39 
8.2.3.3  Sub-population Analyses ....................................................................................................... 39 
8.2.3.4  Interim Analysis ..................................................................................................................... 40 
8.2.4 Exploratory Analyses ....................................................................................................... 40 
8.2.4.1  Effect of Prognostic Factors ................................................................................................... 40 
8.2.4.2  Effect of Lipid Changes and Changes in hsCRP while on Treatment ...................................... 40 
8.2.4.3  Sensitivity Analyses ................................................................................................................ 41 
8.2.5 Safety Analyses ................................................................................................................ 41 
8.2.5.1  Adverse Events ...................................................................................................................... 42 
8.2.5.2 Laboratory Data ...................................................................................................................... 42 
8.2.5.3  Vital Signs ............................................................................................................................... 42 
9. DATA QUALITY ASSURANCE ...................................................................................... 42 
9.1 Assignment of Preferred Terms to Original Terminology ................................................. 43 


CONFIDENTIAL DAL-301 v.5- Page 11 
 
10. STUDY COMMITTEES ............................................................................................... 43 
10.1 Executive Committee and Steering Committee .............................................................. 43 
10.2 Data Safety Monitoring Board (DSMB) .......................................................................... 43 
10.3 Clinical Endpoints Committee (CEC) ............................................................................... 43 
11. REFERENCES ............................................................................................................ 44 
PART II: ETHICS AND GENERAL STUDY ADMINISTRATION .............................................. 45 
12. ETHICAL ASPECTS .................................................................................................... 45 
12.1 Local Regulations/Declaration of Helsinki ...................................................................... 45 
12.2 Informed Consent ......................................................................................................... 45 
12.3 Independent Ethics Committees/Institutional Review Board ......................................... 45 
13. CONDITIONS FOR MODIFYING THE PROTOCOL ........................................................ 46 
14. CONDITIONS FOR TERMINATING THE STUDY ........................................................... 47 
15. STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING ........................................ 47 
15.1 Investigator's Files / Retention of Documents ............................................................... 47 
15.2 Source Documents and Background Data ...................................................................... 48 
15.3 Audits and Inspections .................................................................................................. 48 
15.4 Electronic Case Report Forms ........................................................................................ 48 
16. MONITORING THE STUDY ....................................................................................... 48 
17. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS .......................... 49 
18. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ................................ 49 
Appendix 1 Study Recommended Diet and Principles ...................................................... 50 
Appendix 2 ICH Guidelines for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2 ................................................................... 51 
 
 


CONFIDENTIAL DAL-301 v.5- Page 12 
 
GLOSSARY OF ABBREVIATIONS 
 
ACS 
ADCY9 
 
Acute coronary syndrome 
Adenylate cyclase type 9 
AE 
 
Adverse event 
ALT [SGPT] 
ANCOVA 
 
Alanine aminotransferase 
Analysis of covariance 
AST [SGOT] 
BMI 
 
Aspartate aminotransferase 
Body mass index 
BP 
CABG 
 
Blood pressure 
Coronary artery bypass graft 
CEC 
 
Clinical Endpoints Committee 
CETP 
 
Cholesteryl ester transfer protein 
COVID-19 
 
Coronavirus disease of 2019 
CFR 
 
Code of Federal Regulations 
CHD 
 
Coronary heart disease 
CI 
CK-MB 
 
Confidence interval 
Creatine kinase – isozyme MB 
CPK 
 
Creatine phosphokinase 
CRO 
 
Contract Research Organization 
CV 
CVD 
 
Cardiovascular 
Cardiovascular Disease 
DSMB 
EC 
 
Data Safety Monitoring Board 
Ethics Committee 
ECG 
 
Electrocardiogram 
eCRF 
 
Electronic case report form 
EDC 
 
Electronic data capture 
EEA 
 
European Economic Area 
EEG 
 
Electroencephalogram 
HbA1c 
 
Hemoglobin A1c 
HDL-C 
hsCRP 
 
High density lipoprotein cholesterol 
High-sensitivity C-reactive protein 
IEC 
 
Independent Ethics Committee 
IB 
 
Investigator Brochure 
ICH 
 
International Conference on Harmonization 


CONFIDENTIAL DAL-301 v.5- Page 13 
 
IND 
 
Investigational New Drug  
INR 
 
International normalized ratio 
IRB 
 
Institutional Review Board 
ITT 
 
Intent to treat 
IWRS 
 
Interactive Web Response System 
LBBB 
 
Left bundle branch block 
LDL-C 
 
Low density lipoprotein cholesterol 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MI 
 
Myocardial infarction 
NYHA 
 
New York Heart Association 
PCI 
 
Percutaneous coronary intervention 
SAE 
 
Serious adverse event 
TC 
 
Total cholesterol 
TG 
 
Triglycerides 
UA 
ULN 
 
Unstable angina 
Upper limit of normal  
URL 
 
Upper Reference Limit 
 
 
 


CONFIDENTIAL DAL-301 v.5- Page 14 
 
PART I: 
STUDY DESIGN AND CONDUCT 
1. 
BACKGROUND AND RATIONALE 
1.1 
Background 
Coronary heart disease (CHD) is a major contributor to mortality, affecting individuals of all 
ethnic and sociological backgrounds [1].  CHD is influenced by many potential factors, 
including gender, age, genetics, smoking, high blood pressure, diabetes, and altered plasma 
lipids [2,3]. Specifically, disturbances in plasma lipoprotein profiles, including elevations of 
plasma total and low density lipoprotein cholesterol (LDL-C), elevated plasma triglycerides 
(TG), and decreased high density lipoprotein cholesterol (HDL-C), have all been linked to an 
increased risk of developing CHD [3-7]. 
 
Many studies have demonstrated that high serum levels of LDL-C are a major risk factor for 
CHD. For over two decades, large, well-controlled randomized trials have consistently 
documented the ability of LDL-C reduction with HMG CoA reductase inhibitors (statins) to 
reduce the risk of major coronary events.  Epidemiological studies have also consistently 
shown that decreased HDL-C levels are associated with an increased risk of developing CHD 
[8,9] and treatment guidelines published by the National Cholesterol Education Program 
(NCEP) expert panel suggest that HDL-C values below 40 mg/dL confer a significant risk of 
CHD [10].  However, most clinical trials with HDL-C elevating drugs have failed to 
demonstrate clinically meaningful benefit on the risk of future cardiovascular events. 
 
Cholesteryl ester transfer protein (CETP) inhibition has been under evaluation as a potential 
mechanism to raise HDL-C levels and confer cardio-protection to subjects at risk for CHD.  
To date, four CETP inhibitors have been or are being evaluated in late-stage clinical trials, 
including torcetrapib, dalcetrapib, evacetrapib and anacetrapib.  The development of 
torcetrapib was halted following the observation of increased cardiovascular events and 
total mortality in a large outcome trial.  These effects have been associated with an off-
target effect on the renin-angiotensin-aldosterone axis, and unrelated to CETP inhibition or 
HDL-C elevation.  Evacetrapib and anacetrapib are currently under evaluation in large Phase 
III cardiovascular outcomes trials.  Dalcetrapib has been extensively studied and is 
addressed below. 
1.2 
Rationale 
Dalcetrapib is a compound selected for its capacity to modulate plasma CETP activity and 
increase HDL-C levels. Detailed information on results of preclinical and clinical studies with 
dalcetrapib is contained in the Investigator Brochure (IB). Dalcetrapib has been evaluated in 
several large clinical trials, most notably dal-OUTCOMES, a 15,871 subject trial designed to 


CONFIDENTIAL DAL-301 v.5- Page 15 
 
evaluate its effect in subjects with recent acute coronary syndrome (ACS) [11].  After 
subjects were followed for a median of 31 months, and at a pre-specified interim analysis 
that included 1135 primary end points, the independent data safety monitoring board 
(DSMB) recommended termination of the trial for futility.  As compared with placebo, 
dalcetrapib did not alter the risk of cardiovascular morbidity and mortality or total mortality 
despite an effect on HDL-C levels (30% increase).  However, the trial demonstrated the 
safety and tolerability of dalcetrapib in this population. 
 
With the hypothesis that the responses to dalcetrapib may vary according to the genetic 
profile, the Montreal Heart Institute has recently conducted a pharmacogenomic evaluation 
using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749)[12].  
Results demonstrated that subjects with the AA genotype at variant rs1967309 in the 
adenylate cyclase type 9 (ADCY9) gene experienced a 39% reduction in the risk for 
cardiovascular morbidity and mortality with dalcetrapib compared to placebo [HR=0.61; 
95%CI 0.41, 0.92]. The results were confirmed through a targeted genotyping panel in the 
dal-PLAQUE-2 imaging trial that demonstrated a significant reduction of carotid intima-
media thickness in subjects with the AA genotype treated with dalcetrapib as compared 
with placebo.   Importantly, evaluation of the AA genetic subset demonstrated the safety 
and tolerability of dalcetrapib in this population.  Thus, treatment with dalcetrapib in 
subjects with the AA genotype at variant rs 1967309 in the ADCY9 gene appears to confer 
significant cardiovascular benefit and no augmentation of the adverse profile.    
 
Personalized medicine represents an opportunity to utilize our knowledge of the human 
genome in order to make better treatment decisions for patients. This trial is designed to 
prospectively confirm the results demonstrated in a genetically defined sub-set of subjects 
evaluated in dal-OUTCOMES and dal-PLAQUE-2.   As such, it represents the first late-stage 
personalized medicine initiative directed toward reducing the risk of cardiovascular 
morbidity and mortality in a population at high risk for future events. 
2. 
OBJECTIVES  
2.1 
Primary Objective 
The primary objective of this trial is to evaluate the potential of dalcetrapib to reduce 
cardiovascular morbidity and mortality (cardiovascular death, resuscitated cardiac arrest, 
non-fatal myocardial infarction [MI] and non-fatal stroke) in subjects with a documented 
recent ACS and the AA genotype at variant rs1967309 in the ADCY9 gene.   
2.2 
Secondary Objectives 
Key Secondary objectives of this trial are as listed below:  


CONFIDENTIAL DAL-301 v.5- Page 16 
 
Time to first occurrence of:  
• The composite of cardiovascular (CV) death, resuscitated cardiac arrest, non-fatal MI, 
non-fatal stroke, or hospitalization for ACS (with electrocardiogram [ECG] 
abnormalities) requiring coronary revascularization 
• The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
hospitalization for ACS (with ECG abnormalities), or unanticipated coronary 
revascularization 
• The composite of all cause death, resuscitated cardiac arrest, non-fatal MI, or non-fatal 
stroke  
 
Other Secondary objectives of this trial are as listed below: 
• Assessment of the long-term safety profile of dalcetrapib in this population 
• Evaluation of the effects of dalcetrapib on lipids and high-sensitivity C-reactive 
protein (hsCRP) in this population 
• Evaluation of the effects of dalcetrapib on :  
o The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-
fatal stroke, or hospitalization for new or worsening heart failure 
o The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-
fatal stroke, hospitalization for ACS (with ECG abnormalities) requiring 
coronary revascularization, or hospitalization for new or worsening heart 
failure 
o The composite of all-cause death, resuscitated cardiac arrest, non-fatal MI, 
non-fatal stroke, or hospitalization for new or worsening heart failure 
o Fatal or non-fatal MI 
o All-cause death 
3. 
STUDY DESIGN  
3.1 
Overview of Study Design and Dosing Regimen 
This is a placebo-controlled, randomized, double-blind, parallel group, multicenter study in 
subjects recently hospitalized for ACS and with the appropriate genetic profile.  Subjects will 
provide informed consent before any study-specific procedures are performed.  Subject 
enrollment may begin in the hospital and will continue following release from the hospital.  
Screening procedures may be performed at the time of the index ACS event or anytime 
thereafter, with the condition that randomization must occur within the mandated window 
(1-3 months after the index event). Subjects will be assessed based on their medical history.  
Those who are likely to qualify will undergo centralized genetic testing to evaluate the 
presence of the AA genotype at variant rs 1967309 in the ADCY9 gene. The investigational 
cobas® ADCY9 Genotype CTA will be used for centralized testing and will support the 


CONFIDENTIAL DAL-301 v.5- Page 17 
 
randomization of patients into this trial. Pending the outcome of this trial, this assay may 
potentially become a companion diagnostic to identify patients likely to benefit from 
dalcetrapib. 
 
Those subjects meeting the genetic testing criteria and all other inclusion criteria and none of 
the exclusion criteria will be eligible for randomization.  Eligible subjects must be stabilized on 
contemporary evidence-based medical care for status post-ACS as individually prescribed by 
the treating physician and have completed all planned revascularization procedures prior to 
randomization. Subjects must be randomized between 1 and 3 months from the index event. 
A total of 6,000 eligible subjects in stable condition will be randomized to 600 mg of 
dalcetrapib or placebo in a 1:1 ratio. Subjects will receive study medication or placebo on a 
background of contemporary, evidence-based medical care for ACS. 
 
This is an event driven study and approximately 582 primary events are needed to reach 
85% statistical power assuming a 22% relative risk reduction in the primary endpoint. 
Patients will be expected to remain in the trial until the time at which approximately 582 
primary events have occurred and have been adjudicated.  Participating sites will be 
informed when the study has reached approximately 582 study primary endpoints and will 
be asked to schedule the end of study treatment visit for their subjects.  There is no 
minimum or maximum study treatment duration defined for this trial, but the expected 
overall duration is 54 months including recruitment and follow-up.  Subjects will visit the 
clinic 1 and 6 months after randomization. Thereafter visits will be every 6 months for 
efficacy and safety assessments until completion of the trial as defined in section 5.4.  
Phone assessments will be performed 3 months after randomization and at the end of the 
study for subjects remaining on IP.  Additionally, for any subject prematurely discontinuing 
study medication, assessments will be conducted approximately every 6 months for the 
collection of study endpoints.  
3.1.1 Rationale for Study Design 
A double-blind, randomized trial design was selected to allow for an unbiased evaluation of 
dalcetrapib as a treatment for subjects with a recent event of ACS. A composite endpoint 
including cardiovascular death, resuscitated cardiac arrest, non-fatal MI, and non-fatal 
stroke was selected as the primary measure of efficacy because of its clinical relevance.  
3.1.2 Rationale for Dose Selection 
Doses of 300, 600, and 900 mg of dalcetrapib were evaluated in phase II studies. Increases 
in levels of HDL-C (an indicator of CETP inhibition) were observed when increasing the dose 
from 300 to 600 mg of dalcetrapib, while no substantial further effect on CETP inhibition 
was observed when comparing 600 with 900 mg of dalcetrapib. No significant difference 
between the 600 and 900 mg dose of dalcetrapib was observed with respect to safety 


CONFIDENTIAL DAL-301 v.5- Page 18 
 
assessments in phase II studies. As a result, a dose of 600 mg of dalcetrapib was selected for 
previous phase III studies, including dal-OUTCOMES, which demonstrated that this dose is 
safe and well-tolerated in this population.  Importantly, since the pharmacogenomic 
evaluation conducted in the dal-OUTCOMES study demonstrated a significant reduction in 
the risk for cardiovascular morbidity and mortality with 600 mg dalcetrapib vs. placebo, 600 
mg of dalcetrapib was selected for evaluation in this trial.   
3.1.3 End of Study 
The end of the study is defined as the date of the last visit of the last subject to complete 
the study, or the date at which the last data point, which is required for statistical analysis 
(i.e. key safety and efficacy results for decision making), is received, whichever is the later 
date. 
3.2 
Number of Subjects/ Assignment to Treatment Groups 
Approximately 50,000 subjects will be screened for this study in order to identify 6000 
subjects meeting the single genetic criterion and other inclusion/exclusion criteria required 
for randomization in this trial. Subjects will be assigned to treatment groups in a 1:1 ratio, 
stratified by region (Eastern Europe, Western Europe, North America, South America, and 
other) and ACS index event (MI or hospitalization for ACS [ECG changes without 
biomarkers]), to ensure equal number of subjects receiving active treatment and placebo in 
these strata. 
3.3 
Clinical Trial Centers 
This is a multi-national, multi-center study.  
4. 
STUDY POPULATION 
In order to be included in the trial, subjects must fulfill all of the inclusion criteria and not 
meet any of the exclusion criteria listed below.  
4.1 
Inclusion Criteria 
Subjects with the appropriate genetic profile and recently hospitalized for ACS (between 1 and 
3 months following the index event) will be enrolled in this trial. ACS is defined as the 
occurrence of at least one of the following events: 
Myocardial Infarction 
Spontaneous Myocardial Infarction  
 
A diagnosis of a qualifying MI event will be defined by a rise and/or fall of cardiac biomarkers 
(preferably cardiac troponin) with at least one determination greater than the 99th percentile 
upper reference limit (URL)  plus at least one of the following described below: 
 


CONFIDENTIAL DAL-301 v.5- Page 19 
 
• Symptoms of myocardial ischemia, or 
• New or presumed new significant ST-segment-T wave (ST-T) changes or new left bundle 
branch block, or  
• Development of pathological Q waves in the ECG, or  
• Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality, or 
• Identification of an intracoronary thrombus by angiography 
 
Procedure-Related Myocardial Infarction after Percutaneous Coronary Intervention (PCI) 
 
A procedure-related MI after PCI is defined as an increase of cardiac troponin values with at 
least one determination greater than 5 times the 99th percentile URL in patients with normal 
baseline values (less than or equal to 99th percentile URL) or a rise of cardiac troponin values > 
20% if the baseline values are elevated and are stable or falling; plus at least one of the 
following described below: 
 
• Symptoms suggestive of myocardial ischemia 
• New ischemic ECG changes  
• Imaging demonstration of new loss of viable myocardium or new regional wall motion 
abnormality 
• Angiographic findings consistent with a procedural complication  
 
Hospitalization for ACS (ECG Abnormalities without Biomarkers): 
 
A diagnosis of a qualifying ACS event without increases in cardiac biomarkers will require 
admission to hospital or emergency room (exceeding 23 hrs) with symptoms presumed to be 
caused by myocardial ischemia with an accelerating tempo in the prior 48 hrs and/or prolonged 
(at least 20 min) rest chest discomfort and new ECG findings (or presumed new if no prior ECG 
available) as described below and at least one of the following: 
 
• at least 50% stenosis of an epicardial coronary artery  
• positive exercise or pharmacologic stress indicating reversible ischemia 
• presence of pathologic Q-waves on ECG 
Examples of New ECG Findings Include: 
• New or presumed new ST depression of at least 0.5mm in at least 2 contiguous leads or 
T wave inversion of at least 1mm in leads with predominant R wave or R/S >1 in at least 
2 contiguous leads 


CONFIDENTIAL DAL-301 v.5- Page 20 
 
• New or presumed new ST elevation at the J point in at least 2 contiguous leads with the 
following cut-off points: ≥ 0.2mV in men or ≥ 0.15mV in women in leads V2-V3 and/or 
≥0.1 mV in other leads or new or presumed new left bundle branch block (LBBB) 
• New tall R wave of at least 40ms in V1 and R/S ≥ 1 in V1 and/or V2 with concordant 
positive T- wave in the absence of a conduction defect 
• New Q waves ≥30 ms wide and at least 1mm deep in any 2 leads of a contiguous lead 
grouping or Q wave >20ms or QS complex in leads V2 and V3 (these criteria also apply to 
silent MI detected during a routine follow-up visit) 
 
In addition, the following inclusion criteria apply: 
 
1.  Both male and female subjects age 45 years and over at screening visit (V1) 
2.  Signed informed consent (approved by Institutional Review Board [IRB]/Independent 
Ethics Committee [IEC]) obtained prior to any study specific screening procedures  
3.  AA genotype at variant rs 1967309 in the ADCY9 gene as determined by cobas® ADCY9 
Genotype CTA testing, conducted at a designated investigational testing site (ITS)  
4. Clinically stable, ie, free of ischemic symptoms at rest or with minimal exertion for at 
least 1 week prior to randomization 
5. Prior to randomization, subject must have evidence of guidelines-based management of 
LDL-C, at a minimum to include medical and dietary treatment to a target level of LDL-C 
<100 mg/dl (<2.6 mmol/L). Subjects with an LDL-C level ≥100 mg/dL (≥ 2.6 mmol/L) 
may be randomized if they cannot reach the target goal of less than 100 mg/dL despite 
lipid-lowering regimen, or are unable to tolerate lipid-lowering regimen.   
 
4.2 
Exclusion Criteria 
1.  Females who are pregnant (negative pregnancy test required for all women of child-
bearing potential at Visit 2, Day 0) or breast-feeding  
2.  Women of childbearing potential (women who are not surgically sterile or 
postmenopausal defined as amenorrhea for >12 months) who are not using at least one 
method of contraception  
3.  New York Heart Association (NYHA) Class III or IV heart failure  
4.  Last known hemoglobin < 10 g/dL  
5.  Index ACS event presumed due to uncontrolled hypertension 
6.  Systolic blood pressure (BP) >180 mmHg and/or diastolic blood pressure >110 mmHg by 
the time of randomization despite anti-hypertensive therapy 
7.  Last known serum triglyceride level > 500 mg/dL (> 5.65 mmol/L) as assessed within 6 
months prior to randomization 
8.  Last known hemoglobin A1c (HbA1c) >10% as assessed within 6 months prior to 
randomization 


CONFIDENTIAL DAL-301 v.5- Page 21 
 
9.  Subjects with clinically apparent liver disease, eg, jaundice, cholestasis, hepatic synthetic 
impairment, or active hepatitis  
10.  Last known ALT or AST level > 3 times the upper limit of normal (ULN)or last known 
alkaline phosphatase level > 2 times the ULN as assessed within 6 months prior to 
randomization (excluding index event) 
11.  History of persistent and unexplained creatine phosphokinase (CPK) levels > 3 times the 
ULN as assessed within 6 months prior to randomization (excluding index event) 
12. Last known serum creatinine > 2.2 mg/dL (195 μmol/l) as assessed within 6 months prior 
to randomization  
13. Previous exposure to anacetrapib or evacetrapib, or documented allergic reaction to any 
CETP inhibitor 
14. History of malignancy (except for curatively treated basal cell or squamous cell 
carcinoma of the skin) during the 1 year prior to the screening  
15. Any clinically significant medical condition that according to the investigator could 
interfere with the conduct of the study 
16. Subjects whose life expectancy is shorter than 3 years 
17. Presence of any last known laboratory value as evaluated prior to randomization that is 
considered by the investigator to potentially limit the patient’s successful participation in 
the study 
18. Current alcohol or drug abuse or history thereof within 2 years prior to screening that 
would likely interfere with compliance, based on investigator assessment 
19. Subjects who have received any investigational drug within 1 month of randomization, 
or who expect to participate in any other investigational drug or device study during the 
conduct of this trial  
20. Subjects unable or unwilling to comply with protocol requirements, or deemed by the 
investigator to be unfit for the study  
21. Subjects who have undergone coronary artery bypass graft (CABG) between the index 
event and randomization 
4.3 
Concomitant Medication and Treatment 
Subjects should receive contemporary evidence-based medical care for status post-ACS as 
individually prescribed by the treating physician. 
 
Subjects should also receive instructions on a heart healthy diet. A recommended diet is 
provided in Appendix 1. Subjects should also receive counseling on appropriate life style 
modifications such as weight control, physical activity, smoking cessation etc. 
 


CONFIDENTIAL DAL-301 v.5- Page 22 
 
All background medications should be administered as per the local prescribing information 
and all medications prohibited for concomitant use with any of the standard background 
therapies are not allowed in subjects receiving these background therapies. 
 
Periodic assessment of LDL-C, hemoglobin A1c, and blood pressure may be performed as 
clinically indicated. Investigators may adjust the subject’s background medication (including 
statins which may be increased or decreased) at any time after randomization to meet 
standard of care requirements.  Patient HDL-C levels should not be evaluated by the 
investigator or the patient at any time after randomization, for the duration of the study. 
 
Based on drug-drug interaction studies, there are no medications prohibited to be co-
administered with dalcetrapib. In subjects receiving digoxin, plasma concentrations of 
digoxin should be monitored. For subjects receiving warfarin, the International normalized 
ratio (INR) should be checked on a regular basis to ensure that the INR is within the 
appropriate therapeutic target range. 
 
The use or change in dose of any concomitant medication will be recorded on the electronic 
case report form (eCRF). 
4.4 
Criteria for Premature Study Withdrawal  
Subjects have the right to withdraw consent from the study at any time for any reason.  An 
excessive rate of premature study withdrawals can render the study un-interpretable; 
therefore, unnecessary study withdrawal of subjects should be avoided. Should a subject 
decide to withdraw consent from the study, all efforts will be made to complete and report 
the observations prior to study withdrawal as thoroughly as possible.   
 
The investigator should contact the subject or a responsible relative either by telephone or 
through a personal visit to establish as completely as possible the reason for the study 
withdrawal. A complete final evaluation at the time of the subject’s withdrawal from the 
study must be made with an explanation of why the subject is withdrawing from the study.  
 
4.5 
Criteria for Premature Study Medication Discontinuation 
Based on extensive experience with dalcetrapib 600 mg/day in previous Phase III trials, 
dalcetrapib is well tolerated.  However, if tolerability leads to considerations of study 
medication discontinuation, it is preferable to titrate the patient down to 300 mg/day (1 
tablet per day instead of 2 tablets per day) at the investigator’s discretion rather than 
discontinuing study medication. Any dose changes will be recorded in the eCRF. Subjects 
stopping study medication should be followed until the end of the study with the same 
procedures and not be withdrawn unless the subject refuses to give further information.  


CONFIDENTIAL DAL-301 v.5- Page 23 
 
Additionally, for any subject prematurely discontinuing study medication, assessments will 
be conducted every 6 months for the collection of study endpoints and concomitant 
medications. Every effort must be made to obtain endpoint data through the duration of 
the trial, even if the patient discontinues study medication. 
5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
A detailed schedule of assessments by visit is shown in Table 1.  
5.1 
Screening Assessments and Procedures (Visit 1) 
All subjects must provide written informed consent before any study specific assessments 
or procedures are performed. 
 
The screening assessment will consist of:  1) review of subject history to determine likely 
eligibility based on non-genetic inclusion and exclusion criteria; 2) written informed consent 
and 3) blood draw for investigational cobas® ADCY9 Genotype CTA testing for genetic 
assessment, conducted at a designated investigational testing lab for centralized testing. In 
the unlikely event that the genetic sample is deemed unanalyzable the patient would be 
asked to provide another genetic sample. 
 
Subjects may undergo a blood draw for local laboratory assessments at this visit if the 
investigator determines it necessary to evaluate eligibility (e.g. troponin). Subjects who do 
not meet eligibility criteria at the screening visit based on last known laboratory values may 
undergo repeat testing prior to randomization. 
 
The screening assessments of V1 may be performed at the time of the index ACS event, or 
any time thereafter with the condition that randomization must occur within the mandated 
window (1-3 months) after the ACS event. Investigators may perform the informed consent 
process and screening procedures in the hospital or after discharge in the ambulatory 
setting. 
 
Subjects who meet the eligibility criteria based on the results of the investigational cobas® 
ADCY9 CTA genetic testing, and who meet all other inclusion and no exclusion criteria will 
be allowed to continue in the study and be scheduled for the randomization visit (V2).  All 
other subjects will be recorded as screen failures. 
 
During the 1-3 month window between the index ACS event and randomization, subjects 
should receive information on a heart healthy diet (see Appendix 1) and counseling on 
lifestyle changes as appropriate. Contemporary evidence-based medical care for ACS, 
including antiplatelet agents (aspirin, P2Y12 blocker), statins, beta-blockers, ACE-inhibitors 


CONFIDENTIAL DAL-301 v.5- Page 24 
 
(or angiotensin-receptor blockers), and medication for optimal control of hypertension, 
angina, and diabetes should be initiated as appropriate. Subjects should receive instructions 
on lipid-lowering medications such as statins and/or ezetimibe (ie, start lipid-lowering 
medication if subject is not yet receiving lipid-lowering medication, increase the dose or 
change to a more effective medication if subject is already on a lipid-lowering drug) in order 
to achieve target levels of LDL-C (at a minimum < 100 mg/dL, or < 2.6 mmol/L). 
5.2 
Randomization Procedures (Visit 2) 
 
Subjects who meet all eligibility criteria will be scheduled for Visit 2, the randomization visit.  
Subjects will be randomized between 1 and 3 months following the index ACS event.  
Women of childbearing potential must have a negative pregnancy test at this visit in order 
to proceed with randomization.  At this visit patients will undergo all study procedures as 
outlined in Table 1, Schedule of Assessments, including a physical exam, collection of 
medical history (including smoking history), etc.  
 
Once a subject has fulfilled all eligibility criteria, he/she will be randomized to dalcetrapib or 
matching placebo using an interactive web response system (IWRS).  The importance of 
compliance with study medication should be emphasized.   
 
An optional blood draw for pharmacogenomics (DNA) and soluble biomarker (non-genetic) 
investigations may be performed on patients who volunteer to participate in this sub-study, 
and provide additional informed consent at this visit.  These samples will be frozen and kept 
for future use to evaluate biomarkers related to cardiovascular disease and the response to 
treatment.  
5.3 
Assessments and Procedures During the Double-blind Treatment Period 
 
Subjects will visit the study clinic 1 month and 6 months after randomization and every 6 
months thereafter. With the exception of the screening visit, subjects should ideally be in a 
fasting state (minimum of 10 hours) for all visits requiring a blood draw (Visits 2 and 5) to be 
submitted to the central lab.  Serum creatinine, HbA1c, fasting lipids and hsCRP will be 
evaluated for all subjects at Visits 2 and 5.  If the patient forgot to fast or fasted for less than 
10 hours, the sample should still be collected and sent to the central lab for analysis and 
documented accordingly in the CRF. At each site visit (and phone visit) after randomization, 
subjects will be assessed for the occurrence of adverse events and endpoint events. 
 
Subjects will receive a new drug supply at each visit except at visit 3 (1 month) and visit 4 (3 
month phone call).  At each visit subjects will be required to bring in old unused drug for 


CONFIDENTIAL DAL-301 v.5- Page 25 
 
assessment of compliance and the importance of compliance to study medication is to be 
emphasized. 
 
All study assessments will be performed and lab samples will be collected as outlined in 
Table 1, Schedule of Assessments. 
5.3.1 Assessments and Procedures in Response to COVID-19 
 
During the coronavirus disease of 2019 (COVID-19) pandemic, in-person study visits may be 
replaced by phone visits or virtual visits if necessary. Communication with patients and 
visits may also occur by email and text message when necessary. Procedures that require 
physical contact with patients including the physical exam and vital signs (blood pressure, 
pulse, and weight) are to be performed whenever possible, but may be considered as 
optional in situations where direct physical contact with the patient is not locally allowed or 
determined to be hazardous to the patient and/or staff due to the COVID-19 pandemic. 
Sponsor approval must be obtained within one month if patients are on study drug for more 
than one year without blood pressure, pulse, or weight assessments.  If clinical sites are 
closed or have limited access, the physical exam and vital signs (blood pressure, pulse, and 
weight) may be collected at a location other than the clinical site (i.e. a remote location, the 
patient’s home, etc) where possible and locally allowed.  
 
If study visits at clinical sites are, or are expected to be significantly impacted, study 
medication may be dispensed within a study visit window or in advance through a secure 
delivery method. All study medication will be appropriately handled and tracked to ensure 
compliance with stability parameters. 
 
Patients will be provided directions to save their unused study medication materials (used 
and unused drug supply containers) to return at their next on-site visit. Study medication 
may also be returned by the patient to the site through a secure delivery method. 
 
All COVID-19 related contingency measures will be recorded in the eCRF. 
 5.4 
End of Treatment and Safety Follow-Up 
As an endpoint driven study, subjects will be on study treatment until approximately 582 
study primary endpoints have occurred and have been adjudicated. Participating sites will 
be informed when the study has reached approximately 582 study primary endpoints and 
will be asked to schedule the end of study treatment visit for their subjects.  The end of 
study visit must be scheduled within a month of being notified when possible.   
 


CONFIDENTIAL DAL-301 v.5- Page 26 
 
Patients still taking study medication at the end of treatment visit will also have a safety 
follow-up phone call 14 days (+1 week window if needed) after the end of treatment visit. 
The safety follow-up may be conducted via telephone unless the investigator considers a 
visit necessary because of ongoing adverse events for which he/she would like to obtain a 
follow-up measurement. 
5.5 
Assessments and Procedures for Subjects Who Prematurely Discontinue Study 
medication 
For subjects who prematurely discontinue study medication but wish to remain in the trial, 
they will continue being followed as per the planned study assessments and procedures.  
 
For subjects who prematurely discontinue study medication and also refuse further study 
visits and procedures, every effort should be made to retain the subjects in the study to 
obtain information by phone on the occurrence of endpoint events. 
 
For subjects who refuse further study medication, procedures, or phone contact, an end of 
treatment visit should be performed if possible.  For these patients the investigator should 
make every effort to obtain information on whether or not the subject is alive or dead at 
the end of the study. If these patients are unable to be reached, this information may be 
obtained through publicly available sources and/or as permitted by local regulations.   If 
locally allowed, a third party may be used to locate alternative subject contact information 
and/or vital status in the public domain.   That information will be provided to the 
investigator. 
5.6 
Assessments and Procedures at Occurrence of Efficacy Endpoints 
Occurrence of study endpoints, from randomization to trial completion, must be reported 
to the sponsor within 24 hours of the site’s notification that the study endpoint has 
occurred.  As endpoints will be adjudicated by an independent Clinical Endpoint Committee 
(CEC), endpoint classification forms will be provided as part of the eCRF. The investigator 
will record the event on these electronic forms and forward the supporting documentation 
(hospital admission and discharge note, autopsy reports, ECGs etc.) in a timely manner. 
These data will be provided to the CEC for adjudication of the event. The CEC consists of the 
chairman and additional qualified members.  Procedures and processes for the CEC will be 
detailed in the CEC charter. 
 
 
Table 1 Schedule of Assessments  
Subjects who will be in the study for more than 3 years will continue to visit the clinic every 
6 months and have the same assessments performed as during the second and third year. 
 
V1 
Screening 
V2 
Day 0 
(randomization) 
V3 
 
1M 
V4 
 
3M 
phone 
V5 
 
6M 
V6 
 
12M 
V7 
 
18M 
V8 
 
24M 
V9 
 
30M 
V10 
 
36M 
End of 
Study  
Phone 
14 days after 
end of study 
Visit windows (weeks) 
 
 
 
± 1 
± 3 
± 3 
± 3 
± 4 
± 4 
± 4 
± 4 
 
+ 1 


CONFIDENTIAL DAL-301 v.5- Page 27 
 
Informed Consent for 
Study Protocol 
X 
 
 
 
 
 
 
 
 
 
 
 
ACDY9 genetic 
determinant (blood 
draw) 
X 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographic 
Information 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Query subjects for 
new/changes in contact 
information 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Pregnancy Test (local) 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam and 
Medical History 
 
X 
 
 
 
 
 
 
 
 
X 
 
Blood Pressure, Pulse, 
Weight 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood draw for serum 
creatinine, HbA1c, 
fasting lipids and hsCRP 
(central lab) 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Informed consent for 
optional genetic and 
biomarker evaluations 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood draw for 
optional genetic and 
biomarker evaluations 
 
X 
 
 
X 
 
 
 
 
 
 
 
Prev/Conc Med 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study 
medication 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Return unused Study 
medication 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
*Optional phone calls by the site to the patient may be conducted between 6 month visit 
intervals 
** Procedures that require physical contact with patients such as obtaining, blood pressure, pulse, weight, and 
an End of Study physical exam are to be performed whenever possible, but may be considered as optional in 
situations where direct physical contact with the patient is not locally allowed or determined to be hazardous 
to the patient and/or staff due to the COVID-19 pandemic. 
 
5.7 
Efficacy Assessments and Procedures 
Efficacy assessments of this study are listed below. A detailed description of the analysis of 
these parameters is included in Section 8, ‘Statistical Considerations and Analytical Plan’.  
All primary and secondary endpoint events will be adjudicated by the CEC. 
5.7.1 Primary Efficacy Assessment 
The primary efficacy assessment in this trial is the time to the first occurrence of any 
component of the composite endpoint of: 
 
• 
Cardiovascular (CV) death  
• 
Resuscitated cardiac arrest 
• 
Non-fatal MI 
• 
Non-fatal stroke 
 
A detailed description of criteria for classification of endpoints is documented in the CEC 
charter. The charter will also include information on supporting documents to be provided, 


CONFIDENTIAL DAL-301 v.5- Page 28 
 
data flow and meeting schedule of the CEC. Study sites will be given a list of the documents 
that they will need to provide when an endpoint is suspected. 
 
5.7.2 Secondary Efficacy Assessments 
The key secondary efficacy assessments in this trial are the time to the first occurrence 
of: 
• The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
or hospitalization for ACS (with ECG abnormalities) requiring coronary revascularization 
• The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
hospitalization for ACS (with ECG abnormalities), or unanticipated coronary 
revascularization 
• The composite of all cause death, resuscitated cardiac arrest, non-fatal MI,  or non-fatal 
stroke 
Other secondary efficacy assessments are listed below. 
Time to first occurrence of: 
• The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal 
stroke, or hospitalization for new or worsening heart failure 
• The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal 
stroke, hospitalization for ACS (with ECG abnormalities) requiring coronary 
revascularization, or hospitalization for new or worsening heart failure 
• The composite of all-cause death, resuscitated cardiac arrest, non-fatal MI, non-
fatal stroke, or hospitalization for new or worsening heart failure 
• Fatal or non-fatal MI 
• All-cause death 
 
5.7.3 Exploratory Assessments 
Blood draw for serum creatinine, fasting lipids, hsCRP, and HbA1c will be obtained 
according to the schedule summarized in Table 1 and analyzed by the central laboratory. 
Exploratory laboratory assessments are change from baseline in levels of lipids as well as 
the change in hsCRP. Healthcare resource utilization information will also be collected. 
 
 
Patients who volunteer for the optional biomarker sub-study will have additional blood 
samples collected at Visits 2 and 5 for future genetic and non-genetic analyses. Protection 


CONFIDENTIAL DAL-301 v.5- Page 29 
 
of subject confidentiality will extend to any data generated from the assaying of these 
samples. These samples will be frozen and kept for future use to evaluate biomarkers 
related to cardiovascular disease and the response to treatment. 
 
A laboratory manual providing instructions for the collection and handling of blood samples 
will be provided. 
 
5.8 
Safety Assessments and Procedures  
5.8.1 Adverse Events 
Adverse events will be collected throughout the study after randomization.  At each visit 
starting at V3, the investigator will ask the subject if any untoward medical event occurred 
since the last visit. For each event, the date of onset and end, intensity, relationship to 
study medication, and outcome will be recorded on the eCRF. 
5.8.2 Vital signs 
Seated blood pressure and pulse will be recorded after at least a 5-minute rest. Vital sign 
checks will be performed according to the schedule summarized in Table 1. 
5.8.3 Physical examination and medical history 
Physical examinations will include examination of the following body systems: general 
appearance, chest/lungs, and cardiovascular. All clinically significant changes from 
randomization to trial completion should be reported as an AE in the source data and the 
eCRF. Medical history will consist of detailed information regarding the index ACS event, 
and risk factors for cardiovascular disease.   
5.8.4 Laboratory Assessments 
Blood samples are to be collected at Visit 1 (screening), Visit 2 (Day 0) and Visit 5 (Month 6). 
Blood samples at Visits 2 and 5 are ideally to be collected in the fasting state (minimum of 
10 hours without food; subjects are allowed to drink water, but no coffee or tea).  
The procedures for the collection, handling, storage and shipping of laboratory samples are 
specified in a separate laboratory manual. 
5.8.4.1  
Serum Creatinine and HbA1c  
Blood draw for serum creatinine and HbA1c will be obtained according to the schedule 
summarized in Table 1 and analyzed by the central laboratory.  All clinically significant 
changes from randomization to trial completion should be reported as an AE in the source 
data and the eCRF.   
5.8.4.2  
Pregnancy Test 
β-HCG levels test will be obtained and analyzed locally in all women of childbearing 
potential prior to randomization (Table 1).  


CONFIDENTIAL DAL-301 v.5- Page 30 
 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT  
6.1 
Dose and Schedule of Study medication and Placebo 
DalCor (sponsor) will supply dalcetrapib 300mg film-coated tablets and matching placebo 
tablets to investigators. Subjects will take 600 mg of dalcetrapib or placebo (2 tablets) once 
daily. Study medication should be taken with food, preferably with the largest meal of the 
day. Subjects should be encouraged to take the medication at approximately the same time 
each day. 
 
Subjects who take study medication with breakfast should be instructed not to take study 
medication at home in the morning of V2 and V5 (fasting blood samples are preferred) but 
to wait until after collection of blood at the clinic. 
6.1.1 Dose Modifications and Delays 
In the event of a subject forgetting to take drug with their largest meal that day, they can 
take the study drug later in the day and return to their regular schedule the next day.  In the 
event of a subject not taking drug on a given day, he or she should not take more than the 
daily dose on the following day.   
 
Temporary interruptions of study medication are allowed. Interruptions of study medication 
for longer than 14 days need approval of the sponsor whenever possible. In the event of a 
subject experiencing intolerable adverse events considered related to study medication by 
the investigator, the investigator should consider decreasing the dose to one tablet once 
daily before interrupting or permanently discontinuing study medication.   
6.2 
Formulation, Packaging and Labeling 
Dalcetrapib will be provided as film-coated tablets of 300 mg. Tablets are white and 
capsule-shaped, identical in appearance to placebo tablets. 
 
The study medication must be stored in a locked, secured, temperature controlled location 
of up to 25o C. A daily temperature log must be maintained by the site. Any temperatures 
exceeding 25o C should be reported to the Sponsor/designee immediately along with the 
following information: the minimum and maximum temperature of the excursion, duration 
in hours, and the medication kit numbers involved. The drug should be immediately placed 
at the proper temperature and quarantined (not dispensed to subjects) until notification 
from the Sponsor is received that the drug is acceptable to use or must be 
destroyed/returned. 
 
Likewise, subjects should be informed that study medication must be stored at 25o C or 
below. 


CONFIDENTIAL DAL-301 v.5- Page 31 
 
 
Subjects will take their daily dose of dalcetrapib or placebo as shown below. 
 
No. of Tablets 
Dose Group 
300 mg dalcetrapib tablet 
Placebo 
600 mg of dalcetrapib 
2 
0 
Placebo 
0 
2 
 
Please note that placebo tablets contain lactose (435 mg/tablet) and may lead to problems 
in subjects with severe lactose intolerance. 
 
Each site will receive a supply of individually labeled double-blind study medication kits. 
Each kit will be labeled with a label including dosing instructions, the visit number and the 
subject number to be added by site personnel. 
6.3 
Randomization 
Subjects will be randomized to dalcetrapib 600 mg or placebo in a 1:1 ratio stratified by 
region and ACS index event (MI or hospitalization for ACS [ECG Abnormalities without 
Biomarkers], see sections 4.1.1 and 4.1.2), according to a computer-generated global 
randomization code. The subject randomization numbers will be allocated sequentially in 
the order in which the subjects are enrolled. Investigators are to use the IWRS to obtain 
randomization numbers for subjects they randomize in the study. 
 
The Master Randomization List will be kept in a central repository at the Coordinating 
Center with access to the unblinded statistician only. No open key to the code will be 
available at the study center, to the monitors of the Contract Research Organization (CRO), 
project statisticians, or to the project team.  
6.4 
Blinding and Unblinding 
The blind during the study is maintained by administration of placebo tablets to subjects in 
the placebo group. The Randomization List will not be available at the study center, to the 
Project Manager and monitors of the contract research organization(s) CRO(s), project 
statisticians or to the project team. If the identification of the test medication is necessary 
for subject management (in the case of serious adverse event) the investigator will be able 
to break the code by contacting the IWRS provider. A note to file should be written which 
will be archived with other study documents. Treatment codes should not be broken except 
in the case of emergency situations. If the investigator wishes to know the identity of the 
treatment given to study subjects for any other purpose, this request should first be 
discussed with the DalCor Chief Medical Officer. 
 


CONFIDENTIAL DAL-301 v.5- Page 32 
 
Unblinding for ongoing safety monitoring by the DSMB will be performed according to 
adequate procedures in place to ensure integrity of the data as outlined in a separate DSMB 
charter. 
 
All other individuals directly involved in this study will remain blinded until the final analysis 
of the primary parameter. 
6.5 
Assessment of Compliance 
Accountability and subject compliance will be assessed by maintaining adequate drug 
dispensing and return records. 
 
Subjects will be asked to return all used and unused drug supply containers at each visit as a 
measure of compliance. 
 
A Drug Dispensing Log must be kept current and should contain the following information: 
•  
the identification of the subject to whom the study medication was dispensed 
•  
the date[s] and quantity of the study medication dispensed to the subject 
• 
the date[s] and quantity of the study medication returned by the subject 
 
This inventory must be available for inspection by the Monitor. The dispensing logs must be 
returned to DalCor or DalCor designee at the end of the study. 
6.6 
Destruction of Study Medication 
Each site will be instructed by their monitor on the details of drug return/destruction for 
their site. 
7.  
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
Adverse Events (AEs) and Laboratory Abnormalities 
7.1.1 Clinical AEs 
Per the International Conference of Harmonization [ICH], an AE is any untoward medical 
occurrence in a subject or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign [including an abnormal laboratory 
finding], symptom, or disease temporally associated with the use of a medicinal 
[investigational] product, whether or not considered related to the medicinal 
[investigational] product. Pre-existing conditions which worsen during a study are to be 
reported as AEs. 


CONFIDENTIAL DAL-301 v.5- Page 33 
 
7.1.1.1  
Intensity 
All clinical AEs encountered during the clinical study will be reported on the AE page of the 
eCRF. Intensity of AEs will be graded on a four-point scale [mild, moderate, severe, life-
threatening] and reported in detail on the eCRF. 
 
Mild   
 
discomfort noticed but no disruption of normal daily activity.  
Moderate  
 
discomfort sufficient to reduce or affect daily activity. 
Severe  
 
inability to work or perform normal daily activity 
Life-Threatening 
represents an immediate threat to life 
7.1.1.2  
Drug - Adverse Event Relationship 
Relationship of the AE to the treatment should always be assessed by the investigator as 
either Related or Not Related .  The following criteria should be considered in order to 
assess the relationship: 
 
• reasonable temporal association with administration of the study drug 
• existence of alternative causes that could on their own have caused the reaction, 
like the subject’s medical condition 
• known pattern of response to the suspected drug 
• de- and rechallenge information 
7.1.1.3  
Serious Adverse Events 
A Serious Adverse Event (SAE) is any AE that at any dose fulfills at least one of the following 
criteria: 
– 
is fatal; [results in death; NOTE: death is an outcome, not an event] 
– 
is life-threatening [NOTE: the term "Life-Threatening" refers to an event in which the 
subject was at immediate risk of death at the time of the event; it does not refer to 
an event which could hypothetically have caused a death had it been more severe]. 
– 
required in-patient hospitalization or prolongation of existing hospitalization*; 
– 
results in persistent or significant disability/incapacity; 
– 
is a congenital anomaly/birth defect; 
–  
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
* NOTE: Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. An emergency room visit without hospital admission will not be recorded as a serious 
adverse event (SAE) under this criterion, nor will hospitalization for a procedure scheduled or planned 
before signing of informed consent. However, unexpected complications and/or prolongation of 
hospitalization that occur during elective surgery should be recorded as AEs and assessed for 
seriousness. 


CONFIDENTIAL DAL-301 v.5- Page 34 
 
Admission to the hospital for social or situational reasons (i.e., no place to stay, live too far away to 
come for hospital visits) will not be considered inpatient hospitalizations.  
 
The study will adhere to the full requirements of the ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 and comply with 
local regulatory requirements (see Appendix 2). 
7.1.1.4  
Project-Specific Definition of SAEs 
In this trial, positively adjudicated endpoints by the CEC (irrespective of investigators' 
causality) as well as those negatively adjudicated by the CEC and reported as unrelated to 
study medication by the investigators will be exempted from SAE reporting. However, all 
other events meeting SAE criteria will be reported as SAEs to the Sponsor. 
 
Thus, the following events will not be reported as SAEs unless negatively adjudicated and 
considered study medication related by the investigator: 
  
Cardiovascular (CV) death  
Resuscitated cardiac arrest 
Non-fatal MI  
Non-fatal stroke  
Hospitalization with ACS (with ECG abnormalities) 
Hospitalization for ACS (with ECG abnormalities) requiring coronary 
revascularization 
Unanticipated coronary revascularization 
Hospitalization for new or worsening heart failure 
All-cause death 
 
These events will be reported on the appropriate eCRF pages for the collection of 
information on endpoint events and forwarded to the CEC. 
7.1.2 Treatment and Follow-up of AEs 
All AEs, especially those that could be related to study medication, should be followed-up 
until they have returned to baseline status or stabilized. If after follow-up, return to 
baseline status or stabilization cannot be established an explanation should be recorded on 
the eCRF. 
7.1.3 Laboratory Test Abnormalities  
Any treatment-emergent abnormal laboratory result that is clinically significant, should be 
recorded as a single diagnosis, if possible, on the AE page in the eCRF. 


CONFIDENTIAL DAL-301 v.5- Page 35 
 
7.1.4 Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the tests 
should be repeated and followed up until they have returned to the normal range or 
baseline and/or an adequate explanation of the abnormality is found. If a clear explanation 
is established it should be recorded on the AE page of the eCRF. 
7.2 
Handling of Safety Parameters  
7.2.1 Reporting of AEs 
All new adverse events occurring during the study should be recorded on the AE page of the 
eCRF. Adverse events that occur intermittently should be recorded as one AE. Adverse 
events should be collected and reported from randomization to trial completion. 
7.2.2 Reporting of Serious Adverse Events  
Any clinical AE or abnormal laboratory test value that is serious [as defined in section 
7.1.1.3 above] and which occurs during the course of the study must be reported to the 
sponsor within 24 hours of the investigator becoming aware of the event. 
 
Related Serious Adverse Events MUST be collected and reported regardless of the time 
elapsed from the last study medication administration, even if the study has been closed. 
 
Like AEs in general, unrelated Serious Adverse Events must be collected and reported during 
the study and to trial completion. 
 
The definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 will be adhered 
to. Complete information can be found in Appendix 2. 
7.2.3 Pregnancy 
A female subject must be instructed to stop taking the study medication and immediately 
inform the investigator if she becomes pregnant during the study. The investigator should 
report all pregnancies within 24 hours to the sponsor. The investigator should counsel the 
subject, discuss the risks of continuing with the pregnancy, and the possible effects on the 
fetus. Monitoring of the subject should continue until conclusion of the pregnancy. 
Pregnancies occurring up to 90 days after the completion of the test medication must also 
be reported to the investigator. 
7.3 
Warnings and Precautions 
No evidence available at the time of the approval of this study protocol indicated that 
special warnings or precautions were appropriate, other than those noted in the 
Investigators’ Brochure. 


CONFIDENTIAL DAL-301 v.5- Page 36 
 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
8.1 
Primary and Secondary Study Endpoints 
8.1.1 Primary Endpoint 
The primary endpoint of this study is the time from randomization to first occurrence of any 
component of the composite endpoint as adjudicated by the CEC. Components of the 
primary endpoint are: 
 
•  
Cardiovascular death 
• 
Resuscitated cardiac arrest 
• 
Non-fatal MI 
• 
Non-fatal stroke 
8.1.2 Secondary and Exploratory Endpoints 
The key secondary endpoints of this study are listed below. 
 
Time to first occurrence of:  
• The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
or hospitalization for ACS (with ECG abnormalities) requiring coronary revascularization 
• The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
hospitalization for ACS (with ECG abnormalities), or unanticipated coronary 
revascularization 
• The composite of all cause death, resuscitated cardiac arrest, non-fatal MI, or non-fatal 
stroke  
 
Other secondary endpoints are listed below: 
 
Time to first occurrence of 
• The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
or hospitalization for new or worsening heart failure 
• The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, 
hospitalization for ACS (with ECG abnormalities) requiring coronary revascularization, 
or hospitalization for new or worsening heart failure 
• The composite of all-cause death, resuscitated cardiac arrest, non-fatal MI, non-fatal 
stroke, or hospitalization for new or worsening heart failure 
• Fatal or non-fatal MI 
• All-cause death 
 
Exploratory endpoints are listed below 


CONFIDENTIAL DAL-301 v.5- Page 37 
 
Healthcare resource utilization information 
Change from baseline for:  
• Blood levels of TC, TG, LDL-C, and HDL-C 
• Blood levels of hsCRP 
8.1.3 Safety 
Safety of the treatment will be evaluated by AEs and vital signs.  
8.2 
Statistical and Analytical Methods 
8.2.1 Sample Size 
The sample size calculation is based on the primary endpoint. Under the following 
assumptions:  
 
• an expected relative risk reduction of 22% and 
• a statistical significance defined as a two-sided alpha of 0.05 
 
the trial would have 85% power if it continues until at least 582 primary CEC adjudicated 
events occur in the combined treatment groups. 
 
The total number of subjects to randomize, 6000, is chosen so that the expected number of 
events is at least approximately 582. It is based on the following assumptions, which were 
reviewed according to actual and planned recruitment rate: 
 
• a 2.8-year recruitment period; 
• a 1% yearly lost to follow-up rate; and 
• a 7% event rate at 2 years following randomization in the placebo group. 
 
Sample size was calculated using nQuery, version 7.0. 
8.2.2  
Analysis Populations 
8.2.2.1  
Exclusion of Data from Analysis 
Subjects will be completely excluded from analyses if they do not satisfy the criteria for 
inclusion in the specified analysis population, as defined below. If a subject satisfies the 
criteria for inclusion in an analysis population then no data from that subject will be 
excluded from use. 
8.2.2.2  
Intent to Treat (ITT) Population 
All subjects randomized will be included in the ITT population.  


CONFIDENTIAL DAL-301 v.5- Page 38 
 
8.2.2.3  
Per-Protocol Population 
A per-protocol population is defined as patients who meet all inclusion/exclusion criteria, 
are determined to be at least 80% compliant to study medication, and have completed the 
study with no premature study or medication discontinuation. This population will be used 
only in the context of exploratory analysis as described in section 8.2.4.3. 
8.2.2.4  
Safety Analysis Population 
All subjects who received at least one dose of treatment will be included in the safety 
analysis population. Subjects will be assigned according to the true treatment received for 
analysis purposes. 
8.2.2.5  
Co-Diagnostic Analysis: Intent-to-Diagnose (ITD) 
Patients who provide written informed consent and have blood drawn for screening will be 
tested for RS1967309 of ADCY9 by the cobas® ADCY9 Genotype CTA. Patients with AA 
genotype results will be allowed to proceed in the study and be further evaluated for 
eligibility into the study treatment phase and patients with non-AA genotype will be 
excluded from the study; however, demographic data for both the AA and non-AA groups 
will be recorded for evaluation of the cobas® ADCY9 Genotype CTA as a companion 
diagnostic for dalcetrapib. Patients who have a biologic sample obtained after Informed 
Consent are part of the Intent-to-Diagnose population.  
8.2.3 Efficacy Analysis 
8.2.3.1  
Primary Analysis 
A stratified Cox proportional hazards model will be used to analyze the primary endpoint. 
Time to event will start at randomization and subjects who are lost to follow-up (while 
event free) will be censored at the time that they are last known to be event free. The strata 
will be defined by region (Eastern Europe, Western Europe, North America, South America, 
and other) and the ACS index event (MI or ACS [ECG abnormalities without biomarkers], see 
sections 4.1.1 and 4.1.2). 
 
The null and alternative hypotheses to be tested with the above Cox model are:  
H0: λ = 1 vs. HA: λ ≠ 1 
Where λ is the, assumed constant, hazard ratio for the time to occurrence of the composite 
events of the primary endpoint for the dalcetrapib and placebo treated groups. The hazard 
ratio, within strata, will be assumed to depend on treatment alone. The estimated hazard 
ratio will be presented with a 95.2% confidence interval (CI) and a p-value.  
 
The primary analysis will be based on the ITT population and conducted at the 0.048 
significance level to account for interim assessments of efficacy as outlined in section 
8.2.3.4. 


CONFIDENTIAL DAL-301 v.5- Page 39 
 
 
 
8.2.3.2  
Secondary and Exploratory Analysis 
For the secondary endpoints that are expressed as time to event, an analysis similar to that 
for the primary endpoint will be conducted. 
 
The changes from baseline in TC, TG, LDL-C, HDL-C and hsCRP levels will be compared 
between treatment groups using an analysis of covariance (ANCOVA) adjusting for baseline 
value and for the two stratification factors, ACS index event type and region. Specifically, 
the null and alternative hypotheses to be tested are:  
H0: Dplacebo = Ddalcetrapib vs.  
HA: Dplacebo ≠ Ddalcetrapib 
where Dplacebo is the change in the placebo group and Ddalcetrapib is the change in the 
dalcetrapib group. Estimates of treatment effect will be presented with 95% CI and p-
values.  
 
Secondary and exploratory analyses will be conducted on the ITT population. In order to 
control the Type I error that results from the multiplicity of endpoints, the key secondary 
endpoints will be formally tested using the Hochberg’s step-up procedure only if the 
primary analysis results in significant treatment effect at p < 0.048.  Otherwise, statistical 
tests for the secondary endpoints will be presented solely for illustrative purposes. 
8.2.3.3  
Sub-population Analyses 
For illustrative purposes, the following factors: 
• Geographic location 
• Age 
• Gender 
• Race 
• BMI 
• Diabetes 
 
may be used to define subgroups of subjects within which the primary and selected 
secondary efficacy endpoints will be evaluated using Cox proportional hazards models 
similar to the ones described in section 8.2.3.1, adding to the models a term for the factor 
defining the subgroup and a term for the interaction between the factor and the treatment 
group. This interaction term will be tested at the 0.1 significance level and will determine 
whether the treatment effect is affected by the presence of the factor. In addition, under 
the proposed models, the treatment effect will be estimated and presented with 95% 


CONFIDENTIAL DAL-301 v.5- Page 40 
 
confidence intervals within subgroups.  The sub-population analyses would be conducted 
on the ITT population. 
 
8.2.3.4  
Interim Analysis 
 
When approximately 70% (408) of the primary study endpoints have occurred and been 
positively adjudicated, an interim analysis will be conducted by the independent Data Safety 
Monitoring Board (DSMB).  The DSMB will determine if there is sufficient evidence of 
efficacy benefit to justify continuation of the trial to its completion. This futility assessment 
will be based on the conditional power of the trial derived under various relative risk 
reduction assumptions. Following this assessment, the DSMB may recommend terminating 
the trial.   
 
Full details will be described in the DSMB charter and Statistical Analysis Plan. 
8.2.4 Exploratory Analyses 
8.2.4.1  
Effect of Prognostic Factors 
In order to characterize any potential treatment effect more precisely, an analysis of the 
primary endpoint will be conducted with the hazard ratio assumed to depend on, in 
addition to treatment, the following potentially prognostic factors: 
 
• 
Baseline HDL-C  
• 
Baseline LDL-C  
• 
Baseline TG  
• 
Baseline TC 
•  
Gender 
•  
Age  
 
A factor will be identified as prognostic if the corresponding model term is associated with a 
p-value of less than 0.2 in a multivariate stratified Cox proportional hazards model that 
includes all factors. Factors that are determined to be prognostic by this criterion will be 
included in the final model to provide an estimate of treatment effect that adjusts for 
factors that are likely to influence the primary endpoint. This will be done on the ITT 
population. 
 
8.2.4.2  
Effect of Lipid Changes and Changes in hsCRP while on Treatment 
In order to evaluate risk reduction as it relates to changes or actual values in lipids and 
hsCRP while subjects are on randomized treatment, additional exploratory analyses will be 


CONFIDENTIAL DAL-301 v.5- Page 41 
 
conducted on the primary endpoint. These will include, but will not necessarily be limited 
to, analyses that: 
 
• 
include changes or actual values in lipids and hsCRP as time-dependent covariates in 
proportional hazard regression models 
 
• 
take a subset of subjects who are event free at 6 months and use the change from 
baseline in lipids and hsCRP (or actual values) at that time as fixed covariates in a 
regression analysis of subsequent events. 
 
In all analyses, randomized treatment will be both included and excluded as a factor in the 
regression models in order to evaluate if there are additional effects of treatment beyond 
those that are attributable to changes in lipid levels. These analyses would be conducted on 
the ITT population. 
8.2.4.3  
Sensitivity Analyses 
If a statistically significant treatment effect is demonstrated in the analysis of the primary 
endpoint, the robustness of the results will be evaluated with respect to their potential 
dependence on the assumptions made. 
 
In particular, the effect of censoring subjects who are lost to follow-up (while event free) 
will be evaluated by imputing event outcomes for such subjects in the analysis. Various 
imputation rules will be applied and will be established prior to database closure and the 
breaking of the blind. The sensitivity of the primary analysis to treatments or procedures 
that would be expected to affect the primary endpoint will be assessed by additionally 
censoring such subjects at the time of the treatment or procedure. 
 
The consistency of treatment effect across the ACS index event strata and across regions 
will be tested using a term of treatment by strata interactions in the Cox regression model. 
Interaction will be considered significant if p < 0.1 and in the event that significant 
interactions are observed, estimates of treatment effect will only be reported by strata. 
 
8.2.5 Safety Analyses 
All safety parameters will be summarized and presented in tables based on the safety 
population. 
 
For the evaluations of adverse events and general laboratory data described below, neither 
tests of hypotheses nor estimates of treatment effects will be reported. It is however 
anticipated that in some instances there will be numerical treatment differences in the 


CONFIDENTIAL DAL-301 v.5- Page 42 
 
reported summary statistics that are either of interest or concern; in these instances, more 
extensive exploratory statistical analyses may be performed. The scope of the analyses 
cannot be determined a priori; but would be expected to include standard regression 
methods for estimating relative risks such as odds and hazard ratios. 
8.2.5.1  
Adverse Events 
Treatments will be examined with respect to the incidence of adverse events, serious 
adverse events (SAEs) and adverse events leading to premature study withdrawal or dose 
modifications.  
 
Summary statistics will be presented for all treatment-emergent events and, in addition, by 
intensity and relationship to study medication as judged by the investigator. In the latter 
instances, for subjects experiencing repeated episodes, only the most severe episode and 
the episode with the strongest relationship will be reported. Summary statistics will include 
number and incidence of events where incidence of an event within a treatment group will 
be determined as the simple proportion of subjects in the group experiencing the event.  
 
Adverse events will be grouped and summarized by body system as defined by the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA), following 
classification of investigator assessments into MedDRA preferred terms.  
 
8.2.5.2  
Laboratory Data 
Any clinically significant changes in laboratory data will be reported as an adverse event and 
will be included in the adverse event safety analyses.   
8.2.5.3  
Vital Signs 
Any clinically significant changes in vital signs will be reported as an adverse event and will 
be included in the adverse event safety analyses.  
 
9. 
DATA QUALITY ASSURANCE 
Data for this study will be recorded via an Electronic Data Capture (EDC) system using 
electronic Case Report Forms. The eCRF can be used as the source document if the eCRF is 
the original place of data entry, per the FDA Guidance. Accurate and reliable data collection 
will be assured by verification and cross-check of the eCRFs against the Investigator’s 
records by the study monitor (source document verification), and the maintenance of a 
drug–dispensing log by the Investigator. A comprehensive validation check program will be 
defined and outlined in the Edit Checks Specifications as a part of the Data Management 
Plan. Throughout the study the Study Management Team will review data according to the 
Data Management Plan. 


CONFIDENTIAL DAL-301 v.5- Page 43 
 
9.1 
Assignment of Preferred Terms to Original Terminology 
For classification purposes, preferred terms will be assigned by the lead Data Coordinator, 
reviewed by the Medical Monitor/DalCor Chief Medical Officer based on the original terms 
entered on the eCRF, using the latest version of the MedDRA for adverse events and 
diseases, and WhoDRUG  for medications. 
10. STUDY COMMITTEES 
10.1 Executive Committee and Steering Committee 
The Study Executive Committee is composed of medical and scientific experts and includes 
the Principal Investigator. The Executive Committee, together with the sponsor, developed 
the protocol.  The Executive Committee is also responsible for evaluating any changes in the 
medical environment during the course of the trial that affect the assumptions underlying 
the original protocol design and amending the protocol accordingly.   
 
The Steering Committee is composed of the Executive Committee and the national 
coordinators of each participating country/region. A separate charter describing roles and 
responsibilities of the members of the two committees will be maintained by the sponsor. 
10.2 Data Safety Monitoring Board (DSMB) 
The primary role of the DSMB, which consists of physicians and statisticians, is to ensure the 
safety of the subjects. A detailed description of the procedures, data flow and meeting 
schedule of the DSMB will be maintained in a separate DSMB charter by the sponsor. 
10.3 Clinical Endpoints Committee (CEC) 
The Clinical Endpoints Committee (CEC) consists of independent members and will be 
responsible for the adjudication and classification of deaths and non-fatal cardiovascular 
events. 
 
Criteria for adjudication, procedures, data flow and meeting schedule are described in a 
separate CEC charter maintained by the sponsor. 
 
 
 
 
 
 
 


CONFIDENTIAL DAL-301 v.5- Page 44 
 
11. REFERENCES 
 
1. Murray CJ and Lopez AD. Global mortality, disability, and the contribution of risk factors: 
Global Burden of Disease Study. Lancet 1997; 349:1436-1442. 
 
2. Heart and Stroke Facts: 1995 statistical supplement. 1995. American Heart Association. 
 
3. Stampfer MJ, .Sacks FM, Salvini S, Willet WC, and Hennekens CH. A prospective study of 
cholesterol, apolipoproteins, and the risk of myocardial infarction. NEJM.1991;325: 373-
381. 
 
4. Mack WJ, Krauss RM, Hodis HN. Lipoprotein subclasses in the Monitored Atherosclerosis 
Regression Study (MARS). Treatment effects and relation to coronary angiographic 
progression. Art Thromb Vasc Biol 1996;16:697-704. 
 
5. Zilversmit DB. Atherogenic nature of triglycerides, postprandial lipidemia, and   
triglyceride-rich remnant lipoproteins. Clin Chem 1995; 41:153-158. 
 
6. McGill  JrMcMahan CA,C Malcom GT, Oalmann MC, and Strong JP. Effects of serum 
lipoproteins and smoking on atherosclerosis in young men and women. Art Thromb Vasc 
Biol 1997;17:95-106. 
 
7. Schaefer EJ, Genest JJ Jr, Ordovas JM, Salem DN, and Wilson PW. Familial lipoprotein 
disorders and premature coronary artery disease.  Atherosclerosis. 1994;108:S41-54.  
 
8. Vega GL, Grundy SM. Hypoalphalipoproteinemia (low high density lipoprotein) as a risk 
factor for coronary heart disease. Curr Opin Lipid 1996;7:209-216. 
 
9. Calabresi L and Franceschini G. High density lipoprotein and coronary heart disease: 
insights from mutations leading to low high density lipoprotein. Curr Opin Lipidol. 
1997;8:219-224. 
 
10. Third report of the National Cholesterol Education Program (NCEP) expert panel on 
detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment 
Panel III) – Executive Summary. National Heart, Lung and Blood Institute, National Institute 
of Health, NIH Publication No. 01-3670, May 2001. 
 
11. Schwartz GG, Olsson AG, Abt M, et al. Effects of Dalcetrapib in patients with a recent 
acute coronary syndrome. N Engl J Med 2012; 367: 2089-2099. 
 
12. Tardif, J-C, Rheaume E, Perreault L-P L, et al. Pharmacogenomic Determinants of the 
Cardiovascular Effects of Dalcetrapib. Circgenetics 2015; 114.0000663. 


CONFIDENTIAL DAL-301 v.5- Page 45 
 
PART II: 
ETHICS AND GENERAL STUDY ADMINISTRATION 
12. ETHICAL ASPECTS 
12.1 Local Regulations/Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the individual. 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords greater 
protection to the subject. For studies conducted in the European Union (EU)/ European 
Economic Area (EEA) countries, the investigator will ensure compliance with the EU Clinical 
Trial Directive [2001/20/EC]. For studies conducted in the USA or under US IND, the 
investigator will additionally ensure that the basic principles of “Good Clinical Practice” as 
outlined in the current version of 21 CFR, subchapter D, part 312, “Responsibilities of 
Sponsors and Investigators”, part 50, “Protection of Human Subjects”, and part 56, 
“Institutional Review Boards”, are adhered to. 
 
In other countries where “Guidelines for Good Clinical Practice” exist DalCor and the 
investigators will strictly ensure adherence to the stated provisions. 
12.2 Informed Consent 
It is the responsibility of the investigator, or a person designated by the investigator [if 
acceptable by local regulations], to obtain written informed consent from each subject 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study. The investigator or designee must also explain 
that the subjects are completely free to refuse to enter the study or to withdraw from it at 
any time, for any reason. The electronic Case Report Forms [eCRFs] for this study contain a 
section for documenting informed subject consent, and this must be completed 
appropriately. If new safety information results in significant changes in the risk/benefit 
assessment, the consent form should be reviewed and updated if necessary. All subjects 
[including those already being treated] should be informed of the new information, given a 
copy of the revised form and give their consent to continue in the study. 
An optional informed consent will be provided at randomization for additional future 
genetic and non-genetic testing to explore the relationship between treatment response 
and genetic/non-genetic determinants. 
12.3 Independent Ethics Committees/Institutional Review Board 
Independent Ethics Committees [non-US]: This protocol and any accompanying material 
provided to the subject [such as subject information sheets or descriptions of the study 


CONFIDENTIAL DAL-301 v.5- Page 46 
 
used to obtain informed consent] as well as any advertising or compensation given to the 
subject, will be submitted by the investigator to an Independent Ethics Committee. 
 
Approval from the committee must be obtained before starting the study, and should be 
documented in a letter to the investigator specifying the date on which the committee met 
and granted the approval. 
 
Any modifications made to the protocol after receipt of the Independent Ethics Committee 
approval must also be submitted by the investigator to the Committee in accordance with 
local procedures and regulatory requirements. 
 
When no local review board exists, the investigator is expected to submit the protocol to a 
regional committee.  
 
Institutional Review Board [US]: It is the understanding of the sponsor that this protocol 
[and any modifications] as well as appropriate consent procedures, will be reviewed and 
approved by an Institutional Review Board. This board must operate in accordance with the 
current Federal Regulations. A letter or certificate of approval will be sent by the 
investigator to the sponsor prior to initiation of the study, and also whenever subsequent 
modifications to the protocol are made. 
13. CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between an 
appropriate representative of the sponsor and the investigator [investigator 
representative[s] in the case of a multicenter trial]. Protocol modifications must be 
prepared by a representative of the sponsor and initially reviewed and approved by the 
Chief Medical Officer. 
 
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee or Institutional Review Board for information and approval in accordance with 
local requirements, and to Regulatory Agencies if required. Approval must be awaited 
before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to trial subjects, or when the change[s] involves only logistical or 
administrative aspects of the trial [e.g. change in monitor[s], change of telephone 
number[s]. 


CONFIDENTIAL DAL-301 v.5- Page 47 
 
14. CONDITIONS FOR TERMINATING THE STUDY 
Both the sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange the procedures on an individual study 
basis after review and consultation. In terminating the study, DalCor and the investigator 
will assure that adequate consideration is given to the protection of the subject’s interests. 
 
15. STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING  
15.1 Investigator's Files / Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into two different separate categories [1] Investigator's 
Study File, and [2] subject clinical source documents. 
 
The Investigator's Study File will contain the protocol/amendments, Independent Ethics 
Committee/Institutional Review Board and governmental approval with correspondence, 
sample informed consent, drug records, staff curriculum vitae and authorization forms and 
other appropriate documents/correspondence etc. 
 
Subject clinical source documents [usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs] would include subject hospital/clinic 
records, physician's and nurse's notes, appointment book, original laboratory reports, ECG, 
electroencephalogram (EEG), X-ray, pathology and special assessment reports, signed 
informed consent forms, consultant letters, and subject screening and enrollment logs. The 
Investigator must keep these two categories of documents on file for at least 15 years after 
completion or discontinuation of the study or longer if required by local regulation. After 
that period of time the documents may be destroyed, subject to local regulations. 
 
Should the Investigator wish to assign the study records to another party or move them to 
another location, DalCor must be notified in advance. 
 
If the Investigator cannot guarantee this archiving requirement at the investigational site for 
any or all of the documents, special arrangements must be made between the Investigator 
and DalCor to store these in a sealed container[s] outside of the site so that they can be 
returned sealed to the Investigator in case of a regulatory audit. Where source documents 
are required for the continued care of the subject, appropriate copies should be made for 
storing outside of the site. 


CONFIDENTIAL DAL-301 v.5- Page 48 
 
15.2 Source Documents and Background Data 
The investigator shall supply the sponsor on request with any required background data 
from the study documentation or clinic records. This is particularly important when errors in 
data transcription are suspected. In case of special problems and/or governmental queries 
or requests for audit inspections, it is also necessary to have access to the complete study 
records, provided that subject confidentiality is protected. 
15.3 Audits and Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the DalCor Quality Assurance Unit or its 
designee, or to health authority inspectors after appropriate notification. The verification of 
the eCRF data must be by direct inspection of source documents. 
15.4 Electronic Case Report Forms 
For each subject randomized, an eCRF must be completed and electronically signed by the 
principal investigator or authorized delegate from the study staff. If a subject withdraws 
from the study, the reason must be noted on the eCRF. If a subject is withdrawn from the 
study because of a treatment-limiting AE, thorough efforts should be made to clearly 
document the outcome. Data from subjects enrolled and screened, but who do not get 
randomized (screen failures) will not be collected in the eCRF.  However, some information 
such as demographic data, ACS event type, ACS event date, will be collected in the IWRS 
system for all screened patients.  
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the sponsor in the eCRFs and in all required reports. 
16. MONITORING THE STUDY 
It is understood that the responsible DalCor monitor [or designee] will contact and visit the 
investigator regularly and will be allowed, on request, to inspect the various records of the 
trial [eCRFs and other pertinent data] provided that subject confidentiality is maintained in 
accord with local requirements. 
 
It will be the monitor's responsibility to inspect the eCRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them. The monitor should have access to laboratory 
test reports, study medication and other subject records needed to verify the entries on the 
eCRF. The investigator [or his/her deputy] agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved. 
 


CONFIDENTIAL DAL-301 v.5- Page 49 
 
When site access is not possible due to COVID-19, virtual monitoring may occur where 
locally permitted. 
17. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS 
The investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On eCRFs or other documents 
submitted to the sponsor, subjects should not be identified by their names, but by an 
identification code. The investigator should keep a subject enrollment log showing codes, 
names and addresses. The investigator should maintain documents not for submission to 
DalCor, e.g., subjects’ written consent forms, in strict confidence. 
18. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to DalCor prior to 
submission. This allows the sponsor to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
investigator. 
 
In accord with standard editorial and ethical practice, DalCor will generally support 
publication of multicenter trials only in their entirety and not as individual center data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
 
Any formal publication of the study in which input of DalCor personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and the 
appropriate DalCor personnel. Authorship will be determined by mutual agreement. 
 
 


CONFIDENTIAL DAL-301 v.5- Page 50 
 
Appendix 1 Study Recommended Diet and Principles   
TLC Diet – A diet for high cholesterol heart disease recommended by AHA 
The TLC diet was introduced in May 2001 when the National Cholesterol Education 
Progream (NCEP) released new diet guidelines for people with high cholesterol and risks of 
hear disease.  The American Heart Association (AHA) accepted and endorsed this report and 
began incorporating these recommendations into its materials on dietary and lifestyle 
change for people with high blood cholesterol.  For people at high risk or who hav known 
cardiovascular disease, NCEP and AHA now recommend the new Therapeutic Lifestyle 
Changes (TLC) diet to replace the “old” Step 1 and Step 2 diets. 
 
Summary of the TLC Diet for High Cholesterol 
 
• 
Saturated fat: Less than 7% of total calories 
• 
Polyunsaturated fat: Up to 10% of total calories 
• 
Monounsaturated fat: Up to 20% of total calories 
• 
Carbohydrate: 50% to 60% of total calories 
• 
Soluble fiber: At least 5 to 10 grams a day 
• 
Protein: Approximately 15% of total calories 
• 
Cholesterol: Less than 200 mg a day 
• 
Total calories: Balance calories taken in and calories burned to reach and stay at a 
healthy weight. 
 
For a detailed customized TLC diet plan, please consult with your Registered Dietitian. 
 
 


CONFIDENTIAL DAL-301 v.5- Page 51 
 
 
Appendix 2 ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2  
A serious adverse event is any AE that at any dose fulfills at least one of the following 
criteria: 
 
– 
is fatal; [results in death] [NOTE: death is an outcome, not an event] 
 
– 
is Life-Threatening 
[NOTE: the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe]. 
 
– 
required in-patient hospitalization or prolongation of existing hospitalization; 
 
– 
results in persistent or significant disability/incapacity; 
 
– 
is a congenital anomaly/birth defect; 
 
– 
is medically significant or requires intervention to prevent one or other 
 
of the outcomes listed above 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the patient or may require intervention to prevent one of the outcomes 
listed in the definitions above. These situations should also usually be considered serious. 
 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator. For Serious Adverse Events, possible causes 
of the event are indicated by selecting one or more options. (Check all that apply) 
– 
Pre-existing/Underlying disease – specify 
  
– 
Study treatment – specify the drug(s) related to the event  


CONFIDENTIAL DAL-301 v.5- Page 52 
 
 
– 
Other treatment (concomitant or previous) – specify 
 
– 
Protocol-related procedure  
 
– 
Other (e.g. accident, new or intercurrent illness) – specify 
 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious. For 
example, nausea of several hours' duration may be rated as severe, but may not be clinically 
serious. 
 
A serious adverse event occurring during the study or which comes to the attention of the 
investigator within 14 days during the protocol-defined follow-up period after stopping the 
treatment or during the protocol-defined follow-up period, if this is longer, whether 
considered treatment-related or not, must be reported. In addition, a serious adverse event 
that occurs after this time, should also be reported if considered related to test “drug”. 
 
Such preliminary reports will be followed by detailed descriptions later which will include 
copies of hospital case reports, autopsy reports and other documents when requested and 
applicable. 
 
For serious adverse events, the following must be assessed and recorded on the AEs page of 
the eCRF: intensity, relationship to test substance, action taken, and outcome to date. 
 
The investigator must notify the Ethics Committee/Institutional Review Board of a serious 
adverse event in writing as soon as is practical and in accordance with international and 
local laws and regulations. 
 
 
  
 

SAP_001.pdf: 
 
 
BS-T1-001-05 
Confidential 
Page 1 of 26 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Protocol number: DAL-301 
 
PHASE III, DOUBLE-BLIND, RANDOMIZED PLACEBO-CONTROLLED STUDY TO EVALUATE THE 
EFFECTS OF DALCETRAPIB ON CARDIOVASCULAR (CV) RISK IN A GENETICALLY DEFINED 
POPULATION WITH A RECENT ACUTE CORONARY SYNDROME (ACS): THE dal-GenE TRIAL 
 
DAL-GENE 
 
 
 
 
 
 
Date of Final Statistical Analysis Plan:  
05-NOV-2019 
Amendment No. 1 : 
15-MAR-2021 
Amendment No. 2 : 
10-JUN-2021 
Amendment No. 3 : 
07-JUL-2021 
 
Prepared by: 
Sylvie Levesque, M.Sc. 
Senior Biostatistician 
Montreal Health Innovations Coordinating Center (MHICC) 
4100 Molson, Suite 400 
Montréal, QC  H1Y 3N1 
Phone: 514-461-1300 ext. 2890 / Fax: 514-461-1301 
 
 
 
Confidentiality Statement:  
 
 The information contained in this document is the property of DalCor Pharmaceuticals and may not be 
disclosed to others without authorization from DalCor Pharmaceuticals.   


 
SAP: 07-JUL-2021 / Amendment 3 
Protocol number: DAL-301 
 
 
BS-T1-001-05 
Confidential 
Page 4 of 26 
 
 
Version 
Date 
(DD-MMM-YYYY) 
Author 
Summary of Changes 
Amendment 1 
15-MAR-2021 
Sylvie 
Levesque 
Section 6.4.5.2 (Sensitivity Analysis and 
Robustness Checks) 4) Add sensitivity analysis 
taking into account the adjudicated primary 
efficacy endpoints collected between the end of 
study visit and the 14-day safety follow-up. 
 
Section 6.4.5.3 (Analysis Following the Initiation 
of the COVID-19 Pandemic): Add new section for 
sensitivity analyses to the COVID-19 pandemic. 
 
Section 6.4.5.4 (Analysis Based on Exposure to 
Study Treatment): Add new section for sensitivity 
analyses to evaluate the effect of exposure to 
study treatment. 
 
Section 6.5.2.3 (Adverse Events Leading to 
Premature Drug or to Premature Study 
Withdrawal): Replace “Adverse events leading to 
premature study withdrawal or dose 
modification” by “Adverse events leading to 
premature drug withdrawal” and “Adverse 
events leading to premature study withdrawal”. 
 
Section 6.5.6 (COVID-19 Outbreak Impact): Add 
new section on impact of COVID-19. 
 
Correction of typos throughout the text. 
Amendment 2 
10-JUN-2021 
Sylvie 
Levesque 
Section 3.2 (Intent-To-Treat (ITT) Population): 
Add subject numbers who will be excluded from 
the ITT. 
 
Amendment 3 
07-JUL-2021 
Sylvie 
Levesque 
Section 6.4.1 (Primary Analysis): Correct the 
discrepancy between the level of the confidence 
interval for the hazard ratio and the significance 
level of the test. The correct level is 95% to match 
the 0.05 significance level of the primary analysis.  
 


 
SAP: 07-JUL-2021 / Amendment 3 
Protocol number: DAL-301 
 
BS-T1-001-05 
Confidential 
Page 5 of 26 
 
TABLE OF CONTENTS  
 
List of Abbreviations ................................................................................................................................ 7 
1. Introduction ....................................................................................................................................... 8 
2. Study Description ............................................................................................................................... 8 
2.1  Study Design ................................................................................................................................. 8 
2.2  Study Objectives ......................................................................................................................... 10 
3. Datasets Analyzed ............................................................................................................................ 10 
3.1  Exclusion of Data from Analysis .................................................................................................. 10 
3.2  Intent-To-Treat (ITT) Population ................................................................................................. 10 
3.3  Co-Diagnostic Analysis: Intent-to-Diagnose (ITD) Population ....................................................... 10 
4. Efficacy Endpoint .............................................................................................................................. 11 
4.1  Primary Efficacy Endpoint ........................................................................................................... 11 
4.2  Secondary Efficacy Endpoints ..................................................................................................... 11 
4.3  Exploratory Efficacy Endpoints .................................................................................................... 11 
5. Safety Parameters ............................................................................................................................ 12 
5.1  Adverse Events ........................................................................................................................... 12 
5.2  Serious Adverse Events ............................................................................................................... 12 
5.3  Vital Signs ................................................................................................................................... 12 
5.4  Physical Examination .................................................................................................................. 13 
5.5  Laboratory Parameters ............................................................................................................... 13 
5.6  New Onset Diabetes ................................................................................................................... 13 
6. Statistical Methodology .................................................................................................................... 13 
6.1  Sample Size ................................................................................................................................ 13 
6.2  Statistical Considerations ............................................................................................................ 14 
6.2.1  Interim Assessment of Futility.............................................................................................. 14 
6.3  Study Subjects ............................................................................................................................ 14 
6.3.1  Subject Disposition .............................................................................................................. 14 
6.3.2  Protocol Deviations ............................................................................................................. 14 
6.3.3  Datasets Analyzed ............................................................................................................... 15 
6.3.4  Demographic and Baseline Characteristics ........................................................................... 15 
6.3.5  Concomitant Medications .................................................................................................... 15 
6.3.6  Treatment Compliance ........................................................................................................ 15 
6.4  Efficacy Analysis.......................................................................................................................... 16 
6.4.1  Primary Analysis .................................................................................................................. 16 
6.4.1.1  Evaluation of Primary Endpoint Adjudication ................................................................ 17 
6.4.2  Secondary Analysis .............................................................................................................. 17 
6.4.3  Exploratory Analysis ............................................................................................................ 17 
6.4.4  Sub-population Analyses ..................................................................................................... 18 
6.4.5  Additional Analysis .............................................................................................................. 18 
6.4.5.1  Effect of HDL-C at baseline............................................................................................ 18 
6.4.5.2  Sensitivity Analysis and Robustness Checks................................................................... 18 
6.4.5.3  Analysis Following the Initiation of the COVID-19 Pandemic ......................................... 20 
6.4.5.4  Analysis Based on Exposure to Study Treatment ........................................................... 20 
6.4.6  Adjustment for multiplicity .................................................................................................. 21 
6.5  Safety Analysis ............................................................................................................................ 22 
6.5.1  Treatment Exposure ............................................................................................................ 22 


 
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Protocol number: DAL-301 
 
 
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6.5.2  Adverse Events and Serious Adverse Events......................................................................... 23 
6.5.2.1  Adverse Events ............................................................................................................. 23 
6.5.2.2  Serious Adverse Events ................................................................................................. 23 
6.5.2.3  Adverse Events Leading to Premature Drug or to Premature Study Withdrawal ............ 23 
6.5.2.4  Death ........................................................................................................................... 23 
6.5.3  Laboratory Parameters ........................................................................................................ 23 
6.5.4  Vital Signs ............................................................................................................................ 24 
6.5.5  New Onset Diabetes ............................................................................................................ 24 
6.5.6  COVID-19 Outbreak Impact.................................................................................................. 24 
7. Summary Tables, Figures and Listings ............................................................................................... 25 
8  References ......................................................................................................................................... 26 


 
SAP: 07-JUL-2021 / Amendment 3 
Protocol number: DAL-301 
 
 
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Page 7 of 26 
 
LIST OF ABBREVIATIONS 
 
ACS 
Acute Coronary Syndrome 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below Limit of Quantification 
CEC 
Clinical Endpoint Committee 
CI 
Confidence Interval 
CONSORT 
Consolidated Standards of Reporting  
COVID-19 
Coronavirus Disease of 2019 
CRF 
Case Report Form 
CTA 
Clinical Trial Assay 
CV 
Cardiovascular 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End Of Study 
HbA1c 
Hemoglobin A1c 
hsCRP 
High-Sensitivity C-Reactive Protein 
ITT 
Intent-to-Treat 
HDL-C 
High density lipoprotein cholesterol 
LDL-C 
Low-Density Lipoprotein Cholesterol 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MHICC 
Montreal Health Innovations Coordinating Center 
NOD 
New Onset Diabetes 
Q1  
25th percentile 
Q3 
75th percentile 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
T2DM 
Type 2 Diabetes Mellitus 
TC 
Total Cholesterol 
TEAEs 
Treatment-Emergent Adverse Events 
TG 
Triglycerides 
 
 


 
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1. INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to present the statistical methodology that will be used 
for the final analysis of DalCor protocol number DAL-301. This plan also provides a description of the 
analyses used to produce the tables, figures, and listings that will be included in the final statistical report. 
This SAP is based on the protocol Version 5 dated 11FEB2021 and on the annotated case report form (CRF) 
version 3.1. In case of differences between the SAP and the protocol, the SAP will supersede the protocol. 
Any deviation to this SAP would be reported in the statistical report. 
 
2. STUDY DESCRIPTION 
 
2.1  Study Design 
 
This is a placebo-controlled, randomized, double-blind, parallel group, phase III multicenter study in 
subjects recently hospitalized for acute coronary syndrome (ACS) and with the appropriate genetic profile.  
Subjects provided informed consent before any study-specific procedures were performed.  Subject 
enrollment was allowed to begin in the hospital and to continue following release from the hospital.  
Screening procedures were performed at the time of the index ACS event or anytime thereafter, with the 
condition that randomization had to occur within the mandated window (1-3 months after the index 
event). Subjects were assessed based on their medical history.  Those who were likely to qualify 
underwent Cobas® ADCY9 Genotype CTA (Clinical Trial Assay) testing to evaluate genetic determination 
for the presence of the AA genotype at variant rs 1967309 in the ADCY9 gene. Those meeting the genetic 
testing criteria, all other inclusion criteria and none of the exclusion criteria were eligible for 
randomization.  Eligible subjects had to be stabilized on statin and/or other medical therapy and had to 
complete all planned revascularization procedures prior to randomization. Subjects were randomized 
between 1 and 3 months from the index event. A total of 6149 eligible subjects in stable condition were 
randomized to 600 mg of dalcetrapib or placebo in a 1:1 ratio, stratified by region (Eastern Europe, 
Western Europe, North America, South America and other) and ACS index event (myocardial infarction 
[MI] or hospitalization for ACS [electrocardiogram changes without biomarkers]), to ensure equal number 
of subjects receiving active treatment and placebo in these strata. Subjects received study medication or 
placebo on a background of contemporary, evidence-based medical care for ACS. Subjects visit the clinic 
1 and 6 months after randomization. Thereafter, visits are every 6 months for efficacy and safety 
assessments until completion of the trial.  Phone assessments are performed 3 months after 
randomization and at the end of the study.  Any subject prematurely discontinuing study medication and 
unable or unwilling to continue study visits, have phone assessments conducted every 6 months for the 
collection of study endpoints, with the exception of subjects who only agree to a final phone assessment. 
Due to the coronavirus pandemic of 2019 (COVID-19), to protect subject and study staff safety, it may not 
be possible for subjects to visit their clinic for study visits for some time and several alternatives for in-
person study visits, and dispensing and returning study medication, are allowed as described in the study 
protocol. 
 
This is an event driven study and approximately 582 subjects with a primary event are needed to reach 
85% statistical power assuming a 22% relative risk reduction in the primary endpoint. Subjects will be 
expected to remain in the trial until the time at which approximately 582 subjects have experienced a 
positively adjudicated primary event.  We will model the accumulation of 582 first primary endpoints (a 
combination of adjudicated and completed probable packages), and inform the sites when we expect to 
have the start of the end of study visit window. All subjects who remain in the study (on or off study drug) 


 
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will be asked to return for an end of study (EOS) visit. Subjects still taking study medication at the EOS visit 
will also have a safety follow-up phone call 14 days after the EOS visit for the collection of adverse events, 
including components of the primary and secondary endpoints. All efficacy and safety events will be 
collected through the end of the trial. 
 
The end of trial is defined as the date the last data point required for statistical analysis (i.e. key safety 
and efficacy results) is received, which corresponds to the end of study visit or the 14-day safety follow-
up phone call, whichever is the latest. For the primary and secondary efficacy analyses (described in 
sections 6.4.1 and 6.4.2), follow-up of efficacy endpoints will stop at the end of study visit. In other words, 
any efficacy endpoints collected between the end of study visit and the 14-day safety follow-up phone 
call will still be adjudicated but not be included in primary and secondary efficacy analyses.  
 
An independent Data Safety Monitoring Board (DSMB) will monitor the unblinded safety data during the 
study.  
 
The schedule of assessments is presented in Table 1 below. 
 
Table 1: Schedule of Assessments  
Subjects who will be in the study for more than 3 years will continue to visit the clinic every 6 months and have the same 
assessments performed as during the second and third year. 
 
V1 
Screening 
V2 
Day 0 
(randomization) 
V3 
 
1M 
V4 
 
3M 
phone 
V5 
 
6M 
V6 
 
12M 
V7 
 
18M 
V8 
 
24M 
V9 
 
30M 
V10 
 
36M 
End of 
Study  
VISIT 
Phone 
14 days after end of study visit 
Visit windows (weeks) 
 
 
 
± 1 
± 3 
± 3 
± 3 
± 4 
± 4 
± 4 
± 4 
 
+ 1 
Informed Consent for 
Study Protocol 
X 
 
 
 
 
 
 
 
 
 
 
 
ACDY9 genetic 
determinant (blood 
draw) 
X 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographic 
Information 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Query subjects for 
new/changes in contact 
information 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Pregnancy Test (local) 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam and 
Medical History 
 
X 
 
 
 
 
 
 
 
 
X 
 
Blood Pressure, Pulse, 
Weight 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood draw for serum 
creatinine, HbA1c, 
fasting lipids and hsCRP 
(central lab) 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Informed consent for 
optional genetic and 
biomarker evaluations 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood draw for 
optional genetic and 
biomarker evaluations 
 
X 
 
 
X 
 
 
 
 
 
 
 
Prev/Conc Med 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Study 
medication 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
Return unused Study 
medication 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Note: Optional phone calls by the site to the patient may be conducted between 6 month visit intervals 
 


 
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2.2  Study Objectives 
 
The primary objective of this trial is to evaluate the potential of dalcetrapib to reduce cardiovascular 
morbidity and mortality (cardiovascular [CV] death, resuscitated cardiac arrest, non-fatal myocardial 
infarction [MI] and non-fatal stroke) in subjects with a documented recent ACS and the AA genotype at 
variant rs1967309 in the ADCY9 gene.   
 
The secondary objective of this trial is to evaluate the potential of dalcetrapib to reduce other clinically 
important events, such as hospitalization for ACS (with ECG abnormalities) or unanticipated coronary 
revascularization as well as hospitalization for new or worsening heart failure, in combination with the 
primary endpoint. 
 
Additional objectives of this trial are as listed below: 
x 
Evaluation of the effects of dalcetrapib on lipids and high-sensitivity C-reactive protein (hsCRP) in this 
population  
x 
Assessment of the long-term safety profile of dalcetrapib, including on diabetes, in this population 
 
3. DATASETS ANALYZED 
 
3.1  Exclusion of Data from Analysis 
 
Subjects will be completely excluded from analyses if they do not satisfy the criteria for inclusion in the 
specified analysis population, as defined below. If a subject satisfies the criteria for inclusion in an analysis 
population then no data from that subject will be excluded from use. 
 
3.2  Intent-To-Treat (ITT) Population  
 
All subjects randomized (subjects having a randomization number reported in the electronic case report 
form [eCRF]) will be included in the ITT population. Subjects will be assigned to treatment groups as 
randomized for analysis purposes.  The ITT population will be used for the assessment of efficacy and 
safety. Two subjects will be excluded from the ITT population: subject DAL301-18104007 and subject 
DAL301-36107011 who were randomized in error and never intended to be dosed. None of them took 
study medication. These two subjects to be removed from the ITT were confirmed by the sponsor prior 
to database lock and unblinding. 
 
3.3  Co-Diagnostic Analysis: Intent-to-Diagnose (ITD) Population 
 
Subjects who provide written informed consent and have blood drawn for screening will be tested for 
rs1967309 of ADCY9 by the cobas® ADCY9 Genotype CTA. Subjects with AA genotype results will be 
allowed to proceed in the study and be further evaluated for eligibility into the study treatment phase 
and subjects with non-AA genotype will be excluded from the study; however, demographic data for both 
the AA and non-AA groups will be recorded for evaluation of the cobas® ADCY9 Genotype CTA as a 
companion diagnostic for dalcetrapib. Subjects who have a biologic sample obtained after Informed 
Consent will be included in the ITD population.  
 


 
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4. EFFICACY ENDPOINT 
 
Study endpoints will be adjudicated by an independent Clinical Endpoint Committee (CEC) and endpoint 
classification forms will be provided as part of the eCRF. Procedures and processes for the CEC will be 
detailed in the CEC charter. 
 
4.1  Primary Efficacy Endpoint 
 
The primary endpoint of this study is the time from randomization to first occurrence of any component 
of the composite endpoint as adjudicated by the CEC. Components of the primary endpoint are: 
 
•  
Cardiovascular death 
• 
Resuscitated cardiac arrest 
• 
Non-fatal MI 
• 
Non-fatal stroke 
 
Subjects who discontinued the study without experiencing one of these events will be censored at the 
time they were last known to be event-free. Time to event (or censoring) will be calculated as the 
difference (in days) between the adjudicated event date (or date of censoring) and the date of 
randomization + 1 day.  
 
If a subject reports more than one of the above events, the earliest will be considered for the primary 
endpoint. If more than one event is reported with the same onset date, the subject will be assigned to the 
first event in the order of appearance above. 
 
4.2  Secondary Efficacy Endpoints 
 
The secondary endpoints of this study are time from randomization to first occurrence of each of the 
following composite endpoints, obtained from data adjudicated by the CEC: 
 
x 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, hospitalization 
for ACS (with ECG abnormalities), or unanticipated coronary revascularization 
x 
The composite of CV death, resuscitated cardiac arrest, non-fatal MI, non-fatal stroke, or 
hospitalization for new or worsening heart failure 
 
Note: Composite refers to the occurrence of any of the listed endpoints. 
 
The rules described in 4.1 for censoring, for calculation of time to event (or censoring) and in case of 
multiple events per subject will similarly apply for the secondary endpoints.  
 
4.3  Exploratory Efficacy Endpoints 
 
Exploratory endpoints will include change from baseline to 6 months in: 
 
x 
Blood levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) 
and high-density lipoprotein (HDL-C) 


 
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x 
Blood levels of hsCRP 
 
5. SAFETY PARAMETERS 
 
Safety will be assessed through the following: adverse events (AEs) and serious adverse events (SAEs), 
vital signs, physical examination, laboratory parameters and incidence of new onset diabetes.  
 
5.1  Adverse Events 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign, including an abnormal laboratory finding, 
symptom, or disease temporally associated with the use of an investigational product, whether or not 
considered related to the investigational product. Pre-existing conditions that worsen during a study are 
to be reported as AEs. 
 
AEs will be collected throughout the study after randomization.  At each visit starting at Visit 3 (Month 1), 
the investigator will ask the subject if any untoward medical event occurred since the last visit. For each 
event, the date of onset and end, intensity, relationship to study medication, and outcome will be 
recorded on the eCRF. 
 
5.2  Serious Adverse Events 
 
A SAE is any AE that at any dose fulfills at least one of the following criteria: 
x 
is fatal [results in death; NOTE: death is an outcome, not an event] 
x 
is life-threatening [NOTE: the term "Life-Threatening" refers to an event in which the subject was 
at immediate risk of death at the time of the event; it does not refer to an event that could 
hypothetically have caused a death had it been more severe]. 
x 
required in-subject hospitalization or prolongation of existing hospitalization; 
x 
results in persistent or significant disability/incapacity; 
x 
is a congenital anomaly/birth defect; 
x 
is medically significant or requires intervention to prevent one or other of the outcomes listed 
above 
 
It should be noted that implantable cardioverter-defibrillators (ICD) firings are not considered study 
endpoints but any ICD firing considered by the investigator as clinically relevant and meeting the criteria 
of an SAE will be reported as such. 
 
 5.3  Vital Signs 
 
Seated blood pressure and pulse will be recorded after at least a 5-minute rest. Systolic/diastolic blood 
pressure and pulse will be recorded at Visit 2 (Day 0), Visit 3 (Month 1), Visit 5 (Month 6), Visit 6 (Month 
12), Visit 7 (Month 18), Visit 8 (Month 24), Visit 9 (Month 30), Visit 10 (Month 36) and every 6 months 
thereafter until the end of the study (if possible).   
 


 
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5.4  Physical Examination 
 
Physical examinations will include examination of the following body systems: general appearance, 
chest/lungs and cardiovascular, and will be performed at Visit 2 (Day 0) and at the end of the study. All 
adverse clinically significant changes from randomization to trial completion should be reported as an AE 
in the source data and the eCRF if an end-of-study Physical Exam is performed. 
 
5.5  Laboratory Parameters 
 
Blood samples are to be collected at Visit 2 (Day 0) and Visit 5 (Month 6) for the analysis of serum 
creatinine and hemoglobin A1c (HbA1c) (central lab). All adverse clinically significant changes from 
randomization to trial completion should be reported as an AE in the source data and the eCRF.   
 
5.6  New Onset Diabetes 
 
New onset diabetes (NOD) is defined as a subject: 
 
x 
without a history of diabetes as reported on the eCRF  
x 
with HbA1c less than 6.5%, and  
x 
without hypoglycemic medications  
 
at the time of randomization, who meet one of the following criteria post-randomization: 
 
x 
HbA1c value ≥ 6.5%  
x 
new diagnosis of type 2 diabetes mellitus (T2DM) defined as the occurrence of a diabetes-related 
adverse event  
x 
use of a hypoglycemic medication 
 
6. STATISTICAL METHODOLOGY 
 
6.1  Sample Size 
 
The sample size calculation is based on the primary endpoint. Under the following assumptions:  
 
x 
an expected relative risk reduction of 22% and 
x 
a statistical significance defined as a two-sided alpha of 0.05 
 
the trial would have more than 85% power if it continues until at least 582 subjects experience a 
primary CEC adjudicated event in the combined treatment groups.  
 
The total number of subjects to randomize, 6000, was chosen so that the expected number of subjects 
with an event is at least 582. It is based on the following assumptions, which were reviewed according to 
actual and planned recruitment rate: 
 
x 
a 2.8-year recruitment period; 
x 
a 1% yearly lost to follow-up rate; and 


 
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x 
a 7% event rate at 2 years following randomization in the placebo group. 
 
A total of 6149 are actually randomized in the study. 
 
6.2  Statistical Considerations 
 
Statistical analyses will be performed using SAS, Version 9.4 or higher, or other validated software. Unless 
otherwise specified, all statistical tests will be two-sided.   
 
Study variables are to be presented with descriptive statistics. For continuous variables, the following will 
be reported: number of observations, mean, standard deviation, median, 25th and 75th percentiles (Q1 
and Q3), minimum and maximum. For categorical variables, frequency and percentage will be reported. 
 
Change from baseline is defined as: Post-baseline minus Baseline.  Baseline is defined as randomization 
visit (V2). 
 
6.2.1  Interim Assessment of Futility 
 
On January 23, 2020, after the occurrence of approximately 70% (408) positively adjudicated primary 
study endpoints, an interim assessment of futility was conducted by the independent DSMB, based on the 
separate DSMB futility assessment SAP. Following this assessment, the DSMB recommended to continue 
the trial as planned.   
 
Full details are described in the DSMB charter statistical analysis plan.  
 
6.3  Study Subjects 
 
6.3.1  Subject Disposition  
 
The number of randomized subjects, number of randomized subjects who took study medication, number 
of randomized subjects completing the study and reasons for study discontinuation will be summarized 
by treatment group. The number of subjects with survival status assessed at the end of the study will also 
be presented.  
 
A flow chart following the recommendations of the Consolidated Standards of Reporting (CONSORT) 
statement will also be provided.  
 
A subject data listing of subject disposition will be provided. 
 
6.3.2  Protocol Deviations  
 
Major protocol deviations are defined as: 
 
x 
A subject that did not meet entry criteria 
x 
A subject that received the wrong treatment 
x 
A subject that took an over-dose (more than 2 tablets per day) 


 
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x 
A subject that did not complete a planned revascularization procedure prior to randomization 
 
Major protocol deviations will be captured in the clinical database within the standard eCRFs and included 
in a subject data listing.  
 
6.3.3  Datasets Analyzed  
 
The number of subjects in the ITT population will be summarized.  
 
6.3.4  Demographic and Baseline Characteristics 
 
Demographic data (age, sex [including reproductive status], race, ethnicity) and baseline characteristics 
which includes history of or current cardiovascular and non-cardiovascular diseases (diabetes), subject 
region, height, weight, body mass index, vital signs and smoking history will be presented using descriptive 
statistics by treatment group and overall for the ITT population. For age calculation, missing birth day will 
be replaced by 15 and missing birth day/month will be replaced by 01/JULY.  
 
The following categories for the ACS index will be summarized: 
x 
Diagnosis of spontaneous myocardial infarction 
x 
Diagnosis of procedure-related myocardial infarction after percutaneous coronary intervention 
x 
Hospitalization for ACS index event 
 
Demographic data that was collected on subjects who provided informed consent and had a blood drawn 
for screening for rs1967309 of ADCY9 by the cobas® ADCY9 Genotype CTA, including subjects with AA 
genotype who were allowed to proceed in the study and subjects with non-AA genotype who were 
excluded from the study, will be reported by the Roche Molecular Systems team in a separate report. 
 
6.3.5  Concomitant Medications  
 
The use or change in dose of any medication ongoing or started from the randomization and up to the 
end of study is recorded on the eCRF. Concomitant medications are coded with respect to indication and 
generic name using the WHO drug dictionary (September 2016 or higher). Concomitant medications will 
be presented at randomization.   
 
Frequency of use of medications at randomization will be presented by the level 2 Anatomical Therapeutic 
Chemical (ATC) classification and preferred term, for each treatment arm. Data will be summarized and 
presented as proportion of subjects overall and by treatment group receiving any drug in a treatment 
medication classification at the randomization visit. 
 
A subject data listing of concomitant medications will also be provided. 
 
6.3.6  Treatment Compliance  
 
Accountability and subject compliance will be assessed by maintaining adequate drug dispensing and 
return records. Subjects will be asked to return all used and unused drug supply containers at each visit 
as a measure of compliance.  


 
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An overall compliance calculation will be performed using the study administration intake recorded. 
Compliance for the whole study is derived as follows: 
                                        
                                Compliance   =   # days subject took study medication      X  100  
                                                             # days in the study 
 
# days in the study = Date subject completed the study - date of randomization + 1. 
 
 
Total time on study medication = Date of treatment last dose - date of treatment first dose + 1. 
 
# days subject took study medication (duration of treatment exposure) = Total time on study 
medication - the sum of all interruption durations for each record on the Treatment Inter/ Disc 
Form of the eCRF.  It should be noted that only interruptions over 7 days are captured. 
 
Subjects who died with no report of study drug discontinuation will be considered as discontinuing drug 
on date of death and date of treatment last dose will be imputed as date of death. 
 
Compliance will be summarized by treatment arm using descriptive statistics.   
 
Compliance will also be categorized as follow: < 80% or [80%-100%] and summarized accordingly using 
frequencies and percentages, by treatment arm, for the subjects of the ITT population.   
 
Compliance results will be listed. 
 
6.4  Efficacy Analysis 
 
All efficacy analyses will be conducted on the ITT population. 
 
6.4.1  Primary Analysis 
 
A stratified Cox proportional hazards model will be used to analyze the primary endpoint. Time to event 
will start at randomization and subjects who are event-free will be censored at the time that they are last 
known to be event free. The strata, i.e., as those for randomization, will be defined by region (Eastern 
Europe, Western Europe, North America, South America and other) and the ACS index event (MI1 or 
hospitalization for ACS [ECG abnormalities without biomarkers]). In case of a mismatch between the 
stratum assigned at time of randomization and the stratum confirmed in the eCRF, the stratum confirmed 
in the eCRF will be used.  
 
More precisely, the Cox proportional hazards model will include treatment as a main effect, and region 
and ACS index event type as stratification factors.  
 
The null and alternative hypotheses to be tested with the above Cox model are:  
                                               
1MI corresponds to the following two categories of ACS index event as collected in the eCRF: “Spontaneous 
myocardial infarction” and “Procedure-related myocardial infarction after percutaneous coronary intervention 
(PCI)”. 


 
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H0: λ = 1 vs. HA: λ ≠ 1 
 
Where λ is the, assumed constant, hazard ratio for the time to occurrence of the composite events of the 
primary endpoint for the dalcetrapib and placebo treated groups. The hazard ratio, within strata, will be 
assumed to depend on treatment alone. The estimated hazard ratio will be presented with a 95% 
confidence interval (CI) and a p-value.  
 
The primary analysis will be conducted at the 0.05 significance level. 
 
For descriptive purposes, the number and percentage of subjects with each component of the composite 
primary endpoint will be presented. Time to event will also be graphically displayed using Kaplan-Meier 
curves. 
 
A subject data listing of primary composite endpoint will also be provided. 
 
6.4.1.1  Evaluation of Primary Endpoint Adjudication 
 
In order to evaluate the consistency of subject outcomes as assessed by the investigator and as 
adjudicated by the CEC, the concordance between both assessments for the components of the primary 
endpoint will be summarized using descriptive statistics. 
 
In addition, to go into more depth for death, types of death (CV, non-CV, undetermined), as reported by 
the investigator and as adjudicated by the CEC, will be summarized using descriptive statistics. No 
formal statistical testing will be done. 
 
6.4.2  Secondary Analysis 
 
Secondary endpoints are expressed as time to event and an analysis similar to that for the primary 
endpoint will be conducted. 
 
In order to control the family-wise Type I error that results from the multiplicity of endpoints, the 
secondary endpoints described in section 4.2 will be formally tested using the Hochberg’s step-up 
procedure only if the primary analysis results in significant treatment effect at p < 0.05. Otherwise, 
statistical tests for the secondary endpoints will be presented solely for illustrative purposes. See section 
6.4.6. 
 
Subject data listings will also be provided. 
 
6.4.3  Exploratory Analysis 
 
The changes from baseline to 6 months in TC, TG, LDL-C and HDL-C levels as well as in hsCRP will be 
compared between treatment groups using an analysis of covariance (ANCOVA) adjusting for baseline 
value and for the two stratification factors ACS index event type and region. Specifically, the null and 
alternative hypotheses to be tested are:  


 
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H0: 'placebo = 'dalcetrapib vs. 
HA: 'placebo ≠ 'dalcetrapib 
 
where 'placebo is the change in the placebo group and 'dalcetrapib is the change in the dalcetrapib group. 
Estimates of treatment effect will be presented with 95% CI and p-values.  
 
Because it is expected that the distribution of hsCRP will be skewed, a log-transformation will be applied 
to hsCRP data prior to analysis. Geometric mean and geometric mean percent change will be added to 
the descriptive statistics that will be presented. 
 
Since these analyses are exploratory, a conservative baseline observation carried forward approach will 
be used in subjects with missing 6-month value. Subjects with no baseline value will be excluded from the 
analysis. 
 
6.4.4  Sub-population Analyses 
 
For illustrative purposes, the following factors  
x 
Region (Eastern Europe, Western Europe, North America, South America and other) 
x 
Age (< 65, ≥ 65 to < 75, ≥ 75 years) 
x 
Sex (Male, Female) 
x 
Diabetes reported at baseline (Yes, No) 
 
will be used to define subgroups of subjects within which the primary efficacy endpoints will be evaluated 
using non-stratified Cox proportional hazards models with a term for the treatment group, a term for the 
factor defining the subgroup and a term for the interaction between the factor and the treatment group. 
This interaction term will be tested at the 0.1 significance level and will determine whether the treatment 
effect is affected by the presence of the factor. In addition, under the proposed models, the treatment 
effect will be estimated and presented with 95% confidence intervals within subgroups.  
 
6.4.5  Additional Analysis 
 
6.4.5.1  Effect of HDL-C at baseline  
 
In order to characterize the potential treatment effect more precisely, an analysis of the primary endpoint 
will be conducted with the hazard ratio assumed to depend on, in addition to treatment, baseline HDL-C.  
  
Baseline HDL-C will be included in the stratified Cox proportional hazards model used for the primary 
analysis to provide an estimate of treatment effect that adjusts for HDL-C at baseline.  
 
6.4.5.2  Sensitivity Analysis and Robustness Checks 
 
If a statistically significant treatment effect is demonstrated in the analysis of the primary endpoint, the 
robustness of the results will be evaluated with respect to their potential dependence on the assumptions 
made.  
 


 
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1) The effect of censoring subjects who are lost to follow-up (while event-free), i.e. event-free 
subjects who do not have an end of study visit assessing efficacy endpoints after the start of the 
EOS visit window (common cut-off date), will be evaluated by imputing event outcomes for such 
subjects in the analysis. The following imputations rules will be considered. 
 
a. It will be assumed that an event has occurred shortly after censoring so an event will be 
imputed at the date of censoring in all event-free subjects who will not have an end of 
study visit assessing efficacy endpoints after the start of the EOS visit window. 
 
b. Imputed events will be based on a Weibull regression model that will be fitted to the 
subjects of the placebo group. This model will then be used to simulate a time to event in 
all event-free subjects (of both groups) who will not have an end of study visit assessing 
efficacy endpoints after the start of the EOS visit window (placebo-based imputation) [1]. 
If the simulated time to event is prior to the study cut-off date, it will be used as an 
imputed event. Otherwise, the subject will be censored at the study cut-off date. The 
entire process will be repeated by simulation and will generate multiple imputed 
datasets. On each imputed dataset, the Cox proportional hazards model used for the 
primary analysis will be applied and the resulting hazard ratios will be combined using 
Rubin’s rule [2]. 
 
c. The third approach will be similar to b) above. The imputed events will be based on the 
same Weibull regression model fitted to the subjects of the placebo group. However, 
instead of using the survival distribution of that model to simulate time to events in 
subjects of both groups, the hazard of event will be increased by a factor G (G > 1) when 
simulating time to events in dalcetrapib subjects (G-adjusted hazard imputation) [1]. No 
such increase will be considered when simulating time to events in placebo subjects. The 
factor G will be taken as the inverse of the expected hazard ratio (HR=0.78) and will be set 
to 1.3 [3]. As in b), the entire simulation process will be repeated and the resulting hazard 
ratios will be combined using Rubin’s rule. 
 
2) The primary analysis is based on a Cox proportional hazards model that assumes proportional 
hazards. The assessment of proportional hazard will be done by a visual inspection of the log-
negative-log plot and through a formal test of the interaction between time and group at the 0.05 
significance level. 
 
3) The consistency of treatment effect across ACS index event types will be tested using the 
interaction term in a non-stratified Cox regression model that will include treatment, ACS index 
event type and treatment by ACS index event type interaction as main effects. The interaction 
test will be considered as indicative of a potential interaction in this exploratory analysis if p < 0.1. 
Estimates of treatment effect will be reported separately by strata, along with confidence 
intervals. The same approach will be used to examine the consistency of treatment effect across 
regions. 
 
4) In the primary analysis, follow-up of primary efficacy endpoints will stop at the end of study visit. 
In other words, any primary efficacy endpoints collected between the end of study visit and the 
14-day safety follow-up phone call will still be adjudicated but not be included in primary analysis. 


 
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However, as a sensitivity analysis, the primary analysis will be repeated, using the same model as 
described in section 6.4.1, but will include all adjudicated events, including those occurring 
between the end of study visit and the 14-day safety follow-up phone call.  
 
6.4.5.3  Analysis Following the Initiation of the COVID-19 Pandemic 
 
In order to assess the impact of the COVID-19 pandemic on the primary endpoint, two additional analyses 
will be performed.  
 
1) Exclusion of primary events after the start of the COVID-19 pandemic 
 
The CEC reviewed all events occurring after the first reported case of COVID-19 in each 
participating country (generally the beginning of March, 2020). They assigned terms to each 
event, based on their clinical judgment, as to whether the event was (a) confirmed/related to 
COVID-19, (b) possibly related to COVID-19 or (c) not related to COVID-19. An exploratory analysis 
of the primary endpoint will be performed, excluding all events (a), and also excluding all events 
(a) or (b) from the definition of the primary endpoint as described below: 
 
a. The time from randomization to first occurrence of any component of the composite 
endpoint of CV death, resuscitated cardiac arrest, non-fatal MI or non-fatal stroke 
(primary endpoint), excluding adjudicated events confirmed/related to COVID-19, will 
be analysed using the same model as described in section 6.4.1.  
 
b. The time from randomization to first occurrence of any component of the composite 
endpoint of CV death, resuscitated cardiac arrest, non-fatal MI or non-fatal stroke 
(primary endpoint), excluding adjudicated events confirmed/related or possibly related 
to COVID-19, will be analysed using the same model as described in section 6.4.1.  
 
2) Censoring after SAE diagnosed by investigators as due to COVID-19 
 
Site Investigators were asked to report all serious adverse events related to COVID-19. Subjects in 
whom COVID-19-related SAEs occur will be censored at the time of the COVID-19-related SAE in 
an exploratory analysis of the primary endpoints as described below: 
 
The time from randomization to first occurrence of any component of the composite endpoint of 
CV death, resuscitated cardiac arrest, non-fatal MI or non-fatal stroke (primary endpoint), 
censoring event-free subjects who experienced a COVID-19-related SAE (“COVID” included in the 
SAE term) at the date of first occurrence of COVID-19-related SAE, will be analysed using the same 
model as described in section 6.4.1.  
 
6.4.5.4  Analysis Based on Exposure to Study Treatment 
 
Subjects who were off study treatment for an extended period of time may have a different risk profile as 
compared to the ITT population and two additional analyses will be performed to investigate the effect 
of exposure to study treatment.  
 


 
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1) Excluding events occurring 14 days after last dose of study treatment in subjects who discontinued 
study treatment prematurely 
 
The time from randomization to first occurrence of any component of the composite endpoint of 
CV death, resuscitated cardiac arrest, non-fatal MI or non-fatal stroke (primary endpoint) will be 
calculated as number of days between randomization and event in subjects with an event and 
event-free subjects will be censored at the date they were last known to be event free (as for the 
primary analysis). However, in subjects who discontinued treatment prematurely (i.e. who 
reported a study treatment discontinuation on the Treatment Inter/ Disc Form of the eCRF), any 
event occurring 14 days or more after date of last dose will not count as an event. The analysis 
will be conducted on all randomized subjects (no subject excluded) using the same model as 
described in section 6.4.1. 
 
2) Excluding subjects who discontinued study treatment prematurely and who had their first event 
at least 14 days after last dose of study treatment  
 
The time from randomization to first occurrence of any component of the composite endpoint of 
CV death, resuscitated cardiac arrest, non-fatal MI or non-fatal stroke (primary endpoint) will be 
calculated as number of days between randomization and event in subjects with an event and 
event-free subjects will be censored at the date they were last known to be event free (as for the 
primary analysis). However, subjects who discontinued treatment prematurely (i.e. who reported 
a study treatment discontinuation on the Treatment Inter/ Disc Form of the eCRF) and who had a 
first event occurring 14 days or more after last dose will be excluded. The analysis will not be 
conducted on all randomized subjects since some would be excluded but it will use the same 
model as described in section 6.4.1. 
 
6.4.6  Adjustment for multiplicity 
 
Statistical testing of the primary and secondary endpoints will be done hierarchically to control the type 
1 error rate at level 0.05. This will be done by testing the primary endpoint first and to test the secondary 
endpoints using the Hochberg procedure only if the primary analysis results in a significant treatment 
effect. Other analyses will be interpreted descriptively. The process is described below.  
 
Primary Hypotheses: 
 
The statistical hypotheses to be tested for the primary analysis are: 
H0: O = 1 vs. HA: O ≠ 1 
where O is the HR for the time to occurrence of the primary endpoint for the dalcetrapib and placebo 
groups. 
 
Secondary Hypotheses: 
 
The statistical hypotheses to be tested for the secondary analyses are: 
H0:S1: OS1 = 1 vs. HA:S1: OS1 ≠ 1 
H0:S2: OS2 = 1 vs. HA:S2: OS2 ≠ 1 
where  


 
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OS1 is the HR for time to occurrence of the first secondary endpoint (CV death, resuscitated cardiac arrest, 
non-fatal MI, non-fatal stroke, hospitalization for ACS [with ECG abnormalities], or unanticipated coronary 
revascularization)  
OS2 is the HR for time to occurrence of the second secondary endpoint (CV death, resuscitated cardiac 
arrest, non-fatal MI, non-fatal stroke, or hospitalization for new or worsening heart failure) 
 
Primary Analysis 
 
Reject H0 if p-value from the stratified Cox proportional hazards model is ≤ 0.05.   
 
Secondary Analyses 
 
If H0 is not rejected, the hypotheses for the secondary endpoints will not be formally tested. If H0 is 
rejected, the following rules will be applied:  
 
1. Order the p-values from the stratified Cox proportional hazards models of the secondary null 
hypotheses, H0:S1 and H0:S2, from largest to smallest. 
 
2. If the largest p-value is ≤ 0.05, reject both secondary null hypotheses.   
 
3. If the largest p-value is > 0.05 and the smallest p-value is ≤ 0.05/2 = 0.025, reject the secondary null 
hypotheses corresponding to the smallest p-value.   
 
4. Otherwise, reject none of the secondary null hypotheses H0:S1 and H0:S2. 
 
6.5  Safety Analysis 
 
All safety parameters will be summarized and presented in tables based on the ITT population. 
 
For the evaluations of adverse events and general laboratory data described below, neither tests of 
hypotheses nor estimates of treatment effects will be reported, unless otherwise specified. It is, however, 
anticipated that in some instances there will be numerical treatment differences in the reported summary 
statistics that are either of interest or concern; in these instances, more extensive exploratory statistical 
analyses may be performed. The scope of the analyses cannot be determined a priori, but would be 
expected to include standard regression methods for estimating relative risks such as odds and hazard 
ratios. 
 
6.5.1  Treatment Exposure 
 
Duration of treatment exposure will be defined as number of days on treatment (computed as described 
in 6.3.6).  Duration of treatment exposure will be summarized by treatment group using descriptive 
statistics. Duration of treatment exposure will also be categorized according to the following intervals (No 
exposure, 1-30, 31-182, 183-365, 366-730, 731-1095, and > 1095 days) and summarized accordingly using 
frequencies and percentages, by treatment group.  
 


 
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In addition, as a separate table, the number of subjects who had a permanent study treatment 
discontinuation will be summarized using frequencies and percentages, by treatment group.  
 
Information on treatment exposure, study treatment interruption and study treatment discontinuation 
will also be listed. 
 
6.5.2  Adverse Events and Serious Adverse Events 
 
In general, treatment groups will be compared with respect to the incidence of AEs and SAEs overall and 
by body system.  
 
6.5.2.1  Adverse Events 
 
Summary statistics will be presented by treatment arm for all treatment-emergent adverse events (TEAEs) 
and, in addition, by intensity [Mild, Moderate, Severe, Life-Threatening] and relationship to study 
medication as judged by the investigator [Not Related, Related]. A treatment-emergent AE will be defined 
as an AE with onset date on or after the date of randomization. For subjects experiencing repeated 
episodes, only the most severe episode and the episode with the strongest relationship will be reported. 
Summary statistics will include number and incidence of events where incidence of an event within a 
treatment group will be determined as the simple proportion of subjects in the group experiencing the 
event.  
 
Adverse events will be grouped and summarized by system organ class and preferred term as defined by 
the latest version of the Medical Dictionary for Regulatory Activities (MedDRA, version 19.1 or higher). 
 
All AEs will be included in subject data listings but only treatment-emergent AEs will be summarized.   
 
6.5.2.2  Serious Adverse Events 
 
SAEs will be summarized similarly to all TEAEs and presented in a subject data listing.  
 
6.5.2.3  Adverse Events Leading to Premature Drug or to Premature Study Withdrawal 
 
Adverse events leading to premature drug withdrawal and adverse events leading to premature study 
withdrawal will be summarized similarly to all TEAEs and presented in a subject data listing.  
 
6.5.2.4  Death 
 
A subject data listing for deaths will be provided.  
 
6.5.3  Laboratory Parameters 
 
For serum creatinine, treatments will be examined with respect to mean and median values over time 
using both actual values and changes from baseline. Descriptive statistics will be presented.  Although it 
is a safety endpoint, change from baseline to 6 months in HbA1c will be analyzed using an analysis of 
covariance model as the ones described in section 6.4.3.  
 


 
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Values entered as less than a specified value will be considered as the specified value divided by 2 (e.g. 
entered value <0.2 will be analyzed as 0.1). Values entered as BLQ (Below Limit of Quantification) will be 
considered as the limit of quantification divided by 2. 
 
Any adverse clinically significant changes in laboratory data, from randomization to trial completion, will 
be reported as an adverse event and will be included in the adverse event summary tables described in 
6.5.2.   
 
All laboratory results will be listed.  
 
6.5.4  Vital Signs 
 
For sitting diastolic and systolic blood pressure, as well as for pulse rate, treatments will be examined with 
respect to mean and median values over time using both actual values and changes from randomization. 
Descriptive statistics will be presented.  
 
Post-randomization vital signs assessments will be assigned to time points based on days from 
randomization and not on the scheduled visit at which the assessment was made. 
 
Any clinically significant changes in vital signs, from randomization to trial completion, will be reported as 
an adverse event and will be included in the adverse event summary tables described in 6.5.2. 
 
6.5.5  New Onset Diabetes 
 
Proportion of subjects with NOD will be compared between treatment groups using a Cochran-Mantel-
Haenszel test, accounting for the two stratification factors. This analysis will be done for the ITT 
population, among the subjects with no diabetes at baseline. 
 
6.5.6  COVID-19 Outbreak Impact 
 
Information on visits and study medication allocation impacted by COVID-19 outbreak is to be collected 
for each subject impacted. Collected data for impact on the visits includes: identification of the visit 
impacted, how that visit was conducted (on site or by phone) and visit timing with regard to planned visit 
time windows. Collected data for impact on study medication allocation includes: whether visit to allocate 
study medication was scheduled or not, how the study medication was dispensed to subject, date of 
assignment of study medication (as per IWRS) and number of kits dispensed. 
 
COVID-19 outbreak impact information will be presented in a subject data listing.  
 


 
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7. SUMMARY TABLES, FIGURES AND LISTINGS 
 
See the Table Shells document for the list of summary tables, figures and listings. 


 
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8  REFERENCES 
 
1. Lipkovich I, Ratitch B, O’Kelly M. Sensitivity to censored-at-random assumption in the analysis of time-
to-event endpoints. Pharmaceut. Statist., 2016, 15, 216-229. 
2. Rubin DB. Multiple imputation for nonresponse in surveys. John Wiley and Sons, Inc.: New York, 1987. 
3. Zhao Y, Herring AH, Zhou H, Ali MW, Koch GG. A multiple imputation method for sensitivity analyses of 
time-to-event data with possibly informative censoring. J Biopharm Stat., 2014, 24 229-253