A phase III, double-blind, randomized placebo-controlled study to evaluate the effects of dacetrapib on cardiovascular (CV) risk in a genetically defined population with a recent Acute Coronary Syndrome (ACS): The dal-GenE trial

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:
A) 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:
a. Symptoms of myocardial ischemia, or
b. New or presumed new significant ST-segment-T wave (ST-T) changes or new left
bundle branch block, or
c. Development of pathological Q waves in the ECG, or
d. Imaging evidence of new loss of viable myocardium or new regional wall
motion abnormality, or
e. 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:
a. Symptoms suggestive of myocardial ischemia
b. New ischemic ECG changes
c. Imaging demonstration of new loss of viable myocardium or new regional wall
motion abnormality
d. Angiographic findings consistent with a procedural complication
B) 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 23hrs) with
symptoms presumed to be caused by myocardial ischemia with an accelerating
tempo in the prior 48hrs and/or prolonged (at least 20min) 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:
a. At least 50% stenosis of an epicardial coronary artery
b. Positive exercise or pharmacologic stress indicating reversible ischemia
c. Presence of pathologic Q-waves on ECG
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 obtained prior to any study specific screening
procedures
3. AA genotype at variant rs1967309 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 <100mg/dl (<2.6mmol/L). Subjects with an LDL-C level
*100mg/dl (*2.6mmol/L) may be randomized if they cannot reach the target goal
of less than 100mg/dl despite lipid-lowering regimen, or are unable to tolerate
lipid-lowering regimen.

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 child-bearing 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 <10g/dl
5. Index ACS event presumed due to uncontrolled hypertension
6. Systolic blood pressure (BP) >180mmHg and/or diastolic blood pressure
>110mmHg by the time of randomization despite anti-hypertensive therapy
7. Last known serum triglyceride level >500mg/dl (>5.65mmol/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 > 2.2mg/dl (195*mol/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) surgery
between the index event and randomization