| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stable CHD patients, with a documented recent Acute Coronary Syndrome (ACS) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007649 |
| E.1.2 | Term | Cardiovascular disorder |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this trial is to evaluate the potential of dalcetrapib to
reduce cardiovascular morbidity and mortality in stable CHD patients, with a
documented recent ACS. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of this trial are as listed below:
• Assessment of the long-term safety profile of dalcetrapib
• Evaluation of the effect of dalcetrapib on lipid metabolism and markers of
inflammation and oxidation |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients recently hospitalized for ACS (between 4 and 12 weeks after index event), and whose residual cardiovascular risk
may benefit from an increase in HDL-C as assessed by the investigator, will be enrolled in this trial. ACS is
defined as the occurrence of at least one of the following events:
Myocardial Infarction
- Spontaneous Myocardila Infarction
A diagnosis of a qualifying MI event will be defined by abnormal levels of cardiac biomarkers (troponin I or T or CK-MB mass) with at least one determination > the 99th percentile or upper limits of normal for the laboratory and at least
one of the following described below. Symptoms of myocardial ischemia within 48 hours prior to the MI
• New ECG findings (or presumed new if no prior ECG available) as described below
• Loss of viable myocardium based on imaging evidence of new or presumed new wall motion of perfusion deficit (eg. echocardiography, left ventriculography during cardiac catheterization radionuclide angiography, singlephoton
emission tomography, MRI)
Procedure-Related Myocardial Infarction after PCI
Patients experiencing a myocardial infarction after a PCI will also be included in this study. A procedure-related MI after PCI is defined as follows:
Normal biomarkers (eg. CK-MB or troponin I or T) before the procedure and biomarkers after procedure elevated to > 3 times the 99th percentile or upper limits of normal for the laboratory.
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:
• 50% stenosis of an epicardial coronary artery;
• positive exercise or pharmacologic stress indicating reversible ischemia;
or
• presence of pathologic Q-waves on ECG
Examples of New ECG findings include:
• New or presumed new ST depression > 0.5mm in 2 contiguous leads or T
wave inversion > 1mm in leads with predominant R wave or R/S >1 in 2
contiguous leads.
• New or presumed new ST elevation at the J point in ≥ 2 contiguous leads
with the 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 LBBB
• New tall R wave > 40ms in V1,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 > 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 patients able and willing to give written informed
consent.
2. Age 45 and over at Visit 1
3. Signed informed consent (approved by Institutional Review Board
[IRB]/Independent Ethics Committee [IEC]) obtained prior to any study
specific screening procedures
4. Clinically stable, ie, free of ischemic symptoms at rest or with minimal
exertion for at least 1 week prior to randomization
5. Triglycerides < 400 mg/dL (<4.5 mmol/L) at Visit 2
6. Evidence-based management of LDL-C cholesterol, at a minimum to include
medical and dietary treatment to a target level of <100 mg/dl (<2.6 mmol/L) by the time of randomization, and ideally to include medical and dietary treatment to a target level <70mg/dl (<1.8 mmol/L). Patients with an LDL-C level above > 100mg/dl may be randomized if they cannot reach the target goal of less than 100 mg/dl despite an intensive statin regimen, are on a maximum tolerated dose of statin as determined by the investigator, or are unable to tolerate statins. |
|
| E.4 | Principal exclusion criteria |
1. Females who are pregnant or breast-feeding
2. Women of child bearing potential (women who are not surgically sterile or
post-menopausal defined as amenorrhea for > 12 months) who are not using a highly contraceptive method (failure rates less than 1% per year) such as implants, injectibles, combined oral contraceptives or hormonal intrauterine devices (IUDs). In addition, a negative serum pregnancy test must be available before starting the run-in period.
3. Symptomatic (NYHA Class II or greater) congestive heart failure requiring
and persisting despite such treatment at the end of the run-in period. Patients with NYHA Class II heart failure symptoms may be included if a measurement of left ventricular function is performed and ejection fraction is shown to be > 40%.
4. Severe anemia defined as hemoglobin ≤ 10 g/L at Visit 2
5. Index ACS event presumed due to uncontrolled hypertension and/or systolic
blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg by
the end of the placebo run-in period despite anti-hypertensive therapy
6. Hemoglobin A1c >10% at Visit 2
7. Patients with clinically apparent liver disease, eg, jaundice, choleastasis,
hepatic synthetic impairment, or active hepatitis
8. Hepatic transaminase, alkaline phosphatase or total bilirubin levels >1.5 times
the ULN at the end of the run-in period.
9. Unexplained creatine phosphokinase levels >3 times the ULN at visit 2
10. Serum creatinine > 2.2 mg/dL (194.5 umol/l) at the end of the run-in period.
11. Concomitant treatment with niacin, fibrates, bile acid sequestrants, or
riminabant. Treatment with ezetimibe or fish oil derivatives is permitted.
12. Concomitant treatment with any drug other than dalcetrapib administered for
the purpose of increasing levels of HDL-C.
13. Previous exposure to torcetrapib or any other CETP inhibitor as for example
MK-859
14. History of malignancy (except for curatively treated basal cell or squamous
cell carcinoma of the skin) during the 3 years prior to the screening.
15. Any clinically significant medical condition that according to the investigator
could interfere with the conduct of the study.
16. Patients whose life expectancy is shorter than duration of the trial
17. Presence of any laboratory abnormality performed prior to randomization that
is considered by the investigator to be clinically important.
18. Current alcohol or drug abuse or history thereof within 5 years prior to
screening.
19. Patients exposed to RO4607381 within the last 12 months before the start of
this study
20. Subjects who have received any investigational drug or device within 1
month of visit 1, or who expect to participate in any other investigational drug
or device study during the conduct of this trial
21. Unable or unwilling to comply with protocol requirements, or deemed by the
investigator to be unfit for the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this study is the time to first occurrence of any
component of the composite event; as adjudicated by the Clinical Event
Committee (CEC). Components of the event are:
• Coronary heart disease death
• Major coronary events (nonfatal MI, ,hospitalization for ACS [ECG
abnormalities without biomarkers] and resuscitated cardiac arrest:)
• Stroke, fatal or non-fatal, of presumed atherothrombotic etiology |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 222 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the date of the last patient visit of the last patient 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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