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Events such as myocardial infarction (heart attack) or the need for a revascularization procedure (implantation of a stent in a coronary artery) are signs of severe arterial disease. Events such as these are often referred to as Acute Coronary Syndrome (ACS).  

In general, patients who have experienced an ACS event may receive different medications such as blood thinning medication, drugs to control blood pressure drugs that help to lower cholesterol levels and medication to control blood sugar in diabetics. Nevertheless, there still remains a considerable risk of experiencing another event such as those described above. In this study, we will evaluate whether or not the study drug, dalcetrapib can reduce the risk for another event.  Should you choose to participate, you will continue to take all other medications that your doctor has prescribed for your condition while you are in this study.

Genes hold the necessary instructions to develop all living organisms and are contained in DNA. Most of the DNA is identical between human beings but the small differences that we all have, make each individual unique, for example, our height or the color of our eyes. These types of differences could also explain why some people respond differently to the same drug.

Dalcetrapib is an investigational drug that has been evaluated in several large clinical trials, including dal-OUTCOMES, a study of over 15,000 patients which evaluated its effect in patients with recent ACS. The results of this large study demonstrated that treatment with dalcetrapib did not change the risk of cardiovascular disease in the majority of patients with recent ACS. However, after the study was over, researchers identified a group of patients that had a significant benefit. This group of patients who had a particular variant (AA) of a gene that all humans share, adenylate cyclase type 9 (ADCY9), had their risk of having another cardiovascular event reduced by 39%. Approximately 1 in 5 patients studied had this genetic variant.

A different variant (GG) found in roughly 2 in 5 patients was associated with a 27% increase in risk for a cardiovascular event in patients taking dalcetrapib. There was no difference in other safety or tolerability findings between these groups.

The recently completed dal-GenE study, a clinical trial of over 6,000 patients, evaluated the effects of dalcetrapib in patients with recent ACS and the AA genetic variant. The results of this large study demonstrated that treatment with dalcetrapib did not change the risk of having another cardiovascular event in the majority of patients with recent ACS. However, an analysis was performed which indicated that the COVID-19 pandemic may have impacted the accuracy of this data. When the results collected before the start of the COVID-19 pandemic were evaluated, certain analyses showed that taking dalcetrapib corresponded to a reduction in chance of experiencing a myocardial infarction (heart attack) when compared to those taking placebo (dummy drug). The goal of the present study is to evaluate the effect of dalcetrapib only in patients with the AA genetic variant to confirm these findings of cardiovascular benefit.

Inclusion Criteria:

Myocardial Infarction

Spontaneous Myocardial Infarction (Types 1, 2 and 3)

A diagnosis of a qualifying MI event will be defined as when there is acute myocardial injury with clinical evidence of acute myocardial ischaemia and with detection of 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 ischaemia;
• New ischaemic ECG changes;
• Development of pathological Q waves;

• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology;
• Identification of a coronary thrombus by angiography or autopsy (not for types 2 or 3 MIs).

Patients who experience acute MI secondary to non-atherosclerotic or non-embolic conditions such as vasospasm, spontaneous coronary artery dissection and demand ischemia will not be eligible for inclusion in the study.

Procedure-Related Myocardial Infarction after Percutaneous Coronary Intervention (PCI) (Type 4a)

Percutaneous coronary intervention (PCI) related MI is termed type 4a MI.

Coronary procedure-related MI ≤ 48 hours after the index procedure is arbitrarily defined by an elevation of cTn values > 5 times of the 99th percentile URL in patients with normal baseline values. Patients with elevated pre-procedural cTn values, in whom the pre-procedural cTn level are stable (≤ 20% variation) or falling, must meet the criteria for a > 5 increase and manifest a change from the baseline value of > 20%. In addition with at least one of the following:

• New ischaemic ECG changes;

• Development of new pathological Q waves;

• Imaging evidence of loss of viable myocardium that is presumed to be new and in a pattern consistent with an ischaemic aetiology;

• Angiographic findings consistent with a procedural flow-limiting complication such as coronary dissection, occlusion of a major epicardial artery or graft, side-branch occlusion-thrombus, disruption of collateral flow or distal embolization.

Isolated development of new pathological Q waves meets the type 4a MI criteria with either revascularization procedure if cTn values are elevated and rising but less than the pre-specified thresholds for PCI.

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
• 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. Separate consent forms will be allowed for genetic screening and for full study participation.

3. AA genotype at variant rs 1967309 in the ADCY9 gene as determined by the investigational use only version of the cobas® ADCY9 Genotype Test, 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 including completion of all planned revascularization procedures prior to randomization5. Prior to randomization, subject must have evidence of guidelines-based management of LDL-C, at a minimum to include medical and dietary treatment.

6. Randomization within 3 months of the index ACS event

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 highly effective method of contraception with a failure rate of <1%. These are defined as hormonal contraception associated with inhibition of ovulation, intrauterine devices (IUD), intrauterine hormone-releasing system ( IUS), bilateral tubal occlusion, vasectomised partner and sexual abstinence for the full duration of the study where abstinence is the preferred and usual lifestyle of the subject..

3. New York Heart Association (NYHA) Class III or IV heart failure

4. Index ACS event presumed due to uncontrolled hypertension

5. Systolic blood pressure (BP) >180 mmHg and/or diastolic blood pressure >110 mmHg at the time of randomization despite anti-hypertensive therapy

6. Subjects with clinically apparent liver disease, eg, jaundice, cholestasis, hepatic synthetic impairment, or active hepatitis or last known ALT or AST >3x ULN as assessed within 6 months prior to randomization (excluding index event)

7. History of persistent and unexplained creatine phosphokinase (CPK) levels > 5 times the ULN as assessed within 6 months prior to randomization (excluding index event)

8. Last known eGFR < 30 mL/min/1.73m2 as assessed within 6 months prior to randomization

9. History of malignancy or any other significant comorbidity, the prognosis or management of which is likely to interfere with study conduct or subjects with a life expectancy of less than 3 years

10. 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

11. Current alcohol or drug abuse or history thereof within 2 years prior to screening that would likely interfere with compliance, based on investigator assessment

12. 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

13. Subjects unable or unwilling to comply with protocol requirements, or deemed by the investigator to be unfit for the study

14. Subjects who have undergone coronary artery bypass graft (CABG) between the index event and randomization