Atherosclerosis
Conditions
Keywords
heart disease, Lp-PLA2 inhibitor, cardiovascular disease, coronary heart disease, CV risk, Atherosclerosis
Brief summary
This study will test whether darapladib can safely lower the chances of having a cardiovascular event (such as a heart attack or stroke) in people with coronary heart disease.
Detailed description
Subjects who qualify for the study will be randomized 1:1 to either darapladib or placebo administered in addition to standard therapy. Following the baseline visit, subjects will be expected to return for clinic visits at 1 month, 3 months, and every 6 months until the end of the study. Average time in the study for an individual subject is expected to be about 3 years.
Interventions
DRUGDarapladib
Lp-PLA2 inhibitor administered in addition to standard therapy
DRUGPlacebo
Placebo administered in addition to standard therapy
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men or women at least 18 years old. Women must be post-menopausal or using a highly effective method for avoidance of pregnancy. * Current treatment with statin therapy unless the study doctor determines statins are not appropriate for the subject. * Chronic coronary heart disease * At least one of the following: * At least 60 years old * Diabetes requiring treatment with medication * Low HDL cholesterol (good cholesterol) * Currently smoke cigarettes or stopped smoking within the past 3 months * Diagnosed mild or moderate reduction in kidney function * Cerebrovascular disease (carotid artery disease or ischemic stroke more than 3 months prior to study entry) OR peripheral arterial disease.
Exclusion criteria
* Planned coronary revascularization (such as stent placement or heart bypass) or any other major surgical procedure. * Liver disease * Severe reduction in kidney function OR removal of a kidney OR kidney transplant * Severe heart failure * Blood pressure higher than normal despite lifestyle changes and treatment with medications * Any life-threatening disease expected to result in death within the next 2 years (other than heart disease) * Severe asthma that is poorly controlled with medication * Pregnant (Note: A pregnancy test will be performed on all non-sterile women prior to study entry) * Previous severe allergic response to food, drink, insect stings, etc. * Drug or alcohol abuse within the past 6 months OR mental/psychological impairment that may prevent the subject from complying with study procedures or understanding the goal and potential risks of participating in the study. * Certain medications that may interfere with the study medication (these will be identified by the study doctor) * Participation in a study of an investigational medication within the past 30 days * Current participation in a study of an investigational device
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With First Occurrence of Any Component of the Composite of Major Adverse Cardiovascular Events (Cardiovascular [CV] Death, Non-fatal Myocardial Infarction [MI] or Non-fatal Stroke) During the Time Period for Follow-up of CV Events | From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years) | CV death=death due to a CV cause, which included but was not limited to deaths resulting from stroke, arrhythmia, sudden death (witnessed/unwitnessed), MI, heart failure, pulmonary embolism, peripheral arterial disease, or complications of a CV procedure. Deaths not clearly attributable to non-CV causes are considered to be CV deaths. Acute MI=evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Prior MI diagnosed post-randomization (e.g., silent MI)=the development of new pathological Q waves with/without symptoms OR imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause (pre-event imaging data required for verification of new abnormality), OR pathological findings of a healed/healing MI. Stroke=presence of a new focal neurologic deficit thought to be of vascular origin, with signs/symptoms lasting \>24 hours or results in death (in \<24 hours). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With First Occurrence of Any Event in the Composite of Total Coronary Events (CHD Death, Non-fatal MI, Hospitalization for Unstable Angina, or Any Coronary Revascularization Procedure) During Time Period for FU of CV Events | From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years) | CHD death, acute MI, and prior MI are defined in the previous secondary endpoint (major coronary events). Hospitalization for unstable angina=one of the following, but not fulfilling the criteria for MI: ischemic discomfort at rest associated with electrocardiogram (ECG) changes leading to hospitalization; ischemic discomfort at rest regardless of ECG changes leading to hospitalization and revascularization during the same admission; ischemic discomfort at rest in hospital associated with ECG changes; ischemic discomfort at rest in hospital without ECG changes resulting in revascularization during the same admission. NOTE: The event was not considered to be unstable angina if, after invasive/non-invasive testing or other diagnostic testing, the discomfort is found not to be caused by myocardial ischemia. |
| Number of Participants With CV Death During the Time Period for Follow-up of CV Events | From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years) | CV death is defined as a death due to a CV cause, which included but was not limited to deaths resulting from stroke, arrhythmia, sudden death (witnessed/unwitnessed), MI, heart failure, pulmonary embolism, peripheral arterial disease, or complications of a CV procedure. Deaths not clearly attributable to non-CV causes are considered to be CV deaths. |
| Number of Participants With First Occurrence of MI (Fatal/Non-fatal) During the Time Period for Follow-up of CV Events | From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years) | Acute MI is defined as evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Prior MI diagnosed post-randomization (e.g., silent MI)=the development of new pathological Q waves with/without symptoms OR imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause (pre-event imaging data required for verification of new abnormality), OR pathological findings of a healed/healing MI. |
| Number of Participants With First Occurrence of Any Event in the Composite of Major Coronary Events (Coronary Heart Disease [CHD] Death, Non-fatal MI, or Urgent Coronary Revascularization [CR] for MI) During the Time Period for Follow-up (FU) of CV Events | From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years) | CHD death=occurrence of a fatal MI, death caused by documented cardiac arrest, death resulting from heart failure in a participant with known CHD, death from other forms of acute/chronic CHD, unwitnessed death of unknown origin, or sudden death. Acute MI=evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Prior MI diagnosed post-randomization (e.g.,silent MI)=the development of new pathological Q waves with/without symptoms OR imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause (pre-event imaging data required for verification of new abnormality), OR pathological findings of a healed/healing MI. Urgent CR for MI=ischemic discomfort at rest that prompted CR (percutaneous coronary intervention \[PCI: any attempt at CR even if not successful\] or coronary artery bypass graft) during the same hospitalization or resulted in hospital transfer for the purpose of CR. |
| Number of Participants With First Occurrence of Any Component of the Composite of All-cause Mortality, Non-fatal MI, or Non-fatal Stroke During the Time Period for Follow-up of CV Events | From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years) | Acute MI is defined as evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Prior MI diagnosed post-randomization (e.g., silent MI)=the development of new pathological Q waves with/without symptoms OR imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause (pre-event imaging data required for verification of new abnormality), OR pathological findings of a healed/healing MI. Stroke=presence of a new focal neurologic deficit thought to be of vascular origin, with signs/symptoms lasting \>24 hours or results in death (in \<24 hours). |
| Number of Participants With All-cause Mortality During the Time Period for Vital Status | From randomization until death or study completion (up to 4.49 years/average of 3.65 years) | The number of participants with all-cause mortality was assessed. |
| Number of Participants With First Occurrence of Stroke (Fatal/Non-fatal) During the Time Period for Follow-up of CV Events | From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years) | Stroke is defined as the presence of a new focal neurologic deficit thought to be of vascular origin, with signs/symptoms lasting \>24 hours or results in death (in \<24 hours). |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Czechia, Denmark, Estonia, France, Germany, Greece, Hong Kong, Hungary, India, Italy, Japan, Mexico, Netherlands, New Zealand, Norway, Pakistan, Peru, Philippines, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study consisted of a Screening Phase of up to 8 weeks duration, a Treatment Phase, an End-of-Treatment (EOT) visit, and a Follow-up visit scheduled for 35 +/- 7 days after last study drug intake. The median treatment duration was anticipated to be 2.75 years.
Pre-assignment details
During the Screening Phase of the study, participants presenting with chronic Coronary Heart Disease (CHD) were randomized within 8 weeks. In addition to chronic CHD, participants were required to have at least one additional predictor of cardiovascular risk specified in the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive matching placebo once daily. | 7,904 |
| Darapladib Participants were randomized to receive darapladib 160 milligram (mg) enteric-coated tablets once daily. | 7,924 |
| Total | 15,828 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Investigator Site Closed | 25 | 23 |
| Overall Study | Lost to Follow-up | 69 | 80 |
| Overall Study | Withdrawal by Subject | 179 | 175 |
Baseline characteristics
| Characteristic | Darapladib | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 64.5 years STANDARD_DEVIATION 9.31 | 64.4 years STANDARD_DEVIATION 9.35 | 64.3 years STANDARD_DEVIATION 9.39 |
| Race (NIH/OMB) American Indian or Alaska Native | 106 Participants | 214 Participants | 108 Participants |
| Race (NIH/OMB) Asian | 1351 Participants | 2717 Participants | 1366 Participants |
| Race (NIH/OMB) Black or African American | 175 Participants | 366 Participants | 191 Participants |
| Race (NIH/OMB) More than one race | 55 Participants | 106 Participants | 51 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants | 15 Participants | 11 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6233 Participants | 12410 Participants | 6177 Participants |
| Sex: Female, Male Female | 1461 Participants | 2967 Participants | 1506 Participants |
| Sex: Female, Male Male | 6463 Participants | 12861 Participants | 6398 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 577 / 7,904 | 582 / 7,924 |
| other Total, other adverse events | 4,885 / 7,890 | 5,171 / 7,912 |
| serious Total, serious adverse events | 3,448 / 7,890 | 3,369 / 7,912 |
Outcome results
Primary
Number of Participants With First Occurrence of Any Component of the Composite of Major Adverse Cardiovascular Events (Cardiovascular [CV] Death, Non-fatal Myocardial Infarction [MI] or Non-fatal Stroke) During the Time Period for Follow-up of CV Events
CV death=death due to a CV cause, which included but was not limited to deaths resulting from stroke, arrhythmia, sudden death (witnessed/unwitnessed), MI, heart failure, pulmonary embolism, peripheral arterial disease, or complications of a CV procedure. Deaths not clearly attributable to non-CV causes are considered to be CV deaths. Acute MI=evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Prior MI diagnosed post-randomization (e.g., silent MI)=the development of new pathological Q waves with/without symptoms OR imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause (pre-event imaging data required for verification of new abnormality), OR pathological findings of a healed/healing MI. Stroke=presence of a new focal neurologic deficit thought to be of vascular origin, with signs/symptoms lasting \>24 hours or results in death (in \<24 hours).
Time frame: From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years)
Population: All-randomized Intent-to-treat (ITT) population comprised of all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With First Occurrence of Any Component of the Composite of Major Adverse Cardiovascular Events (Cardiovascular [CV] Death, Non-fatal Myocardial Infarction [MI] or Non-fatal Stroke) During the Time Period for Follow-up of CV Events | 819 Participants |
| Darapladib | Number of Participants With First Occurrence of Any Component of the Composite of Major Adverse Cardiovascular Events (Cardiovascular [CV] Death, Non-fatal Myocardial Infarction [MI] or Non-fatal Stroke) During the Time Period for Follow-up of CV Events | 769 Participants |
p-value: 0.19995.1% CI: [0.85, 1.03]Regression, Cox
Secondary
Number of Participants With All-cause Mortality During the Time Period for Vital Status
The number of participants with all-cause mortality was assessed.
Time frame: From randomization until death or study completion (up to 4.49 years/average of 3.65 years)
Population: All Randomized (ITT) Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With All-cause Mortality During the Time Period for Vital Status | 577 Participants |
| Darapladib | Number of Participants With All-cause Mortality During the Time Period for Vital Status | 582 Participants |
p-value: 0.8795% CI: [0.9, 1.13]Regression, Cox
Secondary
Number of Participants With CV Death During the Time Period for Follow-up of CV Events
CV death is defined as a death due to a CV cause, which included but was not limited to deaths resulting from stroke, arrhythmia, sudden death (witnessed/unwitnessed), MI, heart failure, pulmonary embolism, peripheral arterial disease, or complications of a CV procedure. Deaths not clearly attributable to non-CV causes are considered to be CV deaths.
Time frame: From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years)
Population: All Randomized (ITT) Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With CV Death During the Time Period for Follow-up of CV Events | 373 Participants |
| Darapladib | Number of Participants With CV Death During the Time Period for Follow-up of CV Events | 359 Participants |
p-value: 0.59495% CI: [0.83, 1.11]Regression, Cox
Secondary
Number of Participants With First Occurrence of Any Component of the Composite of All-cause Mortality, Non-fatal MI, or Non-fatal Stroke During the Time Period for Follow-up of CV Events
Acute MI is defined as evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Prior MI diagnosed post-randomization (e.g., silent MI)=the development of new pathological Q waves with/without symptoms OR imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause (pre-event imaging data required for verification of new abnormality), OR pathological findings of a healed/healing MI. Stroke=presence of a new focal neurologic deficit thought to be of vascular origin, with signs/symptoms lasting \>24 hours or results in death (in \<24 hours).
Time frame: From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years)
Population: All Randomized (ITT) Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With First Occurrence of Any Component of the Composite of All-cause Mortality, Non-fatal MI, or Non-fatal Stroke During the Time Period for Follow-up of CV Events | 962 Participants |
| Darapladib | Number of Participants With First Occurrence of Any Component of the Composite of All-cause Mortality, Non-fatal MI, or Non-fatal Stroke During the Time Period for Follow-up of CV Events | 926 Participants |
p-value: 0.39795% CI: [0.88, 1.05]Regression, Cox
Secondary
Number of Participants With First Occurrence of Any Event in the Composite of Major Coronary Events (Coronary Heart Disease [CHD] Death, Non-fatal MI, or Urgent Coronary Revascularization [CR] for MI) During the Time Period for Follow-up (FU) of CV Events
CHD death=occurrence of a fatal MI, death caused by documented cardiac arrest, death resulting from heart failure in a participant with known CHD, death from other forms of acute/chronic CHD, unwitnessed death of unknown origin, or sudden death. Acute MI=evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Prior MI diagnosed post-randomization (e.g.,silent MI)=the development of new pathological Q waves with/without symptoms OR imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause (pre-event imaging data required for verification of new abnormality), OR pathological findings of a healed/healing MI. Urgent CR for MI=ischemic discomfort at rest that prompted CR (percutaneous coronary intervention \[PCI: any attempt at CR even if not successful\] or coronary artery bypass graft) during the same hospitalization or resulted in hospital transfer for the purpose of CR.
Time frame: From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years)
Population: All Randomized (ITT) Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With First Occurrence of Any Event in the Composite of Major Coronary Events (Coronary Heart Disease [CHD] Death, Non-fatal MI, or Urgent Coronary Revascularization [CR] for MI) During the Time Period for Follow-up (FU) of CV Events | 814 Participants |
| Darapladib | Number of Participants With First Occurrence of Any Event in the Composite of Major Coronary Events (Coronary Heart Disease [CHD] Death, Non-fatal MI, or Urgent Coronary Revascularization [CR] for MI) During the Time Period for Follow-up (FU) of CV Events | 737 Participants |
p-value: 0.04595% CI: [0.82, 1]Regression, Cox
Secondary
Number of Participants With First Occurrence of Any Event in the Composite of Total Coronary Events (CHD Death, Non-fatal MI, Hospitalization for Unstable Angina, or Any Coronary Revascularization Procedure) During Time Period for FU of CV Events
CHD death, acute MI, and prior MI are defined in the previous secondary endpoint (major coronary events). Hospitalization for unstable angina=one of the following, but not fulfilling the criteria for MI: ischemic discomfort at rest associated with electrocardiogram (ECG) changes leading to hospitalization; ischemic discomfort at rest regardless of ECG changes leading to hospitalization and revascularization during the same admission; ischemic discomfort at rest in hospital associated with ECG changes; ischemic discomfort at rest in hospital without ECG changes resulting in revascularization during the same admission. NOTE: The event was not considered to be unstable angina if, after invasive/non-invasive testing or other diagnostic testing, the discomfort is found not to be caused by myocardial ischemia.
Time frame: From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years)
Population: All Randomized (ITT) Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With First Occurrence of Any Event in the Composite of Total Coronary Events (CHD Death, Non-fatal MI, Hospitalization for Unstable Angina, or Any Coronary Revascularization Procedure) During Time Period for FU of CV Events | 1269 Participants |
| Darapladib | Number of Participants With First Occurrence of Any Event in the Composite of Total Coronary Events (CHD Death, Non-fatal MI, Hospitalization for Unstable Angina, or Any Coronary Revascularization Procedure) During Time Period for FU of CV Events | 1159 Participants |
p-value: 0.01995% CI: [0.84, 0.98]Regression, Cox
Secondary
Number of Participants With First Occurrence of MI (Fatal/Non-fatal) During the Time Period for Follow-up of CV Events
Acute MI is defined as evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Prior MI diagnosed post-randomization (e.g., silent MI)=the development of new pathological Q waves with/without symptoms OR imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause (pre-event imaging data required for verification of new abnormality), OR pathological findings of a healed/healing MI.
Time frame: From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years)
Population: All Randomized (ITT) Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With First Occurrence of MI (Fatal/Non-fatal) During the Time Period for Follow-up of CV Events | 405 Participants |
| Darapladib | Number of Participants With First Occurrence of MI (Fatal/Non-fatal) During the Time Period for Follow-up of CV Events | 361 Participants |
p-value: 0.10895% CI: [0.77, 1.03]Regression, Cox
Secondary
Number of Participants With First Occurrence of Stroke (Fatal/Non-fatal) During the Time Period for Follow-up of CV Events
Stroke is defined as the presence of a new focal neurologic deficit thought to be of vascular origin, with signs/symptoms lasting \>24 hours or results in death (in \<24 hours).
Time frame: From randomization until the End-of-Treatment visit or the last date on which endpoints were able to be assessed (up to 4.25 years/average of 3.51 years)
Population: All Randomized (ITT) Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With First Occurrence of Stroke (Fatal/Non-fatal) During the Time Period for Follow-up of CV Events | 152 Participants |
| Darapladib | Number of Participants With First Occurrence of Stroke (Fatal/Non-fatal) During the Time Period for Follow-up of CV Events | 154 Participants |
p-value: 0.9295% CI: [0.81, 1.27]Regression, Cox