Acute Coronary Syndrome
Conditions
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.
Interventions
DRUGdalcetrapib
Cholesterol Ester Transfer Protein inhibitor
DRUGPlacebo
matching placebo tablets
Sponsors
The Montreal Health Innovations Coordinating Center (MHICC)
Medpace, Inc.
Roche Molecular Systems, Inc
DalCor Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with the appropriate genetic background and recently hospitalized for ACS (between 4 and 12 weeks following the index event), will be enrolled in this trial. * AA genotype at variant gene as determined by Genotype Assay testing, conducted at a designated investigational testing site (ITS) * Clinically stable, ie, free of ischemic symptoms at rest or with minimal exertion for at least 1 week prior to randomization * 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).
Exclusion criteria
* Females who are pregnant (negative pregnancy test required for all women of child-bearing potential at Visit 2, Day 0) or breast-feeding * 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\* * New York Heart Association (NYHA) Class III or IV heart failure * Last known hemoglobin \<10 g/dL * Index ACS event presumed due to uncontrolled hypertension (\*) Varies by region
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, and Non-Fatal Stroke | From randomization to the first occurrence of any component of the composite primary endpoint (median duration of follow-up was 39.9 months) | All efficacy endpoints were adjudicated by an independent clinical endpoint committee (CEC). The primary efficacy endpoint was the time from randomization to the first occurrence of any component of the composite endpoint, which included death from cardiovascular causes, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke, as positively adjudicated by the CEC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Endpoint of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, Non-Fatal Stroke, Hospitalization for ACS (With Electrocardiogram Abnormalities) or Unanticipated Coronary Revascularization | From randomization to the first occurrence of any component of the composite secondary endpoint (median duration of follow-up was 39.9 months) | All efficacy endpoints were adjudicated by an independent clinical endpoint committee (CEC). The primary efficacy endpoint was the time from randomization to the first occurrence of any component of the composite endpoint, which included death from cardiovascular causes, resuscitated cardiac arrest, non-fatal myocardial infarction, non-fatal stroke, hospitalization for acute coronary syndrome (with electrocardiogram abnormalities) or unanticipated coronary revascularization, as positively adjudicated by the CEC. |
| Composite Endpoint of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, Non-Fatal Stroke or Hospitalization for New or Worsening Heart Failure | From randomization to the first occurrence of any component of the composite secondary endpoint (median duration of follow-up was 39.9 months) | All efficacy endpoints were adjudicated by an independent clinical endpoint committee (CEC). The secondary efficacy endpoint was the time from randomization to the first occurrence of any component of the composite secondary endpoint, which included death from cardiovascular causes, cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for new or worsening heart failure, as positively adjudicated by the CEC. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Puerto Rico, Romania, Russia, Slovakia, South Africa, Spain, Sweden, Switzerland, Turkey (Türkiye), United Arab Emirates, United Kingdom, United States
Participant flow
Recruitment details
Trial enrolment began in April 2016 and was completed in December 2018. A total of 45,005 patients with recent acute coronary syndrome were screened in order to identify participants meeting the single genetic criterion (AA genotype at rs1967309 in the ADCY9 gene) and other inclusion criteria and no exclusion criteria required for randomization.
Pre-assignment details
A total of 6149 eligible patients underwent randomization, among whom two were randomized by error and excluded.
Participants by arm
| Arm | Count |
|---|---|
| Dalcetrapib Participants received dalcetrapib 600 mg (two 300 mg tablets) orally once daily.
dalcetrapib: Cholesterol Ester Transfer Protein inhibitor, 300 mg tablets | 3,071 |
| Placebo Participants received dalcetrapib placebo tablets matching dalcetrapib orally once daily.
Placebo: dalcetrapib matching placebo tablets | 3,076 |
| Total | 6,147 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 180 | 179 |
| Overall Study | Lost to Follow-up | 27 | 24 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 24 | 39 |
Baseline characteristics
| Characteristic | Placebo | Total | Dalcetrapib |
|---|---|---|---|
| Acute Coronary Syndrome (ACS) Index Event Details: Hospitalization duration | 6.22 days STANDARD_DEVIATION 5.03 | 6.14 days STANDARD_DEVIATION 4.69 | 6.06 days STANDARD_DEVIATION 4.33 |
| Acute Coronary Syndrome (ACS) Index Event Details: Time since ACS index event | 54.01 days STANDARD_DEVIATION 18.31 | 53.91 days STANDARD_DEVIATION 18.2 | 53.82 days STANDARD_DEVIATION 18.09 |
| Acute Coronary Syndrome (ACS) Index Event Diagnosis Hospitalization for Acute Coronary Syndrome (Electrocardiogram abnormalities without biomarkers) | 306 Participants | 601 Participants | 295 Participants |
| Acute Coronary Syndrome (ACS) Index Event Diagnosis Procedure-related Myocardial Infarction (MI) after Percutaneous Coronary Intervention (PCI) | 28 Participants | 48 Participants | 20 Participants |
| Acute Coronary Syndrome (ACS) Index Event Diagnosis Spontaneous Myocardial Infarction (MI) | 2742 Participants | 5498 Participants | 2756 Participants |
| Acute Coronary Syndrome (ACS) Index Event Diagnosis: Second ACS event since qualifying index event No | 3008 Participants | 6006 Participants | 2998 Participants |
| Acute Coronary Syndrome (ACS) Index Event Diagnosis: Second ACS event since qualifying index event Yes | 68 Participants | 141 Participants | 73 Participants |
| Age, Continuous | 62.34 years STANDARD_DEVIATION 9.25 | 62.26 years STANDARD_DEVIATION 9.21 | 62.19 years STANDARD_DEVIATION 9.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 469 Participants | 938 Participants | 469 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2550 Participants | 5101 Participants | 2551 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 57 Participants | 108 Participants | 51 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 12 Participants | 23 Participants | 11 Participants |
| Race (NIH/OMB) Asian | 59 Participants | 117 Participants | 58 Participants |
| Race (NIH/OMB) Black or African American | 123 Participants | 253 Participants | 130 Participants |
| Race (NIH/OMB) More than one race | 68 Participants | 153 Participants | 85 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 15 Participants | 30 Participants | 15 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 2798 Participants | 5569 Participants | 2771 Participants |
| Region of Enrollment Argentina | 74 participants | 148 participants | 74 participants |
| Region of Enrollment Australia | 102 participants | 202 participants | 100 participants |
| Region of Enrollment Austria | 27 participants | 50 participants | 23 participants |
| Region of Enrollment Belgium | 17 participants | 39 participants | 22 participants |
| Region of Enrollment Brazil | 213 participants | 431 participants | 218 participants |
| Region of Enrollment Bulgaria | 185 participants | 386 participants | 201 participants |
| Region of Enrollment Canada | 228 participants | 437 participants | 209 participants |
| Region of Enrollment Chile | 50 participants | 94 participants | 44 participants |
| Region of Enrollment Czechia | 78 participants | 151 participants | 73 participants |
| Region of Enrollment Denmark | 71 participants | 137 participants | 66 participants |
| Region of Enrollment Finland | 11 participants | 20 participants | 9 participants |
| Region of Enrollment France | 50 participants | 99 participants | 49 participants |
| Region of Enrollment Germany | 41 participants | 69 participants | 28 participants |
| Region of Enrollment Hungary | 101 participants | 183 participants | 82 participants |
| Region of Enrollment Israel | 175 participants | 373 participants | 198 participants |
| Region of Enrollment Italy | 54 participants | 123 participants | 69 participants |
| Region of Enrollment Netherlands | 147 participants | 276 participants | 129 participants |
| Region of Enrollment New Zealand | 74 participants | 149 participants | 75 participants |
| Region of Enrollment Poland | 169 participants | 335 participants | 166 participants |
| Region of Enrollment Portugal | 27 participants | 54 participants | 27 participants |
| Region of Enrollment Puerto Rico | 4 participants | 14 participants | 10 participants |
| Region of Enrollment Romania | 87 participants | 179 participants | 92 participants |
| Region of Enrollment Russia | 240 participants | 455 participants | 215 participants |
| Region of Enrollment Slovakia | 27 participants | 48 participants | 21 participants |
| Region of Enrollment South Africa | 101 participants | 222 participants | 121 participants |
| Region of Enrollment Spain | 104 participants | 188 participants | 84 participants |
| Region of Enrollment Sweden | 30 participants | 65 participants | 35 participants |
| Region of Enrollment Switzerland | 15 participants | 36 participants | 21 participants |
| Region of Enrollment Turkey | 26 participants | 57 participants | 31 participants |
| Region of Enrollment United Arab Emirates | 7 participants | 16 participants | 9 participants |
| Region of Enrollment United Kingdom | 183 participants | 383 participants | 200 participants |
| Region of Enrollment United States | 358 participants | 728 participants | 370 participants |
| Reproductive status if female Childbearing potential with double contraceptive protection | 24 Participants | 48 Participants | 24 Participants |
| Reproductive status if female Childbearing potential without double contraceptive potential | 1 Participants | 2 Participants | 1 Participants |
| Reproductive status if female Other | 3 Participants | 7 Participants | 4 Participants |
| Reproductive status if female Postmenopausal | 584 Participants | 1186 Participants | 602 Participants |
| Reproductive status if female Surgically sterilized | 60 Participants | 152 Participants | 92 Participants |
| Sex: Female, Male Female | 672 Participants | 1395 Participants | 723 Participants |
| Sex: Female, Male Male | 2404 Participants | 4752 Participants | 2348 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 180 / 3,076 | 182 / 3,071 |
| other Total, other adverse events | 818 / 3,076 | 971 / 3,071 |
| serious Total, serious adverse events | 923 / 3,076 | 900 / 3,071 |
Outcome results
Primary
Composite of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, and Non-Fatal Stroke
All efficacy endpoints were adjudicated by an independent clinical endpoint committee (CEC). The primary efficacy endpoint was the time from randomization to the first occurrence of any component of the composite endpoint, which included death from cardiovascular causes, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke, as positively adjudicated by the CEC.
Time frame: From randomization to the first occurrence of any component of the composite primary endpoint (median duration of follow-up was 39.9 months)
Population: All subjects randomized to treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Composite of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, and Non-Fatal Stroke | 327 Participants |
| Dalcetrapib | Composite of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, and Non-Fatal Stroke | 292 Participants |
Comparison: A stratified Cox proportional hazards model was used to analyze the primary endpoint. This model included treatment as a main effect, and region and acute coronary syndrome (ACS) index event type as stratification factors. The null and alternative hypotheses tested with the above Cox model were: H0: λ = 1 vs HA: λ ≠ 1, where λ is the, assumed constant, hazard ratio (HR) for the time to occurrence of the composite events of the primary endpoint for the dalcetrapib and placebo treated groups.p-value: 0.1295% CI: [0.75, 1.03]Stratified Cox proportional hazard model
Secondary
Composite Endpoint of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, Non-Fatal Stroke, Hospitalization for ACS (With Electrocardiogram Abnormalities) or Unanticipated Coronary Revascularization
All efficacy endpoints were adjudicated by an independent clinical endpoint committee (CEC). The primary efficacy endpoint was the time from randomization to the first occurrence of any component of the composite endpoint, which included death from cardiovascular causes, resuscitated cardiac arrest, non-fatal myocardial infarction, non-fatal stroke, hospitalization for acute coronary syndrome (with electrocardiogram abnormalities) or unanticipated coronary revascularization, as positively adjudicated by the CEC.
Time frame: From randomization to the first occurrence of any component of the composite secondary endpoint (median duration of follow-up was 39.9 months)
Population: All subjects randomized to treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Composite Endpoint of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, Non-Fatal Stroke, Hospitalization for ACS (With Electrocardiogram Abnormalities) or Unanticipated Coronary Revascularization | 471 Participants |
| Dalcetrapib | Composite Endpoint of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, Non-Fatal Stroke, Hospitalization for ACS (With Electrocardiogram Abnormalities) or Unanticipated Coronary Revascularization | 471 Participants |
Comparison: Secondary endpoints were expressed as time to event and an analysis similar to that for the primary endpoint was conducted. In order to control the family-wise Type I error that results from the multiplicity of endpoints, the secondary endpoints were 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 were presented solely for illustrative purposes.p-value: 0.9595% CI: [0.88, 1.13]Stratified Cox proportional hazard model
Secondary
Composite Endpoint of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, Non-Fatal Stroke or Hospitalization for New or Worsening Heart Failure
All efficacy endpoints were adjudicated by an independent clinical endpoint committee (CEC). The secondary efficacy endpoint was the time from randomization to the first occurrence of any component of the composite secondary endpoint, which included death from cardiovascular causes, cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for new or worsening heart failure, as positively adjudicated by the CEC.
Time frame: From randomization to the first occurrence of any component of the composite secondary endpoint (median duration of follow-up was 39.9 months)
Population: All subjects randomized to treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Composite Endpoint of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, Non-Fatal Stroke or Hospitalization for New or Worsening Heart Failure | 346 Participants |
| Dalcetrapib | Composite Endpoint of Cardiovascular Death, Resuscitated Cardiac Arrest, Non-Fatal Myocardial Infarction, Non-Fatal Stroke or Hospitalization for New or Worsening Heart Failure | 321 Participants |
Comparison: Secondary endpoints were expressed as time to event and an analysis similar to that for the primary endpoint was conducted. In order to control the family-wise Type I error that results from the multiplicity of endpoints, the secondary endpoints were 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 were presented solely for illustrative purposes.p-value: 0.2795% CI: [0.79, 1.07]Stratified Cox proportional hazard model