Atherosclerotic Cardiovascular Disease
Conditions
Brief summary
Primary Objective: To compare the effect of alirocumab with placebo on the occurrence of cardiovascular (CV) events (composite endpoint of coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), fatal and non-fatal ischemic stroke, unstable angina (UA) requiring hospitalization) in participants who experienced an acute coronary syndrome (ACS) event 4 to 52 weeks prior to randomization and were treated with evidence-based medical and dietary management of dyslipidemia. Secondary Objectives: * To evaluate the effect of alirocumab on secondary endpoints (any CHD event , major CHD event, any CV event, composite of all cause mortality/non-fatal MI/non-fatal ischemic stroke, CHD deaths, CV deaths, all cause mortality). * To evaluate the safety and tolerability of alirocumab. * To evaluate the effect of alirocumab on lipid parameters.
Detailed description
18924 number of participants aged \>= 40 years old were randomized in the study.
Interventions
DRUGAlirocumab
Alirocumab administered as SC injection of 1 mL in the abdomen or thigh with a disposable auto-injector.
DRUGPlacebo
Placebo matched to alirocumab administered as a SC injection of 1 mL in the abdomen or thigh with a disposable auto-injector.
DRUGLMT
Statins (atorvastatin or rosuvastatin) at stable maximal tolerated dose of statin with or without other LMT as clinically indicated.
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: Recently (\< 52 weeks) hospitalized for ACS.
Exclusion criteria
* Age \< 40 years. * ACS event occurring more than 52 weeks prior to randomization visit. * LDL-C likely to be \<70 mg/dL (\<1.81 mmo/L), and apolipoprotein B (ApoB) \<80 mg/dL (\<0.8 g/L), and non - high-density lipoprotein cholesterol (HDL-C) \<100 mg/dL (\<2.59 mmol/L) with evidence-based medical and dietary management of dyslipidemia. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Major Adverse Cardiovascular Event (MACE); Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | All MACE positively adjudicated by Clinical Events Committee (CEC) in a blinded fashion, were used in the analysis of the composite cardiovascular (CV) outcome measure comprised of Coronary Heart Disease (CHD) death, non-fatal Myocardial Infarction (MI), fatal and non-fatal ischemic stroke (IS), or unstable angina (UA) requiring hospitalization. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of MACE over time. Percentage of observed participants with outcome measure events during the study were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Any Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | All CHD events positively adjudicated by CEC in a blinded fashion, were used in the analysis of the composite CHD endpoint comprised of any CHD death, non-fatal non-fatal MI, UA requiring hospitalization, or ischemia-driven coronary revascularization procedure. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any CHD event over time. Percentage of observed participants with outcome measure events during the study were reported. |
| Time to First Occurrence of Any Major Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | All Major CHD events positively adjudicated by CEC in a blinded fashion, were used in the analysis of the composite CHD endpoint comprised of any CHD death and non-fatal MI. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any major CHD event over time. Percentage of observed participants with outcome measure events during the study were reported. |
| Time to First Occurrence of Any Cardiovascular Event; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | All CV events positively adjudicated by CEC in a blinded fashion, were used in the analysis of the composite CV endpoint comprised of any non-fatal CHD event, any CV death and non-fatal IS. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any CV event over time. Percentage of observed participants with outcome measure events during the study were reported. |
| Time to First Occurrence of All-Cause Mortality, Non-Fatal Myocardial Infarction, Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | All-cause mortality, non-fatal MI and non-fatal IS positively adjudicated by CEC in a blinded fashion, were used in the analysis of this endpoint. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of all-cause mortality, non-fatal MI and non-fatal IS over time. Percentage of observed participants with outcome measure events during the study were reported. |
| Time to Coronary Heart Disease Death; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the CHD death over time. Percentage of observed participants with CHD death (positively adjudicated by CEC in a blinded fashion) were reported. |
| Time to Cardiovascular Death; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the CV death over time. Percentage of observed participants with CV death (positively adjudicated by CEC in a blinded fashion) were reported. |
| Time to First Occurrence of Any Ischemia-Driven Coronary Revascularization Procedure; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any ischemia-driven coronary revascularization procedure over time. Percentage of observed participants with any ischemia-driven coronary revascularization procedure (positively adjudicated by CEC in a blinded fashion) were reported. |
| Time to First Occurrence of Any Congestive Heart Failure (CHF) Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any CHF requiring hospitalization over time. Percentage of observed participants with any CHF requiring hospitalization (positively adjudicated by CEC in a blinded fashion) were reported. |
| Time to All-Cause Death; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the all-cause death over time. Percentage of observed participants with all-cause death (positively adjudicated by CEC in a blinded fashion) were reported. |
| Time to First Occurrence of Any Non-Fatal Myocardial Infarction; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any non-fatal MI over time. Percentage of observed participants with any non-fatal MI (positively adjudicated by CEC in a blinded fashion) were reported. |
| Time to First Occurrence of Fatal or Any Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of fatal or any non-fatal IS over time. Percentage of observed participants with fatal or any non-fatal IS (positively adjudicated by CEC in a blinded fashion) were reported. |
| Time to First Occurrence of Any Unstable Angina Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study | From randomization up to 64 months | Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any UA requiring hospitalization over time. Percentage of observed participants with any UA requiring hospitalization (positively adjudicated by CEC in a blinded fashion) were reported. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: ITT Analysis | Baseline, Months 4, 12 and 48 | Adjusted means and standard errors at Month 4, 12 and 48 from multiple imputation approach (to account for missing data) followed by analyses of covariance (ANCOVA) model with the fixed categorical effect of treatment group and the continuous fixed covariate of baseline LDL-C value, including all available post-baseline data from Month 1 up to Month 48 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: On-Treatment Analysis | Baseline, Months 4, 12 and 48 | Adjusted Least-squares (LS) means and standard errors at Month 4, 12 and 48 were obtained from a mixed-effect model with repeated measures (MMRM) including available post-baseline on-treatment data from Month 1 up to Month 48 (i.e. up to 21 days after last injection). |
Countries
Argentina, Australia, Austria, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Denmark, Estonia, Finland, France, Georgia, Germany, Greece, Guatemala, Hong Kong, Hungary, India, Israel, Italy, Japan, Latvia, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, North Macedonia, Norway, Peru, Philippines, Poland, Portugal, Romania, Russia, Serbia, Singapore, Slovakia, Slovenia, South Africa, South Korea, Spain, Sri Lanka, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 1387 sites in 57 countries. Of these, 1328 active sites randomized at least 1 participant. Overall, 35,437 participants were screened between 11 October 2012 and 17 Jan 2017; of whom 16,513 were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment details
Randomization was stratified according to country. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1 ratio (alirocumab: placebo), with permuted-block randomization.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo (for alirocumab) SC injection Q2W added to stable LMT for up to 64 months. | 9,462 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W Alirocumab 75 mg SC injection Q2W added to stable LMT for up to 64 months. Alirocumab dose up-titrated to 150 mg Q2W from Month 2 when LDL-C levels \>=50 mg/dL (1.29 mmol/L) at Month 1; or if up-titration was missed due to unavailability of LDL-C value, it was up-titrated at month 4 based on LDL-C value at Month 2. For participants receiving 150 mg Q2W, alirocumab dose was down-titrated in a blinded manner to 75 mg Q2W if two consecutive values of LDL-C were \<25 mg/dL (0.65 mmol/L). For participants receiving 75 mg Q2W, alirocumab dose was switched to placebo in a blinded manner if two consecutive values of LDL-C were \<15 mg/dL (0.39 mmol/L). | 9,462 |
| Total | 18,924 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 347 | 362 |
| Overall Study | Lost to Follow-up | 17 | 15 |
| Overall Study | Other than specified above | 172 | 147 |
| Overall Study | Participant moved | 139 | 104 |
| Overall Study | Physician Decision | 77 | 62 |
| Overall Study | Poor compliance to protocol | 529 | 454 |
| Overall Study | Randomized but not treated | 19 | 11 |
| Overall Study | Related to study drug administration | 96 | 105 |
| Overall Study | Site terminated by sponsor | 1 | 3 |
| Overall Study | Two consecutive LDL-C <15 mg/dL | 0 | 730 |
| Overall Study | Withdrawal by Subject | 118 | 91 |
Baseline characteristics
| Characteristic | Placebo | Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Total |
|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 9.4 | 58.5 years STANDARD_DEVIATION 9.3 | 58.6 years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1555 Participants | 1581 Participants | 3136 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7721 Participants | 7700 Participants | 15421 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 186 Participants | 181 Participants | 367 Participants |
| Race/Ethnicity, Customized Asian | 1247 Participants | 1251 Participants | 2498 Participants |
| Race/Ethnicity, Customized Black or African American | 238 Participants | 235 Participants | 473 Participants |
| Race/Ethnicity, Customized Other | 449 Participants | 469 Participants | 918 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 7524 Participants | 7500 Participants | 15024 Participants |
| Sex: Female, Male Female | 2372 Participants | 2390 Participants | 4762 Participants |
| Sex: Female, Male Male | 7090 Participants | 7072 Participants | 14162 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 278 / 9,443 | 238 / 9,451 |
| other Total, other adverse events | 2,181 / 9,443 | 2,203 / 9,451 |
| serious Total, serious adverse events | 2,350 / 9,443 | 2,202 / 9,451 |
Outcome results
Primary
Time to First Occurrence of Major Adverse Cardiovascular Event (MACE); Percentage of Observed Participants With Outcome Measure Events During the Study
All MACE positively adjudicated by Clinical Events Committee (CEC) in a blinded fashion, were used in the analysis of the composite cardiovascular (CV) outcome measure comprised of Coronary Heart Disease (CHD) death, non-fatal Myocardial Infarction (MI), fatal and non-fatal ischemic stroke (IS), or unstable angina (UA) requiring hospitalization. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of MACE over time. Percentage of observed participants with outcome measure events during the study were reported.
Time frame: From randomization up to 64 months
Population: Intent-to-treat (ITT) population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of Major Adverse Cardiovascular Event (MACE); Percentage of Observed Participants With Outcome Measure Events During the Study | 11.1 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of Major Adverse Cardiovascular Event (MACE); Percentage of Observed Participants With Outcome Measure Events During the Study | 9.5 percentage of participants |
Comparison: Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world).p-value: 0.000395% CI: [0.78, 0.93]Log Rank
Secondary
Time to All-Cause Death; Percentage of Observed Participants With Outcome Measure Events During the Study
Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the all-cause death over time. Percentage of observed participants with all-cause death (positively adjudicated by CEC in a blinded fashion) were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to All-Cause Death; Percentage of Observed Participants With Outcome Measure Events During the Study | 4.1 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to All-Cause Death; Percentage of Observed Participants With Outcome Measure Events During the Study | 3.5 percentage of participants |
Secondary
Time to Cardiovascular Death; Percentage of Observed Participants With Outcome Measure Events During the Study
Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the CV death over time. Percentage of observed participants with CV death (positively adjudicated by CEC in a blinded fashion) were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Cardiovascular Death; Percentage of Observed Participants With Outcome Measure Events During the Study | 2.9 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to Cardiovascular Death; Percentage of Observed Participants With Outcome Measure Events During the Study | 2.5 percentage of participants |
Secondary
Time to Coronary Heart Disease Death; Percentage of Observed Participants With Outcome Measure Events During the Study
Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the CHD death over time. Percentage of observed participants with CHD death (positively adjudicated by CEC in a blinded fashion) were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Coronary Heart Disease Death; Percentage of Observed Participants With Outcome Measure Events During the Study | 2.3 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to Coronary Heart Disease Death; Percentage of Observed Participants With Outcome Measure Events During the Study | 2.2 percentage of participants |
Comparison: Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world). Testing according to the hierarchical testing procedure (continued only if the previous endpoint was statistically significant).p-value: 0.382495% CI: [0.76, 1.11]Log Rank
Secondary
Time to First Occurrence of All-Cause Mortality, Non-Fatal Myocardial Infarction, Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study
All-cause mortality, non-fatal MI and non-fatal IS positively adjudicated by CEC in a blinded fashion, were used in the analysis of this endpoint. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of all-cause mortality, non-fatal MI and non-fatal IS over time. Percentage of observed participants with outcome measure events during the study were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of All-Cause Mortality, Non-Fatal Myocardial Infarction, Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study | 11.9 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of All-Cause Mortality, Non-Fatal Myocardial Infarction, Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study | 10.3 percentage of participants |
Comparison: Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world). Testing according to the hierarchical testing procedure (continued only if the previous endpoint was statistically significant).p-value: 0.000395% CI: [0.79, 0.93]Log Rank
Secondary
Time to First Occurrence of Any Cardiovascular Event; Percentage of Observed Participants With Outcome Measure Events During the Study
All CV events positively adjudicated by CEC in a blinded fashion, were used in the analysis of the composite CV endpoint comprised of any non-fatal CHD event, any CV death and non-fatal IS. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any CV event over time. Percentage of observed participants with outcome measure events during the study were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of Any Cardiovascular Event; Percentage of Observed Participants With Outcome Measure Events During the Study | 15.6 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of Any Cardiovascular Event; Percentage of Observed Participants With Outcome Measure Events During the Study | 13.7 percentage of participants |
Comparison: Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world). Testing according to the hierarchical testing procedure (continued only if the previous endpoint was statistically significant).p-value: 0.000395% CI: [0.81, 0.94]Log Rank
Secondary
Time to First Occurrence of Any Congestive Heart Failure (CHF) Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study
Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any CHF requiring hospitalization over time. Percentage of observed participants with any CHF requiring hospitalization (positively adjudicated by CEC in a blinded fashion) were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of Any Congestive Heart Failure (CHF) Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study | 1.9 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of Any Congestive Heart Failure (CHF) Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study | 1.9 percentage of participants |
Secondary
Time to First Occurrence of Any Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study
All CHD events positively adjudicated by CEC in a blinded fashion, were used in the analysis of the composite CHD endpoint comprised of any CHD death, non-fatal non-fatal MI, UA requiring hospitalization, or ischemia-driven coronary revascularization procedure. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any CHD event over time. Percentage of observed participants with outcome measure events during the study were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of Any Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study | 14.3 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of Any Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study | 12.7 percentage of participants |
Comparison: Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region(North America,South America,Western Europe,Eastern Europe,Asia, Rest of the world).A hierarchical testing approach was used to control the overall type-I error at 0.0249 one-sided alpha level(0.0498 two-sided).Testing was then performed sequentially in the order endpoints were reported.Hierarchical testing sequence continued only if the previous endpoint was statistically significant.p-value: 0.001395% CI: [0.81, 0.95]Log Rank
Secondary
Time to First Occurrence of Any Ischemia-Driven Coronary Revascularization Procedure; Percentage of Observed Participants With Outcome Measure Events During the Study
Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any ischemia-driven coronary revascularization procedure over time. Percentage of observed participants with any ischemia-driven coronary revascularization procedure (positively adjudicated by CEC in a blinded fashion) were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of Any Ischemia-Driven Coronary Revascularization Procedure; Percentage of Observed Participants With Outcome Measure Events During the Study | 8.8 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of Any Ischemia-Driven Coronary Revascularization Procedure; Percentage of Observed Participants With Outcome Measure Events During the Study | 7.7 percentage of participants |
Secondary
Time to First Occurrence of Any Major Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study
All Major CHD events positively adjudicated by CEC in a blinded fashion, were used in the analysis of the composite CHD endpoint comprised of any CHD death and non-fatal MI. Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any major CHD event over time. Percentage of observed participants with outcome measure events during the study were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of Any Major Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study | 9.5 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of Any Major Coronary Heart Disease Event; Percentage of Observed Participants With Outcome Measure Events During the Study | 8.4 percentage of participants |
Comparison: Analysis was performed using Cox proportional hazard model and log rank test stratified on geographical region (North America, South America, Western Europe, Eastern Europe, Asia, Rest of the world). Testing was performed according to the hierarchical testing procedure (continued only if the previous endpoint was statistically significant).p-value: 0.00695% CI: [0.8, 0.96]Log Rank
Secondary
Time to First Occurrence of Any Non-Fatal Myocardial Infarction; Percentage of Observed Participants With Outcome Measure Events During the Study
Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any non-fatal MI over time. Percentage of observed participants with any non-fatal MI (positively adjudicated by CEC in a blinded fashion) were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of Any Non-Fatal Myocardial Infarction; Percentage of Observed Participants With Outcome Measure Events During the Study | 7.6 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of Any Non-Fatal Myocardial Infarction; Percentage of Observed Participants With Outcome Measure Events During the Study | 6.6 percentage of participants |
Secondary
Time to First Occurrence of Any Unstable Angina Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study
Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of any UA requiring hospitalization over time. Percentage of observed participants with any UA requiring hospitalization (positively adjudicated by CEC in a blinded fashion) were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of Any Unstable Angina Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study | 0.6 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of Any Unstable Angina Requiring Hospitalization; Percentage of Observed Participants With Outcome Measure Events During the Study | 0.4 percentage of participants |
Secondary
Time to First Occurrence of Fatal or Any Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study
Kaplan Meier plots of the cumulative incidence rate by treatment groups were used to depict the first occurrence of fatal or any non-fatal IS over time. Percentage of observed participants with fatal or any non-fatal IS (positively adjudicated by CEC in a blinded fashion) were reported.
Time frame: From randomization up to 64 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to First Occurrence of Fatal or Any Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study | 1.6 percentage of participants |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Time to First Occurrence of Fatal or Any Non-Fatal Ischemic Stroke; Percentage of Observed Participants With Outcome Measure Events During the Study | 1.2 percentage of participants |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: ITT Analysis
Adjusted means and standard errors at Month 4, 12 and 48 from multiple imputation approach (to account for missing data) followed by analyses of covariance (ANCOVA) model with the fixed categorical effect of treatment group and the continuous fixed covariate of baseline LDL-C value, including all available post-baseline data from Month 1 up to Month 48 regardless of status on- or off-treatment.
Time frame: Baseline, Months 4, 12 and 48
Population: ITT Population. Here, 'number analyzed' corresponds to the number of participants with the parameter measured and baseline measure available for each time-point. A multiple approach was used to account for participants with missing data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: ITT Analysis | Month 4 | 4.4 Percent change | Standard Error 0.3 |
| Placebo | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: ITT Analysis | Month 12 | 8.0 Percent change | Standard Error 0.4 |
| Placebo | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: ITT Analysis | Month 48 | 16.4 Percent change | Standard Error 1.8 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: ITT Analysis | Month 4 | -55.8 Percent change | Standard Error 0.3 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: ITT Analysis | Month 12 | -45.7 Percent change | Standard Error 0.4 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: ITT Analysis | Month 48 | -23.5 Percent change | Standard Error 1.6 |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: On-Treatment Analysis
Adjusted Least-squares (LS) means and standard errors at Month 4, 12 and 48 were obtained from a mixed-effect model with repeated measures (MMRM) including available post-baseline on-treatment data from Month 1 up to Month 48 (i.e. up to 21 days after last injection).
Time frame: Baseline, Months 4, 12 and 48
Population: Randomized and treated population. Here, 'number analyzed' signifies participants evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: On-Treatment Analysis | Month 4 | 4.4 Percent change | Standard Error 0.3 |
| Placebo | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: On-Treatment Analysis | Month 12 | 8.2 Percent change | Standard Error 0.4 |
| Placebo | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: On-Treatment Analysis | Month 48 | 14.6 Percent change | Standard Error 1 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: On-Treatment Analysis | Month 12 | -52.8 Percent change | Standard Error 0.4 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: On-Treatment Analysis | Month 48 | -40.1 Percent change | Standard Error 1 |
| Alirocumab 75 mg Q2W/Up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Months 4, 12, and 48: On-Treatment Analysis | Month 4 | -58.3 Percent change | Standard Error 0.3 |