Hypercholesterolemia
Conditions
Brief summary
Alirocumab (SAR236553/REGN727) is a fully human monoclonal antibody that binds PCSK9 (proprotein convertase subtilisin/kexin type 9). Primary Objective of the study: To evaluate the long-term safety and tolerability of alirocumab in high cardiovascular risk participants with hypercholesterolemia not adequately controlled with their current lipid modifying therapy (LMT). Secondary Objectives: * To evaluate the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels after 24 weeks of treatment in comparison with placebo. * To evaluate the effect of alirocumab in comparison with placebo on LDL-C at other time points. * To evaluate the effects of alirocumab on other lipid parameters.
Detailed description
The maximum study duration was to be 89 weeks per participant, including a 3-week screening period, a 78-week randomized treatment period and 8-week follow-up period.
Interventions
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a pre-filled syringe.
DRUGAlirocumab
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a pre-filled syringe.
Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose with or without other LMT as clinically indicated.
Sponsors
Regeneron Pharmaceuticals
Sanofi
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
Either A or B below and who were not adequately controlled with their lipid-modifying therapy: A) Participants with heterozygous familial hypercholesterolemia (heFH) with or without established coronary heart disease (CHD) or CHD risk equivalents OR B) Participants with hypercholesterolemia together with established CHD or CHD risk equivalents.
Exclusion criteria
* Age \< 18 years * LDL-C \<70 mg/dL (\< 1.81 mmol/L) * Fasting serum triglycerides \> 400 mg/dL (\>4.52 mmol/L) The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Adverse Events (AEs) | Up to 10 weeks after last study drug administration (maximum of 86 weeks) | Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'treatment-emergent period' (the time from the first dose of study drug up to the last dose of study drug +70 days). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. |
| Percent Change From Baseline in Apo A1 at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis | From Baseline to Week 52 | Adjusted least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were used in the model (ITT analysis). |
| Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). |
| Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Calculated LDL-C at Week 12 - On-treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). |
| Percent Change From Baseline in Measured LDL-C at Week 24 - ITT Analysis | From Baseline to Week 52 | Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo A1 at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). |
| Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). |
| Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percentage of Very High Cardiovascular (CV) Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | Up to Week 52 | Very high CV risk: Heterozygous Familial Hypercholesterolemia (heFH) participants with coronary heart disease (CHD) or CHD risk equivalents or non- Familial Hypercholesterolemia (FH). High CV risk: heFH participants without CHD or CHD risk equivalents. CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (estimated glomerular filtration rate, 30 to \<60 ml/minute/1.73 m\^2 of body-surface area), or diabetes mellitus plus 2 or more additional risk factors (hypertension; ankle-brachial index of ≤0.90; microalbuminuria, macroalbuminuria, or a urinary dipstick result of \>2+ protein; preproliferative or proliferative retinopathy or laser treatment for retinopathy; or family history of premature CHD). Adjusted percentages at Week 24 were obtained from multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in imputation model. |
| Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | Up to Week 52 | Adjusted percentages at Week 24 were from multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). |
| Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | Up to Week 52 | Adjusted percentages at Week 24 were obtained from multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model. |
| Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | Up to Week 52 | Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline data from Week 4 to Week 52 (i.e. up to 21 days after last injection). |
| Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment were included in the imputation model. |
| Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis | From Baseline to Week 78 | Adjusted LS means and standard errors at Week 78 from MMRM model including all available post-baseline data from Week 4 to Week 78 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis | From Baseline to Week 78 | Adjusted LS means and standard errors at Week 78 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 78 (i.e. up to 21 days after last injection). |
| Percentage of Participants Who Experienced Cardiovascular (CV) Events | Up to 10 weeks after last study drug administration (maximum of 86 weeks) | CV events included coronary heart disease (CHD) death; non-fatal myocardial infarction (MI); fatal and non-fatal ischemic stroke; unstable angina requiring hospitalization; congestive heart failure (CHF) requiring hospitalization; ischemia-driven coronary revascularization procedure. Reported events are CV events as confirmed by an independent Clinical Events Committee (CEC) that occurred during the treatment emergent period ( i.e. from first dose up to the last dose of study drug + 70 days). |
| Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 52 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). |
Countries
Argentina, Belgium, Bulgaria, Canada, Chile, Colombia, Czechia, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Mexico, Netherlands, Norway, Poland, Portugal, Romania, Russia, South Africa, Spain, Sweden, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 320 centers in 27 countries. Overall, 5144 participants were screened between January 2012 and March 2013, 2801 of whom were screen failures. Screen failures were mainly due to exclusion criteria met. In addition 2 participants received study drug but did not undergo randomization. They were excluded from analysis.
Pre-assignment details
Randomization was stratified as per diagnosis of heterozygous familial hypercholesterolemia (heFH), prior history of myocardial infarction (MI) or ischemic stroke, intensity of statin treatment and geographic region. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:2 ratio (placebo:alirocumab).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Q2W Placebo (for alirocumab) SC injection Q2W added to stable LMT for 78 weeks. | 788 |
| Alirocumab 150 mg Q2W Alirocumab 150 mg SC injection Q2W added to stable LMT for 78 weeks. | 1,553 |
| Total | 2,341 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 48 | 113 |
| Overall Study | Consent withdrawn by participant | 34 | 72 |
| Overall Study | Death | 6 | 2 |
| Overall Study | Last visit outside protocol visit window | 51 | 143 |
| Overall Study | Other | 3 | 6 |
| Overall Study | Participant moved | 5 | 19 |
| Overall Study | Physician Decision | 0 | 4 |
| Overall Study | Poor compliance to protocol | 38 | 60 |
| Overall Study | Potential lost to follow-up | 3 | 0 |
| Overall Study | Randomized but not treated | 0 | 3 |
| Overall Study | Related to study drug administration | 5 | 14 |
| Overall Study | Selection criteria finally not met | 0 | 1 |
| Overall Study | Site closure | 0 | 3 |
Baseline characteristics
| Characteristic | Alirocumab 150 mg Q2W | Total | Placebo Q2W |
|---|---|---|---|
| Age, Continuous | 60.4 years STANDARD_DEVIATION 10.4 | 60.5 years STANDARD_DEVIATION 10.4 | 60.6 years STANDARD_DEVIATION 10.4 |
| Calculated LDL-C in mg/dL | 122.7 mg/dL STANDARD_DEVIATION 42.6 | 122.4 mg/dL STANDARD_DEVIATION 42.2 | 121.9 mg/dL STANDARD_DEVIATION 41.4 |
| Calculated LDL-C in mmol/L | 3.178 mmol/L STANDARD_DEVIATION 1.102 | 3.171 mmol/L STANDARD_DEVIATION 1.092 | 3.157 mmol/L STANDARD_DEVIATION 1.073 |
| Sex: Female, Male Female | 570 Participants | 884 Participants | 314 Participants |
| Sex: Female, Male Male | 983 Participants | 1457 Participants | 474 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 366 / 788 | 707 / 1,550 |
| serious Total, serious adverse events | 154 / 788 | 290 / 1,550 |
Outcome results
Primary
Percentage of Participants Who Experienced Adverse Events (AEs)
Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'treatment-emergent period' (the time from the first dose of study drug up to the last dose of study drug +70 days).
Time frame: Up to 10 weeks after last study drug administration (maximum of 86 weeks)
Population: Safety population: all randomized participants who received at least one dose or part of a dose of a study drug (treated).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Q2W | Percentage of Participants Who Experienced Adverse Events (AEs) | Any AE | 82.5 percentage of participants |
| Placebo Q2W | Percentage of Participants Who Experienced Adverse Events (AEs) | Any Serious AE | 19.5 percentage of participants |
| Placebo Q2W | Percentage of Participants Who Experienced Adverse Events (AEs) | Any AE leading to death | 1.3 percentage of participants |
| Placebo Q2W | Percentage of Participants Who Experienced Adverse Events (AEs) | Any AE leading to treatment discontinuation | 5.8 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Who Experienced Adverse Events (AEs) | Any AE leading to treatment discontinuation | 7.2 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Who Experienced Adverse Events (AEs) | Any AE | 81.0 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Who Experienced Adverse Events (AEs) | Any AE leading to death | 0.5 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Who Experienced Adverse Events (AEs) | Any Serious AE | 18.7 percentage of participants |
Secondary
Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
Adjusted percentages at Week 24 were obtained from multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model.
Time frame: Up to Week 52
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 8.0 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 79.3 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [53.3, 104.4]Regression, Logistic
Secondary
Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time frame: Up to Week 52
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | 8.0 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | 81.2 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [68.2, 138.9]Regression, Logistic
Secondary
Percentage of Very High Cardiovascular (CV) Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis
Very high CV risk: Heterozygous Familial Hypercholesterolemia (heFH) participants with coronary heart disease (CHD) or CHD risk equivalents or non- Familial Hypercholesterolemia (FH). High CV risk: heFH participants without CHD or CHD risk equivalents. CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (estimated glomerular filtration rate, 30 to \<60 ml/minute/1.73 m\^2 of body-surface area), or diabetes mellitus plus 2 or more additional risk factors (hypertension; ankle-brachial index of ≤0.90; microalbuminuria, macroalbuminuria, or a urinary dipstick result of \>2+ protein; preproliferative or proliferative retinopathy or laser treatment for retinopathy; or family history of premature CHD). Adjusted percentages at Week 24 were obtained from multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in imputation model.
Time frame: Up to Week 52
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Very High Cardiovascular (CV) Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | 8.5 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Very High Cardiovascular (CV) Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | 80.7 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [51.6, 99.1]Regression, Logistic
Secondary
Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis
Adjusted percentages at Week 24 were from multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time frame: Up to Week 52
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | 8.5 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | 82.8 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [66.1, 132]Regression, Logistic
Secondary
Percent Change From Baseline in Apo A1 at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Apo A1 ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apo A1 at Week 12 - ITT Analysis | 0.6 percent change | Standard Error 0.5 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apo A1 at Week 12 - ITT Analysis | 4.6 percent change | Standard Error 0.3 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [2.8, 5.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apo A1 at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants of the ITT population with one baseline and at least one post-baseline Apo A1 value on- or off-treatment (Apo A1 ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apo A1 at Week 24 - ITT Analysis | 1.2 percent change | Standard Error 0.6 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apo A1 at Week 24 - ITT Analysis | 4.0 percent change | Standard Error 0.4 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [1.6, 4.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apo B at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Apo B ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | 0.5 percent change | Standard Error 0.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apo B at Week 12 - ITT Analysis | -55.5 percent change | Standard Error 0.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-58.3, -53.7]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 52
Population: Participants of the mITT population with one baseline and at least one post-baseline Apo-B value on-treatment (Apo B mITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | 1.2 percent change | Standard Error 0.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | -54.3 percent change | Standard Error 0.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-57.7, -53.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment (Apo B ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | 1.2 percent change | Standard Error 1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis | -52.8 percent change | Standard Error 0.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-56.3, -51.7]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | 1.5 percent change | Standard Error 1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | -63.3 percent change | Standard Error 0.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-67.2, -62.4]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 12 - On-treatment Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 52
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - On-treatment Analysis | 1.4 percent change | Standard Error 1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - On-treatment Analysis | -64.2 percent change | Standard Error 0.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-67.9, -63.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis
Adjusted least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were used in the model (ITT analysis).
Time frame: From Baseline to Week 52
Population: ITT population: all randomized participants with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis | 0.8 percent change | Standard Error 1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis | -61.0 percent change | Standard Error 0.7 |
Comparison: Alirocumab group was compared to placebo group using an appropriate contrast statement.p-value: <0.000195% CI: [-64.3, -59.4]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis).
Time frame: From Baseline to Week 52
Population: Modified ITT (mITT) population: all randomized and treated participants with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | 0.7 percent change | Standard Error 1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis | -62.8 percent change | Standard Error 0.7 |
Comparison: A hierarchial testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchial testing sequence continued only when previous endpoint was statistically significant at 0.05 level.p-value: <0.000195% CI: [-65.9, -61.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | 1.2 percent change | Standard Error 1.1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | -16.7 percent change | Standard Error 0.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-20.5, -15.3]Regression, Robust
Secondary
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | 1.8 percent change | Standard Error 1.2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | -15.6 percent change | Standard Error 0.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-20.1, -14.6]Regression, Robust
Secondary
Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: HDL-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | 0.2 percent change | Standard Error 0.5 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | 5.8 percent change | Standard Error 0.4 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [4.3, 6.8]Mixed Models Analysis
Secondary
Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment (HDL-C ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | -0.6 percent change | Standard Error 0.5 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | 4.0 percent change | Standard Error 0.4 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [3.3, 5.9]Mixed Models Analysis
Secondary
Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis
Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | -3.1 percent change | Standard Error 1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis | -28.2 percent change | Standard Error 0.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-27.4, -22.7]Regression, Robust
Secondary
Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis
Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment were included in the imputation model.
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | -3.7 percent change | Standard Error 1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis | -29.3 percent change | Standard Error 0.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-28.1, -23.1]Regression, Robust
Secondary
Percent Change From Baseline in Measured LDL-C at Week 24 - ITT Analysis
Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants of the ITT population with one baseline and at least one post-baseline measured LDL-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Measured LDL-C at Week 24 - ITT Analysis | 3.5 percent change | Standard Error 1.1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Measured LDL-C at Week 24 - ITT Analysis | -57.8 percent change | Standard Error 0.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-64, -58.5]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Non-HDL-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | 0.9 percent change | Standard Error 0.8 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | -53.7 percent change | Standard Error 0.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-56.6, -52.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 52
Population: Participants of the mITT population with one baseline and at least one post-baseline non-HDL-C value on-treatment (non-HDL-C mITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | 0.6 percent change | Standard Error 0.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | -53.1 percent change | Standard Error 0.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-55.7, -51.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment (non-HDL-C ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | 0.7 percent change | Standard Error 0.9 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | -51.6 percent change | Standard Error 0.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-54.4, -50.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Total-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | 0.2 percent change | Standard Error 0.6 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | -38.8 percent change | Standard Error 0.4 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-40.4, -37.5]Mixed Models Analysis
Secondary
Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: Participants of the ITT population with one baseline and at least one post-baseline Total-C value on- or off-treatment (Total-C ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | -0.3 percent change | Standard Error 0.7 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | -37.8 percent change | Standard Error 0.5 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-39.1, -35.9]Mixed Models Analysis
Other Pre-specified
Percentage of Participants Who Experienced Cardiovascular (CV) Events
CV events included coronary heart disease (CHD) death; non-fatal myocardial infarction (MI); fatal and non-fatal ischemic stroke; unstable angina requiring hospitalization; congestive heart failure (CHF) requiring hospitalization; ischemia-driven coronary revascularization procedure. Reported events are CV events as confirmed by an independent Clinical Events Committee (CEC) that occurred during the treatment emergent period ( i.e. from first dose up to the last dose of study drug + 70 days).
Time frame: Up to 10 weeks after last study drug administration (maximum of 86 weeks)
Population: Safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Participants Who Experienced Cardiovascular (CV) Events | 5.1 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Who Experienced Cardiovascular (CV) Events | 4.6 percentage of participants |
Post Hoc
Percentage of Participants Who Experienced Major Adverse CV Events
Major adverse CV events were defined as all adverse CV events except Congestive heart failure (CHF) requiring hospitalization; and ischemia-driven coronary revascularization procedure.
Time frame: Up to 10 weeks after last study drug administration (maximum of 86 weeks)
Population: Safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Q2W | Percentage of Participants Who Experienced Major Adverse CV Events | 3.3 percentage of participants |
| Alirocumab 150 mg Q2W | Percentage of Participants Who Experienced Major Adverse CV Events | 1.7 percentage of participants |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 52
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | 4.4 percent change | Standard Error 1.2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | -56.8 percent change | Standard Error 0.8 |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 52 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 52
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | 4.6 percent change | Standard Error 1.1 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | -59.9 percent change | Standard Error 0.8 |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis
Adjusted LS means and standard errors at Week 78 from MMRM model including all available post-baseline data from Week 4 to Week 78 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 78
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis | 3.6 percent change | Standard Error 1.3 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis | -52.4 percent change | Standard Error 0.9 |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 78 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 78 (i.e. up to 21 days after last injection).
Time frame: From Baseline to Week 78
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Q2W | Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis | 3.9 percent change | Standard Error 1.2 |
| Alirocumab 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis | -58.0 percent change | Standard Error 0.9 |