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 demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to stable maximally tolerated daily statin therapy in comparison with ezetimibe after 24 weeks of treatment in participants with hypercholesterolemia at high cardiovascular (CV) risk. Secondary Objectives: * To evaluate the effect of alirocumab in comparison with ezetimibe on LDL-C at other time points * To evaluate the effect of alirocumab on other lipid parameters * To evaluate the safety and tolerability of alirocumab
Detailed description
The maximum study duration was 115 weeks per participant, including a 3-week screening period, 104-week randomized treatment period and 8-week follow-up period.
Interventions
DRUGAlirocumab
1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using the autoinjector.
1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using the autoinjector.
DRUGEzetimibe
One over-encapsulated tablet orally once daily at approximately the same time of the day with or without food.
One capsule once daily orally at approximately the same time of the day with or without food.
Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose.
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
Participants with hypercholesterolemia and established coronary heart disease (CHD) or CHD risk equivalents who were not adequately controlled with a maximally tolerated daily dose of statin at stable dose for at least 4 weeks prior to the screening visit (Week -2).
Exclusion criteria
* Age \< 18 or legal age of adulthood, whichever was greater * Participants without established CHD or CHD risk equivalents * LDL-C \<70 mg/dL (\<1.81 mmol/L) and participants with a history of documented cardiovascular disease * LDL-C \<100 mg/dL (\<2.59 mmol/L) and participants without a history of documented CV disease * 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 |
|---|---|---|
| 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 A-1 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 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 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 or 3 days after the last capsule, whichever came first). |
| 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 a MMRM 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 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 or 3 days after the last capsule, whichever came first). |
| Percent Change From Baseline in Apolipoprotein B (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 B 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 or 3 days after the last capsule, whichever came first). |
| 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 up 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 or 3 days after the last capsule, whichever came first). |
| 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 Calculated LDL-C at Week 52 - ITT Analysis | From Baseline to Week 52 | Adjusted LS means and standard errors at Week 52 from a MMRM model including all available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment. |
| Percentage of Participants Achieving 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 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 Achieving 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 including available post-baseline on-treatment data from week 4 to week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). |
| 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. |
| 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 Apolipoprotein A-1 (Apo A-1) 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 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 104 - On-Treatment Analysis | From Baseline to Week 104 | Adjusted LS means and standard errors at Week 104 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 104 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). |
| 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 or 3 days after the last capsule, whichever came first). |
| Percent Change From Baseline in Calculated LDL-C at Week 104 - ITT Analysis | From Baseline to Week 104 | Adjusted LS means and standard errors at Week 104 from MMRM including all available post-baseline data from Week 4 to Week 104 regardless of status on-or off-treatment. |
Countries
Canada, Denmark, France, Hungary, Israel, Russia, South Africa, South Korea, Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 126 centers in 10 countries. Overall, 1112 participants were screened between August 2012 and May 2013, 392 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment details
Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, intensity of statin treatment and geographical region. Assignment to arms was done centrally using Interactive Voice/Web Response System in 2:1 ratio (alirocumab: ezetimibe) after confirmation of selection criteria. 720 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Alirocumab 75 /up to 150 mg Q2W Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8. | 479 |
| Ezetimibe 10 mg Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks. | 241 |
| Total | 720 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 44 | 20 |
| Overall Study | Consent withdrawn by participant | 14 | 7 |
| Overall Study | Death | 4 | 3 |
| Overall Study | Last visit outside protocol visit window | 14 | 16 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Other than specified above | 6 | 7 |
| Overall Study | Participant moved | 7 | 2 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | Poor compliance to protocol | 26 | 14 |
| Overall Study | Related to auto-injector administration | 2 | 2 |
| Overall Study | Selection criteria finally not met | 2 | 0 |
| Overall Study | Site closure | 1 | 1 |
Baseline characteristics
| Characteristic | Ezetimibe 10 mg | Total | Alirocumab 75 /up to 150 mg Q2W |
|---|---|---|---|
| Age, Continuous | 61.3 years STANDARD_DEVIATION 9.2 | 61.6 years STANDARD_DEVIATION 9.3 | 61.7 years STANDARD_DEVIATION 9.4 |
| Calculated LDL-C in mg/dL | 104.6 mg/dL STANDARD_DEVIATION 34.1 | 107.3 mg/dL STANDARD_DEVIATION 35.7 | 108.6 mg/dL STANDARD_DEVIATION 36.5 |
| Calculated LDL-C in mmol/L | 2.710 mmol/L STANDARD_DEVIATION 0.884 | 2.778 mmol/L STANDARD_DEVIATION 0.926 | 2.812 mmol/L STANDARD_DEVIATION 0.945 |
| Sex: Female, Male Female | 71 Participants | 190 Participants | 119 Participants |
| Sex: Female, Male Male | 170 Participants | 530 Participants | 360 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 185 / 479 | 90 / 241 |
| serious Total, serious adverse events | 124 / 479 | 60 / 241 |
Outcome results
Primary
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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis | -50.6 percent change | Standard Error 1.4 |
| Ezetimibe 10 mg | Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis | -20.7 percent change | Standard Error 1.9 |
Comparison: Alirocumab group was compared to ezetimibe group using an appropriate contrast statement.p-value: <0.000195% CI: [-34.4, -25.3]Mixed Models Analysis
Secondary
Percentage of Participants Achieving 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 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) |
|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 77 percentage of participants |
| Ezetimibe 10 mg | Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 45.6 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: [3.7, 7.9]Regression, Logistic
Secondary
Percentage of Participants Achieving 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 including available post-baseline on-treatment data from week 4 to week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).
Time frame: Up to Week 52
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | 78.9 percentage of participants |
| Ezetimibe 10 mg | Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | 47.4 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: [3.9, 8.8]Regression, Logistic
Secondary
Percent Change From Baseline in Apo A-1 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 A-1 ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis | 1.5 percent change | Standard Error 0.5 |
| Ezetimibe 10 mg | Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis | -2.9 percent change | Standard Error 0.7 |
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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Apo-B at Week 12 - ITT Analysis | -39.7 percent change | Standard Error 1 |
| Ezetimibe 10 mg | Percent Change From Baseline in Apo-B at Week 12 - ITT Analysis | -17.2 percent change | Standard Error 1.3 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-25.7, -19.2]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 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 or 3 days after the last capsule, whichever came first).
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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | -42.1 percent change | Standard Error 1 |
| Ezetimibe 10 mg | Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis | -19.1 percent change | Standard Error 1.4 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-26.5, -19.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) 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 A-1 value on- or off-treatment (Apo A-1 ITT population).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis | 5 percent change | Standard Error 0.6 |
| Ezetimibe 10 mg | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis | -1.3 percent change | Standard Error 0.8 |
Secondary
Percent Change From Baseline in Apolipoprotein B (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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT Analysis | -40.7 percent change | Standard Error 1.1 |
| Ezetimibe 10 mg | Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT Analysis | -18.3 percent change | Standard Error 1.5 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-26, -18.8]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 a MMRM 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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | -51.2 percent change | Standard Error 1.3 |
| Ezetimibe 10 mg | Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis | -21.8 percent change | Standard Error 1.8 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-33.7, -25.1]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 or 3 days after the last capsule, whichever came first).
Time frame: From Baseline to Week 52
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis | -52.4 percent change | Standard Error 1.2 |
| Ezetimibe 10 mg | Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis | -22.7 percent change | Standard Error 1.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-33.8, -25.6]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 or 3 days after the last capsule, whichever came first).
Time frame: From Baseline to Week 52
Population: Modified ITT population (mITT): 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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL--C at Week 24 - On--Treatment Analysis | -52.4 percent change | Standard Error 1.3 |
| Ezetimibe 10 mg | Percent Change From Baseline in Calculated LDL--C at Week 24 - On--Treatment Analysis | -21.8 percent change | Standard Error 1.8 |
Comparison: A hierarchical 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 hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.p-value: <0.000195% CI: [-34.9, -26.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
Adjusted LS means and standard errors at Week 52 from a 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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | -49.5 percent change | Standard Error 1.5 |
| Ezetimibe 10 mg | Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | -18.3 percent change | Standard Error 2.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-36.3, -26.1]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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | -13 percent change | Standard Error 1.5 |
| Ezetimibe 10 mg | Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | -12.8 percent change | Standard Error 2 |
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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | -13 percent change | Standard Error 1.5 |
| Ezetimibe 10 mg | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | -12.8 percent change | Standard Error 2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: 0.911795% CI: [-5.1, 4.6]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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | 8.7 percent change | Standard Error 0.7 |
| Ezetimibe 10 mg | Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis | 2.8 percent change | Standard Error 1 |
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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | 8.6 percent change | Standard Error 0.8 |
| Ezetimibe 10 mg | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | 0.5 percent change | Standard Error 1.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [5.4, 10.7]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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis | -22.1 percent change | Standard Error 1.2 |
| Ezetimibe 10 mg | Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis | 1.1 percent change | Standard Error 1.7 |
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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis | -27.8 percent change | Standard Error 1.4 |
| Ezetimibe 10 mg | Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis | -6.1 percent change | Standard Error 2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-26.4, -17]Regression, Robust
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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | -42.6 percent change | Standard Error 1.1 |
| Ezetimibe 10 mg | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | -20.6 percent change | Standard Error 1.5 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-25.6, -18.3]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 or 3 days after the last capsule, whichever came first).
Time frame: From Baseline up 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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | -43.7 percent change | Standard Error 1.1 |
| Ezetimibe 10 mg | Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis | -20.2 percent change | Standard Error 1.6 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-27.2, -19.7]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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | -42.1 percent change | Standard Error 1.2 |
| Ezetimibe 10 mg | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis | -19.2 percent change | Standard Error 1.7 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-26.9, -18.9]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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | -29.4 percent change | Standard Error 0.8 |
| Ezetimibe 10 mg | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | -15.1 percent change | Standard Error 1.1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-17.1, -11.6]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 |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | -29.3 percent change | Standard Error 0.9 |
| Ezetimibe 10 mg | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis | -14.6 percent change | Standard Error 1.2 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-17.7, -11.7]Mixed Models Analysis
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 104 - ITT Analysis
Adjusted LS means and standard errors at Week 104 from MMRM including all available post-baseline data from Week 4 to Week 104 regardless of status on-or off-treatment.
Time frame: From Baseline to Week 104
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 104 - ITT Analysis | -44.2 Percent change | Standard Error 1.7 |
| Ezetimibe 10 mg | Percent Change From Baseline in Calculated LDL-C at Week 104 - ITT Analysis | -15.2 Percent change | Standard Error 2.4 |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 104 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 104 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 104 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).
Time frame: From Baseline to Week 104
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 104 - On-Treatment Analysis | -48.9 Percent change | Standard Error 1.7 |
| Ezetimibe 10 mg | Percent Change From Baseline in Calculated LDL-C at Week 104 - On-Treatment Analysis | -17.0 Percent change | Standard Error 2.4 |
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 or 3 days after the last capsule, whichever came first).
Time frame: From Baseline to Week 52
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Alirocumab 75 /up to 150 mg Q2W | Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | -51.8 Percent change | Standard Error 1.5 |
| Ezetimibe 10 mg | Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis | -19.7 Percent change | Standard Error 2.1 |