Hypercholesterolemia
Conditions
Brief summary
This is a randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-national, multi-center study to compare alirocumab (REGN727/SAR236553) versus ezetimibe in participants with primary hypercholesterolemia and moderate, high, or very high CV risk, who are intolerant to statins. An atorvastatin arm is added to determine that the population selected in the study is a truly statin intolerant population by assessing skeletal muscle-related adverse events.
Interventions
DRUGAtorvastatin
Atorvastatin over-encapsulated tablets.
DRUGEzetimibe
Ezetimibe over-encapsulated tablet.
DRUGAlirocumab
Alirocumab SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.
DRUGPlacebo
Placebo for alirocumab, ezitimibe and atorvastatin.
Sponsors
Sanofi
Regeneron Pharmaceuticals
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
Inclusion: 1. Patients with primary hypercholesterolemia \[Heterozygous Familial Hypercholesterolemia (heFH) or non-FH\] with moderate, high or very high CV risk and a history of statin intolerance 2. Provide signed informed consent Exclusion: 1. Calculated serum LDL-C \<70 mg/dL (1.81 mmol/L) and very high CV risk at the screening visit 2. Calculated serum LDL-C \<100 mg/dL (2.59 mmol/L) and high or moderate CV risk at the screening visit 3. A 10-year fatal cardiovascular disease risk score \<1% at the screening visit (The inclusion/
Exclusion criteria
provided above is not intended to contain all considerations relevant to a patient's potential participation in this 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 24 | Calculated LDL-C values were obtained from Friedewald formula. 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 24 regardless of status on- or off-treatment were used in the model (ITT analysis). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated LDL-C at Week 24 - On--Treatment Analysis | From Baseline to Week 24 | Calculated LDL-C values were obtained from Friedewald formula. 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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis). |
| Percent Change From Baseline in Calculated LDL--C at Week 12 -- ITT Analysis | From Baseline to Week 12 | Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 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 12 | Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis). |
| Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 -- ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post--baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo B at Week 24 -- On--Treatment Analysis | From Baseline to Week 24 | 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 24 (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 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 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 24 | 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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first). |
| Percent Change From Baseline in Total Cholesterol (Total--C) at Week 24 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apo B at Week 12 -- ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | Up to Week 24 | Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). |
| Percent Change in Fasting Triglycerides From Baseline to Week 12 -- ITT Analysis | From Baseline to Week 12 | Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment. |
| Percent Change From Baseline in Apo A--1 at Week 12 -- ITT Analysis | From Baseline to Week 12 | Least squares (LS) means and standard errors (SE) taken from MMRM (mixed effect model with repeated measures) analysis. |
| Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate 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 24 | Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first (on-treatment analysis). |
| Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | Up to Week 24 | Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis). |
| Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | Up to Week 24 | Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first (on-treatment analysis). |
| Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis | From Baseline to Week 24 | Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment. |
| Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | From Baseline to Week 24 | Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment. |
| Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Lipoprotein(a) at Week 12 -- ITT Analysis | From Baseline to Week 12 | Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment. |
| Percent Change in HDL-C From Baseline to Week 12 -- ITT Analysis | From Baseline to Week 12 | Least-squares (LS) means and standard errors (SE) taken from MMRM (mixed-effect model with repeated measures) analysis |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE) | From Baseline up to Week 24 | Skeletal muscle-related adverse events were a predefined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness and muscle fatigue. Events that developed during treatment emergent adverse events period (the time from the first double-blindstudy treatment \[injection or capsules, whichever came first\] up to the day of the last double-blind injection + 70 days ) are reported. |
| Percent Change From Baseline in Calculated LDL-C at Week 24 Versus Atorvastatin - Raw Data Description - Intent-To-Treat (ITT) Analysis | From Baseline up to Week 24 | — |
Countries
Austria, Canada, France, Israel, Italy, Norway, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 67 sites in 8 countries. Overall, 519 participants were screened between 28 September 2012 and 11 August 2013, 158 of whom were screen failures. Screen failures were mainly due to exclusion criteria met. After screening, 361 participants entered into a 4-week single blind placebo run-in period.
Pre-assignment details
At the end of the single blind placebo run-in period, eligible participants were randomized to treatment arms centrally using a 2:2:1 (alirocumab:ezetimibe:atorvastatin) ratio. Randomization was stratified according to prior history of myocardial infarction or ischemic stroke. 314 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Atorvastatin (Statin Rechallenge Arm) Atorvastatin 20 mg over-encapsulated tablets orally QD for 24 weeks and placebo (for alirocumab) SC injection Q2W for 24 weeks added to stable lipid-modifying therapy (LMT). | 63 |
| Ezetimibe (Active Comparator) Ezetimibe 10 mg over-encapsulated tablets orally QD for 24 weeks and placebo (for alirocumab) SC injection Q2W for 24 weeks added to stable LMT. | 125 |
| Alirocumab 75 mg/ up to 150 mg Alirocumab 75 mg SC injection Q2W for 24 weeks and placebo (for atorvastatin/ezetimibe) over-encapsulated tablets orally QD for 24 weeks added to stable LMT. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on cardiovascular risk. | 126 |
| Total | 314 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 16 | 31 | 23 |
| Overall Study | Other | 3 | 11 | 7 |
| Overall Study | Poor compliance to protocol | 2 | 0 | 0 |
| Overall Study | Randomized but not treated | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Atorvastatin (Statin Rechallenge Arm) | Ezetimibe (Active Comparator) | Alirocumab 75 mg/ up to 150 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 63.4 years STANDARD_DEVIATION 9.5 | 62.8 years STANDARD_DEVIATION 10.1 | 64.1 years STANDARD_DEVIATION 9 | 63.4 years STANDARD_DEVIATION 9.5 |
| LDL-C in mmol/L | 4.85 mmol/L STANDARD_DEVIATION 1.54 | 5.011 mmol/L STANDARD_DEVIATION 1.837 | 4.951 mmol/L STANDARD_DEVIATION 1.883 | 4.954 mmol/L STANDARD_DEVIATION 1.796 |
| Low Density Lipoprotein Cholesterol (LDL-C) in mg/dL | 187.3 mg/dL STANDARD_DEVIATION 59.5 | 193.5 mg/dL STANDARD_DEVIATION 70.9 | 191.1 mg/dL STANDARD_DEVIATION 72.7 | 191.3 mg/dL STANDARD_DEVIATION 69.3 |
| Sex: Female, Male Female | 28 Participants | 58 Participants | 56 Participants | 142 Participants |
| Sex: Female, Male Male | 35 Participants | 67 Participants | 70 Participants | 172 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 35 / 63 | 63 / 124 | 57 / 126 |
| serious Total, serious adverse events | 7 / 63 | 10 / 124 | 12 / 126 |
Outcome results
Primary
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--To-Treat (ITT) Analysis
Calculated LDL-C values were obtained from Friedewald formula. 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 24 regardless of status on- or off-treatment were used in the model (ITT analysis).
Time frame: From Baseline to Week 24
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 |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--To-Treat (ITT) Analysis | -14.6 percent change | Standard Error 2.2 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--To-Treat (ITT) Analysis | -45.0 percent change | Standard Error 2.2 |
Comparison: Alirocumab group was compared to the corresponding active control group using an appropriate contrast statement.p-value: <0.000195% CI: [-36.6, -24.2]Mixed Models Analysis
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 a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).
Time frame: Up to Week 24
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 0.8 percentage of participants |
| Alirocumab 75 mg/ up to 150 mg | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | 32.5 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a last observation carried forward (LOCF) approach followed by Exact conditional logistic regression model.p-value: <0.000195% CI: [11.1, 3022.1]Regression, Exact Conditional 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 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first (on-treatment analysis).
Time frame: Up to Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | 0.8 percentage of participants |
| Alirocumab 75 mg/ up to 150 mg | Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis | 39.0 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a LOCF approach followed by Exact conditional logistic regression model.p-value: <0.000195% CI: [16.5, 4759.3]Regression, Exact Conditional Logistic
Secondary
Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis
Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).
Time frame: Up to Week 24
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe | Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | 4.4 percentage of participants |
| Alirocumab 75 mg/ up to 150 mg | Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | 41.9 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.p-value: <0.000195% CI: [6.9, 55.2]Regression, Logistic
Secondary
Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate 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 obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first (on-treatment analysis).
Time frame: Up to Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe | Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | 5.6 percentage of participants |
| Alirocumab 75 mg/ up to 150 mg | Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | 51.2 percentage of participants |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.p-value: <0.000195% CI: [8.6, 71.9]Regression, Logistic
Secondary
Percent Change From Baseline in Apo A--1 at Week 12 -- ITT Analysis
Least squares (LS) means and standard errors (SE) taken from MMRM (mixed effect model with repeated measures) analysis.
Time frame: From Baseline to Week 12
Population: Apo A-1 ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Apo A--1 at Week 12 -- ITT Analysis | 3.9 percent change | Standard Error 1 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Apo A--1 at Week 12 -- ITT Analysis | 5.5 percent change | Standard Error 1 |
Secondary
Percent Change From Baseline in 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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis | 2.9 percent change | Standard Error 1.2 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis | 4.8 percent change | Standard Error 1.2 |
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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
Population: Apo B ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Apo B at Week 12 -- ITT Analysis | -11.6 percent change | Standard Error 1.5 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Apo B at Week 12 -- ITT Analysis | -36.1 percent change | Standard Error 1.5 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-28.7, -20.4]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 24 (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 24
Population: Participants analyzed: participants of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Apo B at Week 24 -- On--Treatment Analysis | -14.4 percent change | Standard Error 1.4 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Apo B at Week 24 -- On--Treatment Analysis | -42.6 percent change | Standard Error 1.3 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-32.1, -24.4]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 -- ITT Analysis | -11.2 percent change | Standard Error 1.7 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 -- ITT Analysis | -36.3 percent change | Standard Error 1.7 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-29.8, -20.4]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL--C at Week 12 -- ITT Analysis
Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
Population: ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Calculated LDL--C at Week 12 -- ITT Analysis | -15.6 percent change | Standard Error 2 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Calculated LDL--C at Week 12 -- ITT Analysis | -47.0 percent change | Standard Error 1.9 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-36.9, -26.1]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 12 - On--Treatment Analysis
Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
Time frame: From Baseline to Week 12
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Calculated LDL-C at Week 12 - On--Treatment Analysis | -18.0 percent change | Standard Error 1.8 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 12 - On--Treatment Analysis | -51.2 percent change | Standard Error 1.7 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-38, -28.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated LDL-C at Week 24 - On--Treatment Analysis
Calculated LDL-C values were obtained from Friedewald formula. 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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
Time frame: From Baseline to Week 24
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 |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Calculated LDL-C at Week 24 - On--Treatment Analysis | -17.1 percent change | Standard Error 2 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 24 - On--Treatment Analysis | -52.2 percent change | Standard Error 2 |
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 5% level.p-value: <0.000195% CI: [-40.7, -29.5]Mixed Models Analysis
Secondary
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
Time frame: From Baseline to Week 24
Population: Participants analyzed: participants of the ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | -3.6 percent change | Standard Error 2.8 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | -9.3 percent change | Standard Error 2.7 |
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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | 6.8 percent change | Standard Error 1.7 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis | 7.7 percent change | Standard Error 1.7 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: =0.699795% CI: [-3.8, 5.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Lipoprotein(a) at Week 12 -- ITT Analysis
Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
Time frame: From Baseline to Week 12
Population: Lipoprotein(a) ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Lipoprotein(a) at Week 12 -- ITT Analysis | -4.5 percent change | Standard Error 2.3 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Lipoprotein(a) at Week 12 -- ITT Analysis | -21.7 percent change | Standard Error 2.2 |
Secondary
Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis
Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
Time frame: From Baseline to Week 24
Population: Participants analyzed: participants of the ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis | -7.3 percent change | Standard Error 2.5 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis | -25.9 percent change | Standard Error 2.4 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant). Statistical analysis used a multiple imputation approach followed by a robust regression model.p-value: <0.000195% CI: [-25.5, -11.8]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
Population: Non-HDL-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | -15.8 percent change | Standard Error 1.5 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis | -41.5 percent change | Standard Error 1.5 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-29.9, -21.5]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 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (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 24
Population: Participants analyzed: participants of the mITT population with one baseline and at least one post-baseline Non-HDL-C value on-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Non--HDL-C at Week 24 -- On--Treatment Analysis | -17.1 percent change | Standard Error 1.5 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Non--HDL-C at Week 24 -- On--Treatment Analysis | -46.9 percent change | Standard Error 1.4 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-33.9, -25.8]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Non--High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 -- ITT Analysis | -14.6 percent change | Standard Error 1.7 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Non--High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 -- ITT Analysis | -40.2 percent change | Standard Error 1.7 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-30.4, -20.8]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 12
Population: Total-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | -11.6 percent change | Standard Error 1.2 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Total-C at Week 12 - ITT Analysis | -32.7 percent change | Standard Error 1.2 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-24.5, -17.7]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 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline total-C value on- or off-treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Total Cholesterol (Total--C) at Week 24 - ITT Analysis | -10.9 percent change | Standard Error 1.4 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Total Cholesterol (Total--C) at Week 24 - ITT Analysis | -31.8 percent change | Standard Error 1.4 |
Comparison: Testing according to the hierarchical testing procedure (previous endpoints were statistically significant).p-value: <0.000195% CI: [-24.7, -17]Mixed Models Analysis
Secondary
Percent Change in Fasting Triglycerides From Baseline to Week 12 -- ITT Analysis
Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
Time frame: From Baseline to Week 12
Population: Fasting Triglycerides ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change in Fasting Triglycerides From Baseline to Week 12 -- ITT Analysis | -9.4 percent change | Standard Error 2.6 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change in Fasting Triglycerides From Baseline to Week 12 -- ITT Analysis | -8.0 percent change | Standard Error 2.5 |
Secondary
Percent Change in HDL-C From Baseline to Week 12 -- ITT Analysis
Least-squares (LS) means and standard errors (SE) taken from MMRM (mixed-effect model with repeated measures) analysis
Time frame: From Baseline to Week 12
Population: HDL-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change in HDL-C From Baseline to Week 12 -- ITT Analysis | 7.6 percent change | Standard Error 1.2 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change in HDL-C From Baseline to Week 12 -- ITT Analysis | 9.0 percent change | Standard Error 1.2 |
Other Pre-specified
Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE)
Skeletal muscle-related adverse events were a predefined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness and muscle fatigue. Events that developed during treatment emergent adverse events period (the time from the first double-blindstudy treatment \[injection or capsules, whichever came first\] up to the day of the last double-blind injection + 70 days ) are reported.
Time frame: From Baseline up to Week 24
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ezetimibe | Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE) | Any skeletal muscle-related AE | 46.0 Percentage of Participants |
| Ezetimibe | Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE) | Leading to treatment discontinuation | 22.2 Percentage of Participants |
| Alirocumab 75 mg/ up to 150 mg | Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE) | Any skeletal muscle-related AE | 41.1 Percentage of Participants |
| Alirocumab 75 mg/ up to 150 mg | Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE) | Leading to treatment discontinuation | 20.2 Percentage of Participants |
| Alirocumab 75 mg/ up to 150 mg | Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE) | Any skeletal muscle-related AE | 32.5 Percentage of Participants |
| Alirocumab 75 mg/ up to 150 mg | Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE) | Leading to treatment discontinuation | 15.9 Percentage of Participants |
Other Pre-specified
Percent Change From Baseline in Calculated LDL-C at Week 24 Versus Atorvastatin - Raw Data Description - Intent-To-Treat (ITT) Analysis
Time frame: From Baseline up to Week 24
Population: ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe | Percent Change From Baseline in Calculated LDL-C at Week 24 Versus Atorvastatin - Raw Data Description - Intent-To-Treat (ITT) Analysis | -31.9 percent change | Standard Deviation 25.1 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 24 Versus Atorvastatin - Raw Data Description - Intent-To-Treat (ITT) Analysis | -15.2 percent change | Standard Deviation 22.4 |
| Alirocumab 75 mg/ up to 150 mg | Percent Change From Baseline in Calculated LDL-C at Week 24 Versus Atorvastatin - Raw Data Description - Intent-To-Treat (ITT) Analysis | -47.3 percent change | Standard Deviation 22.7 |