Hypercholesterolemia
Conditions
Brief summary
Primary Objective: 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 to ezetimibe 10 mg daily after 24 weeks of treatment in Asia in participants with hypercholesterolemia at high cardiovascular (CV) risk. Secondary Objectives: * To evaluate the effect of alirocumab 75 mg in comparison with ezetimibe 10 mg on LDL-C after 12 weeks of treatment. * To evaluate the effect of alirocumab on other lipid parameters: e.g., apolipoprotein B (Apo B), non-high density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), lipoprotein a (Lp\[a\]), HDL-C, triglycerides (TG), apolipoprotein A-1 (Apo A-1). * To evaluate the safety and tolerability of alirocumab. * To evaluate the development of anti-alirocumab antibodies. * To evaluate the pharmacokinetics (PK) of alirocumab.
Detailed description
The maximum study duration was 35 weeks per participant, which included a screening period of up to 3 weeks, a 24-week randomized treatment period, and an 8-week post-treatment follow-up period.
Interventions
DRUGAlirocumab
Pharmaceutical form:solution Route of administration: subcutaneous
DRUGPlacebo for alirocumab
Pharmaceutical form:solution Route of administration: subcutaneous
DRUGezetimibe
Pharmaceutical form:capsule Route of administration: oral
Pharmaceutical form:capsule Route of administration: oral
DRUGatorvastatin
Pharmaceutical form:tablet Route of administration: oral
DRUGrosuvastatin
Pharmaceutical form:tablet Route of administration: oral
DRUGsimvastatin
Pharmaceutical form:tablet Route of administration: oral
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 are not adequately controlled with a maximally tolerated daily dose of statin at a stable dose for at least 4 weeks prior to the screening visit (Week -3).
Exclusion criteria
* Participants without established CHD or CHD risk equivalents. * LDL-C \<70 mg/dL (\<1.81 mmol/L) at the screening visit (Week -3) in participants with history of documented CV disease. * LDL-C \<100 mg/dL (\<2.59 mmol/L) at the screening visit (Week -3) in participants without history of documented CV disease. * Change in statin dose or dose regimen from screening to randomization. * Currently taking a statin other than atorvastatin, rosuvastatin, or simvastatin. * Atorvastatin, rosuvastatin, or simvastatin was not taken daily or not taken at a registered dose. * Daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg. * Use of cholesterol absorption inhibitor (ie, ezetimibe), omega-3 fatty acid (at doses ≥1000 mg daily), nicotinic acid, fibrates, bile acid-binding sequestrant, or red yeast rice products in the past 4 weeks prior to screening visit (Week -3). * Fasting serum triglycerides \>400 mg/dL (\>4.52 mmol/L) at the screening period. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 24: Intent-to-treat (ITT) Analysis | From Baseline to Week 24 | Adjusted least square (LS) means and standard errors at Week 24 were obtained from mixed models analysis 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 Low Density Lipoprotein Cholesterol at Week 12: ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 were obtained 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 Low Density Lipoprotein Cholesterol at Week 12: On-Treatment Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including all 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 B (Apo B) at Week 24: ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 were obtained 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 Apolipoprotein 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 all 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 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 were obtained 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-High Density Lipoprotein Cholesterol 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 all 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 Total Cholesterol (Total-C) at Week 24: ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all available post-baseline data from Week 4 up to Week 24 regardless of status on- or off-treatment. |
| Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 were obtained 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-High Density Lipoprotein Cholesterol at Week 12: ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 were obtained 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 Cholesterol at Week 12: ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 were obtained 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 Low Density Lipoprotein Cholesterol 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 all 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 Low Density Lipoprotein Cholesterol <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 multiple imputation approach including all 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) (Lp[a]) at Week 24: ITT Analysis | From Baseline to Week 24 | Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling 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. |
| Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 24: ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 were obtained 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 (TG) at Week 24: ITT Analysis | From Baseline to Week 24 | Adjusted means and standard errors at Week 24 were obtained by using multiple imputation approach followed by robust regression 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 Apolipoprotein A-1 (Apo A-1) at Week 24: ITT Analysis | From Baseline to Week 24 | Adjusted LS means and standard errors at Week 24 were obtained 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 | Adjusted means and standard errors at Week 12 were obtained from multiple imputation approach followed by robust regression 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 High Density Lipoprotein Cholesterol at Week 12: ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 were obtained 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 12: ITT Analysis | From Baseline to Week 12 | Adjusted means and standard errors at Week 12 were obtained by using multiple imputation approach followed by a robust regression 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 Apolipoprotein A-1 at Week 12 : ITT Analysis | From Baseline to Week 12 | Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. |
| Percentage of Participants Reaching Calculated Low Density Lipoprotein Cholesterol <70 mg/dL (1.81 mmol/L) at Week 24: ITT Analysis | Up to Week 24 | 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 24 regardless of status on- or off-treatment were included in the imputation model. |
Countries
China, India, Thailand
Participant flow
Recruitment details
The study was conducted at 61 centers in China, India and Thailand. Overall 1163 participants were screened between 27 July 2016 and 18 December 2017, of whom 548 were screen failures. Screen failures were mainly due to exclusion criteria met. A total of 615 participants were randomized in 2:1 ratio to alirocumab: ezetimibe.
Pre-assignment details
Randomization was stratified according to prior history of myocardial infarction (MI) or ischemic stroke \[Yes/No\], and high-intensity statin treatment (Yes: atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily, no: atorvastatin below 40 mg daily, rosuvastatin below 20 mg daily or simvastatin whatever the dose daily) and country.
Participants by arm
| Arm | Count |
|---|---|
| Ezetimibe 10 mg Oral ezetimibe 10 mg capsule once daily with or without food for 24 weeks and subcutaneous placebo injection for alirocumab Q2W for 22 weeks added to LMT. | 208 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe once daily with or without food added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C level was \>=70 mg/dL (1.81 mmol/L) at Week 8. | 407 |
| Total | 615 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 6 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Other than specified above | 11 | 15 |
| Overall Study | Participant moved | 1 | 3 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Randomized but not treated | 1 | 2 |
Baseline characteristics
| Characteristic | Ezetimibe 10 mg | Alirocumab 75 mg Q2W/up to 150 mg Q2W | Total |
|---|---|---|---|
| Age, Continuous | 58.3 Years STANDARD_DEVIATION 11.2 | 58.8 Years STANDARD_DEVIATION 10.7 | 58.6 Years STANDARD_DEVIATION 10.8 |
| Calculated LDL-C in mmol/L | 2.875 mmol/L STANDARD_DEVIATION 1.287 | 2.862 mmol/L STANDARD_DEVIATION 1.253 | 2.866 mmol/L STANDARD_DEVIATION 1.264 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 208 Participants | 407 Participants | 615 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 62 Participants | 92 Participants | 154 Participants |
| Sex: Female, Male Male | 146 Participants | 315 Participants | 461 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 206 | 2 / 406 |
| other Total, other adverse events | 41 / 206 | 71 / 406 |
| serious Total, serious adverse events | 23 / 206 | 41 / 406 |
Outcome results
Primary
Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 24: Intent-to-treat (ITT) Analysis
Adjusted least square (LS) means and standard errors at Week 24 were obtained from mixed models analysis 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 included 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 10 mg | Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 24: Intent-to-treat (ITT) Analysis | -20.3 percent change | Standard Error 2 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 24: Intent-to-treat (ITT) Analysis | -56.0 percent change | Standard Error 1.5 |
Comparison: Alirocumab group was compared to ezetimibe group using an appropriate contrast statement.p-value: <0.000195% CI: [-40.6, -30.7]Mixed Models Analysis
Secondary
Percentage of Participants Reaching Calculated Low Density Lipoprotein Cholesterol <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 24 regardless of status on- or off-treatment were included in the imputation model.
Time frame: Up to Week 24
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ezetimibe 10 mg | Percentage of Participants Reaching Calculated Low Density Lipoprotein Cholesterol <70 mg/dL (1.81 mmol/L) at Week 24: ITT Analysis | 40.5 percentage of participants |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percentage of Participants Reaching Calculated Low Density Lipoprotein Cholesterol <70 mg/dL (1.81 mmol/L) at Week 24: ITT Analysis | 85.1 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: [7.1, 17.7]Regression, Logistic
Secondary
Percentage of Participants Reaching Calculated Low Density Lipoprotein Cholesterol <70 mg/dL (1.81 mmol/L) at Week 24: On-Treatment Analysis
Adjusted percentages at Week 24 were obtained from multiple imputation approach including all 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 10 mg | Percentage of Participants Reaching Calculated Low Density Lipoprotein Cholesterol <70 mg/dL (1.81 mmol/L) at Week 24: On-Treatment Analysis | 42.1 percentage of participants |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percentage of Participants Reaching Calculated Low Density Lipoprotein Cholesterol <70 mg/dL (1.81 mmol/L) at Week 24: On-Treatment Analysis | 87.0 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: [8.3, 22.3]Regression, Logistic
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 were obtained 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 from 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 |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24: ITT Analysis | -0.2 percent change | Standard Error 0.8 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24: ITT Analysis | 3.2 percent change | Standard Error 0.6 |
Secondary
Percent Change From Baseline in Apolipoprotein A-1 at Week 12 : ITT Analysis
Adjusted LS means and standard errors at Week 12 were obtained 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 A-1 ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Apolipoprotein A-1 at Week 12 : ITT Analysis | 1.1 percent change | Standard Error 0.8 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Apolipoprotein A-1 at Week 12 : ITT Analysis | 3.7 percent change | Standard Error 0.6 |
Secondary
Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Analysis
Adjusted LS means and standard errors at Week 24 were obtained 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 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 |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Analysis | -16.2 percent Change | Standard Error 1.4 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Analysis | -43.5 percent Change | Standard Error 1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-30.8, -23.9]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Analysis
Adjusted LS means and standard errors at Week 12 were obtained 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 10 mg | Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Analysis | -16.5 percent Change | Standard Error 1.4 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Analysis | -43.0 percent Change | Standard Error 1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-29.8, -23.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Apolipoprotein B at Week 24: On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all 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: 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 |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Apolipoprotein B at Week 24: On-Treatment Analysis | -17.4 percent Change | Standard Error 1.4 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Apolipoprotein B at Week 24: On-Treatment Analysis | -45.2 percent Change | Standard Error 1 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-31.2, -24.4]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 12: ITT Analysis
Adjusted LS means and standard errors at Week 12 were obtained 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 10 mg | Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 12: ITT Analysis | -22.2 percent change | Standard Error 1.9 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 12: ITT Analysis | -57.1 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: [-39.5, -30.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 12: On-Treatment Analysis
Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including all 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 10 mg | Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 12: On-Treatment Analysis | -22.7 percent change | Standard Error 1.9 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 12: On-Treatment Analysis | -58.1 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: [-40, -30.7]Mixed Models Analysis
Secondary
Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 24: On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all 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 included 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 10 mg | Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 24: On-Treatment Analysis | -21.3 percent change | Standard Error 2 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 24: On-Treatment Analysis | -58.7 percent change | Standard Error 1.4 |
Comparison: A hierarchical testing method 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: [-42.1, -32.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Fasting Triglycerides at Week 12: ITT Analysis
Adjusted means and standard errors at Week 12 were obtained by using multiple imputation approach followed by a robust regression 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 (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Fasting Triglycerides at Week 12: ITT Analysis | -13.585 percent change | Standard Error 1.929 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides at Week 12: ITT Analysis | -9.965 percent change | Standard Error 1.379 |
Secondary
Percent Change From Baseline in Fasting Triglycerides (TG) at Week 24: ITT Analysis
Adjusted means and standard errors at Week 24 were obtained by using multiple imputation approach followed by robust regression 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: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Fasting Triglycerides (TG) at Week 24: ITT Analysis | -14.409 percent change | Standard Error 1.904 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Fasting Triglycerides (TG) at Week 24: ITT Analysis | -14.462 percent change | Standard Error 1.341 |
Secondary
Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 12: ITT Analysis
Adjusted LS means and standard errors at Week 12 were obtained 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: HDL-C ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 12: ITT Analysis | 6.1 percent change | Standard Error 1.2 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 12: ITT Analysis | 7.3 percent change | Standard Error 0.9 |
Secondary
Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 24: ITT Analysis
Adjusted LS means and standard errors at Week 24 were obtained 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 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 |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 24: ITT Analysis | 6.5 percent change | Standard Error 1.3 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 24: ITT Analysis | 8.3 percent change | Standard Error 0.9 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: 0.22895% CI: [-1.2, 4.9]Mixed Models Analysis
Secondary
Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Analysis
Adjusted means and standard errors at Week 12 were obtained from multiple imputation approach followed by robust regression 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 (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Analysis | 6.313 percent Change | Standard Error 2.056 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Analysis | -30.064 percent Change | Standard Error 1.449 |
Secondary
Percent Change From Baseline in Lipoprotein (a) (Lp[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 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.
Time frame: From Baseline to Week 24
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Lipoprotein (a) (Lp[a]) at Week 24: ITT Analysis | 3.956 percent Change | Standard Error 2.095 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Lipoprotein (a) (Lp[a]) at Week 24: ITT Analysis | -30.317 percent Change | Standard Error 1.461 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-39.262, -29.285]Regression, Robust
Secondary
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 12: ITT Analysis
Adjusted LS means and standard errors at Week 12 were obtained 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 10 mg | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 12: ITT Analysis | -20.7 percent Change | Standard Error 1.6 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 12: ITT Analysis | -47.4 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: [-30.5, -22.8]Mixed Models Analysis
Secondary
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 24: On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all 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: 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 |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 24: On-Treatment Analysis | -20.4 percent Change | Standard Error 1.7 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 24: On-Treatment Analysis | -49.1 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: [-32.6, -24.7]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 were obtained 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 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 |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24: ITT Analysis | -19.4 percent Change | Standard Error 1.7 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24: ITT Analysis | -47.0 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: [-31.8, -23.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Total Cholesterol at Week 12: ITT Analysis
Adjusted LS means and standard errors at Week 12 were obtained 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 10 mg | Percent Change From Baseline in Total Cholesterol at Week 12: ITT Analysis | -14.9 percent Change | Standard Error 1.2 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Total Cholesterol at Week 12: ITT Analysis | -34.2 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: [-22.1, -16.5]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 were obtained from MMRM model including all available post-baseline data from Week 4 up to Week 24 regardless of status on- or off-treatment.
Time frame: From Baseline to Week 24
Population: Participants from 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 |
|---|---|---|---|
| Ezetimibe 10 mg | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24: ITT Analysis | -13.8 percent Change | Standard Error 1.2 |
| Alirocumab 75 mg Q2W/up to 150 mg Q2W | Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24: ITT Analysis | -33.9 percent Change | Standard Error 0.9 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).p-value: <0.000195% CI: [-23.1, -17.2]Mixed Models Analysis