Evaluation of Alirocumab Versus Ezetimibe on Top of Statin in Asia in High Cardiovascular Risk Patients With Hypercholesterolemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Double-blind, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe in Asia in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Statin Therapy

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: Alirocumab
* Drug: Placebo for alirocumab
* Drug: ezetimibe
* Drug: placebo for ezetimibe
* Drug: atorvastatin
* Drug: rosuvastatin
* Drug: simvastatin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ezetimibe 10 mg<br>Oral ezetimibe 10 mg capsule once daily with or without food for 24 weeks and subcutaneous placebo injection for alirocumab every 2 weeks (Q2W) for 22 weeks added to lipid modifying therapy (LMT). | Drug: Placebo for alirocumab<br>* Pharmaceutical form:solution Route of administration: subcutaneous<br>Drug: ezetimibe<br>* Pharmaceutical form:capsule Route of administration: oral<br>Drug: atorvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: rosuvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: simvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>|
| Experimental: Alirocumab 75 mg Q2W/up to 150 mg Q2W<br>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 milligrams per deciliter (mg/dL) (1.81 millimoles per liter [mmol/L]) at Week 8. | Drug: Alirocumab<br>* Pharmaceutical form:solution Route of administration: subcutaneous<br>* Other names: SAR236553 (REGN727);Drug: placebo for ezetimibe<br>* Pharmaceutical form:capsule Route of administration: oral<br>Drug: atorvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: rosuvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: simvastatin<br>* Pharmaceutical form:tablet Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | From Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | From Baseline to Week 24 | 
| 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. | From Baseline to Week 12 | 
| 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). | From Baseline to Week 12 | 
| 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. | From Baseline to Week 24 | 
| 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). | From Baseline to Week 24 | 
| 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. | From Baseline to Week 24 | 
| 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). | From Baseline to Week 24 | 
| 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. | From Baseline to Week 24 | 
| 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. | From Baseline to Week 12 | 
| 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. | From Baseline to Week 12 | 
| 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. | From Baseline to Week 12 | 
| 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. | Up to Week 24 | 
| 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). | Up to Week 24 | 
| 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. | From Baseline to Week 24 | 
| 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. | From Baseline to Week 24 | 
| 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. | From Baseline to Week 24 | 
| 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. | From Baseline to Week 24 | 
| 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. | From Baseline to Week 12 | 
| 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. | From Baseline to Week 12 | 
| 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. | From Baseline to Week 12 | 
| 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. | From Baseline to Week 12 |