Evaluation of Alirocumab in Addition to Lipid-Modifying Therapy in Patients With High Cardiovascular Risk and Hypercholesterolemia in South Korea and Taiwan

Study Overview
=================
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 with or without other lipid-modifying therapy (LMT) in comparison with placebo after 24 weeks of treatment in high cardiovascular risk participants with hypercholesterolemia in South Korea and Taiwan. Secondary Objectives: To evaluate the effect of alirocumab in comparison with placebo on LDL-C after 12 weeks of treatment. To evaluate the effect of alirocumab on other lipid parameters: apolipoprotein B (Apo B), non high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), lipoprotein (a) (Lp [a]), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), and apolipoprotein A-1 (Apo A-1). To evaluate the safety and tolerability of alirocumab. To evaluate the development of anti-alirocumab antibodies (ADA).

Detailed Description
-----------------
The maximum study duration was approximately 35 weeks per participant, including up to 3 weeks screening period, 24 weeks double-blind treatment period, and 8 weeks follow-up period.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy in South Korea and Taiwan

Conditions
-----------------
Hypercholesterolemia

Intervention / Treatment
-----------------
* Drug: Placebo (for Alirocumab)
* Drug: Alirocumab
* Drug: Lipid-Modifying Therapy (LMT)


Participation Criteria
=================
Eligibility Criteria
-----------------
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 with or without other LMT, both at stable dose for at least 4 weeks prior to screening visit (Week -3). Exclusion criteria: Aged <18 years or legal age of adulthood, whichever was greater. Participants without established CHD or CHD risk equivalent. LDL-C <70 mg/dL (<1.81 mmol/L) in participants with a history of documented cardiovascular disease. LDL-C <100 mg/dL (<2.59 mmol/L) in participants without a history of documented cardiovascular disease. Not on a stable dose of LMT (including statin) for at least 4 weeks prior to the screening visit (Week -3) or between screening to randomization visits. 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 20 mg or simvastatin 40 mg. 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 participants's potential participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Q2W<br>Placebo (for alirocumab) subcutaneous (SC) injection every 2 weeks (Q2W) added to stable Lipid-Modifying Therapy (LMT) for 24 weeks. | Drug: Placebo (for Alirocumab)<br>* Solution for injection, one subcutaneous injection in the abdomen with a disposable auto-injector.<br>Drug: Lipid-Modifying Therapy (LMT)<br>* Statins (Rosuvastatin, Simvastatin or Atorvastatin) at stable dose with or without other LMT as clinically indicated.<br>|
| Placebo Comparator: Alirocumab 75 mg Q2W/Up to 150 mg Q2W<br>Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8. | Drug: Alirocumab<br>* Solution for injection, one subcutaneous injection in the abdomen with a disposable auto-injector.<br>* Other names: Praluent®;Drug: Lipid-Modifying Therapy (LMT)<br>* Statins (Rosuvastatin, Simvastatin or Atorvastatin) at stable dose with or without other LMT as clinically indicated.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 up 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 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 up to Week 24 (i.e. up to 21 days after last injection) (on-treatment analysis). | From Baseline to Week 24 | 
| Percent Change From Baseline in Calculated LDL-C 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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis | Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data up to Week 24 (i.e. up to 21 days after last injection). | From Baseline to Week 24 | 
| Percent Change From Baseline in Apolipoprotein (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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| 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 up to Week 24 (i.e. up to 21 days after last injection). | 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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| 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 up to Week 24 (i.e. up to 21 days after last injection). | 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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in Apo 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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in Non-HDL-C 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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in Total-C 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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | Adjusted percentages at Week 24 were obtained from multiple imputation approach model for handling of missing data. All available post-baseline data up to Week 24 regardless of status on- or off-treatment were included in the imputation model. | From Baseline to Week 24 | 
| 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 multiple imputation approach model including available post-baseline on-treatment data up to Week 24 (i.e. up to 21 days after last injection). | From Baseline to Week 24 | 
| 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 up 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 (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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model including all available post-baseline data up 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 up 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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in HDL-C 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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | Adjusted means and standard errors at Week 12 were obtained from multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 | 
| Percent Change From Baseline in Apo 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 up to Week 24 regardless of status on- or off-treatment. | From Baseline to Week 24 |