Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) in Patients With Primary Hypercholesterolemia on Stable Atorvastatin Therapy in Japan

Study Overview
=================
Brief Summary
-----------------
Alirocumab (SAR236553/REGN727) is a fully human monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9). Primary Objective of the study: To evaluate the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels after 12 weeks of treatment in comparison with placebo in participants with LDL-C ≥100 mg/dL (≥2.59 mmol/L) on ongoing stable atorvastatin therapy. Secondary Objectives: To evaluate the effects of alirocumab on other lipid levels after 12 weeks of treatment in comparison with placebo To evaluate the safety and tolerability of alirocumab To evaluate the development of anti-alirocumab antibodies To evaluate the pharmacokinetics of alirocumab

Detailed Description
-----------------
The duration of study participation depended on the status of the participant at screening: 21 to 27 weeks including a screening/run-in period of 1 to 7 weeks, a double-blind treatment period of 12 weeks, followed by an 8-week follow-up period.

Official Title
-----------------
A Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Study Evaluating the Efficacy and Safety of Three Doses of SAR236553 (REGN727) Over 12 Weeks in Patients With Primary Hypercholesterolemia and LDL-cholesterol ≥100 mg/dL (≥2.59 mmol/L) on Ongoing Stable Atorvastatin Therapy

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

Intervention / Treatment
-----------------
* Drug: Alirocumab
* Drug: Placebo (for alirocumab)
* Drug: Atorvastatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria : - Participants with primary hypercholesterolemia treated with atorvastatin at stable dose of 5-20 mg for at least 6 weeks prior to screening and likely to have LDL-C ≥100 mg/dL (≥2.59 mmol/L) at the screening visit. OR - Participants with primary hypercholesterolemia who were receiving a lipid-lowering treatment other than atorvastatin, or who were not at stable dose of atorvastatin 5-20 mg for at least 6 weeks prior to screening if they were likely to have LDL-C ≥100 mg/dL (≥2.59 mmol/L) after a 6-week run-in treatment period on atorvastatin therapy. Exclusion criteria: LDL-C <100 mg/dL (<2.59 mmol/L) at screening visit for participants who were being treated with stable dose of atorvastatin 5-20 mg for at least 6 weeks prior to screening OR at the end of the 6-week run-in period on atorvastatin for participants receiving a lipid lowering treatment other than atorvastatin, or not at stable dose of atorvastatin 5-20 mg for at least 6 weeks prior to screening Participants with type 1 diabetes Participants with type 2 diabetes treated with insulin, or without, and considered poorly controlled at screening. 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
-----------------
Minimum Age: 20 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo (for alirocumab) every 2 weeks (Q2W) for 12-weeks in combination with atorvastatin stable dose. | Drug: Placebo (for alirocumab)<br>* Two subcutaneous (SC) injections in the abdomen only Route of administration: subcutaneous injection (1 mL) in the abdomen<br>Drug: Atorvastatin<br>* Orally once daily at a stable dose of 5 to 20 mg as background therapy Route of administration: oral administration in the evening<br>|
| Experimental: Alirocumab 50 mg Q2W<br>Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose. | Drug: Alirocumab<br>* Two SC injections in the abdomen only<br>* Other names: RGEN727;Drug: Atorvastatin<br>* Orally once daily at a stable dose of 5 to 20 mg as background therapy Route of administration: oral administration in the evening<br>|
| Experimental: Alirocumab 75 mg Q2W<br>Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose. | Drug: Alirocumab<br>* Two SC injections in the abdomen only<br>* Other names: RGEN727;Drug: Atorvastatin<br>* Orally once daily at a stable dose of 5 to 20 mg as background therapy Route of administration: oral administration in the evening<br>|
| Placebo Comparator: Alirocumab 150 mg Q2W<br>Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose. | Drug: Alirocumab<br>* Two SC injections in the abdomen only<br>* Other names: RGEN727;Drug: Atorvastatin<br>* Orally once daily at a stable dose of 5 to 20 mg as background therapy Route of administration: oral administration in the evening<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 12 - On-Treatment Analysis | Calculated LDL-C values were obtained using the Friedewald formula. Baseline adjusted least squares (LS) means and standard errors were estimated using an analysis of covariance (ANCOVA) model including available post-baseline data on treatment from first investigational product (IP) injection up to 21 days after last IP injection (on-treatment analysis). Missing Week 12 data were imputed by last observation carried forward [LOCF] method. | Baseline to Week 12 (LOCF) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 12 - On-Treatment Analysis | Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint. | Baseline to Week 12 (LOCF) | 
| Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 12 - On-Treatment Analysis | Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint. | Baseline to Week 12 (LOCF) | 
| Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 12 - On-Treatment Analysis |  | Week 12 (LOCF) | 
| Percent Change From Baseline in Total Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C), Non-HDL-C, and Apolipoprotein B (Apo-B) at Week 12 - On-Treatment Analysis | Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint. | Baseline to Week 12 (LOCF) | 
| Percent Change From Baseline in Fasting Triglycerides and Lipoprotein (a) at Week 12 - On-Treatment Analysis | Since the assumptions of normal distribution and equality of variances were not verified for the lipid parameters, percent changes were expressed as median (inter-quartile range). | Baseline to Week 12 (LOCF) | 
| Absolute Change From Baseline in Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) Ratio at Week 12 - On-Treatment Analysis | Adjusted LS mean and standard errors were estimated using the same ANCOVA as for primary endpoint. | From Baseline to Week 12 (LOCF) |