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

Study Overview
=================
Brief Summary
-----------------
Primary Objective: To evaluate the effect of alirocumab (SAR236553/REGN727) 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: For participants receiving atorvastatin 10 mg, 20 mg, or 40 mg at a stable dose for at least 6 weeks prior to screening, the study participation was to be approximately 21 weeks including a screening period of 1 week, a double-blind treatment period of 12 weeks and a follow-up period of 8 weeks. For participants receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening, or drug naive participants, the study participation was to be approximately 27 weeks including a screening period of 1 week, a run-in treatment period with atorvastatin 10 mg, 20 mg, or 40 mg at a stable dose of 6 weeks, a double-blind treatment period of 12 weeks, and a follow-up period of 8 weeks.

Official Title
-----------------
A Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicenter Study Evaluating the Efficacy and Safety of Five Doses and Two Dose Regimens of SAR236553 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 receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening period or drug naive participants if they are likely to have low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥ 2.59 mmol/L) at the end of the 6-week run-in treatment period on atorvastatin therapy OR Participants with primary hypercholesterolemia treated with atorvastatin at stable dose of 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening period and likely to have LDL-C ≥ 100 mg/dL (≥ 2.59 mmol/L) at the screening visit Exclusion criteria: LDL-C < 100 mg/dL (< 2.59 mmol/L): After the run-in period on atorvastatin (10 mg, 20 mg, or 40 mg) for participants receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to the screening, or drug naive participant OR At the first visit for participants who were being treated with stable dose of atorvastatin (10 mg, 20 mg, or 40 mg) for at least 6 weeks prior to screening Participants not previously instructed on a cholesterol-lowering diet Participants with type 1 diabetes Participants with type 2 diabetes treated with insulin Participants with type 2 diabetes and with an glycated hemoglobin (HbA1c) ≥ 8.5% at screening visit (considered poorly controlled) Laboratory findings measured before randomization: Triglycerides (TG) > 350 mg/dL (> 3.95 mmol/L) at screening visit Positive serum or urine pregnancy test in females of childbearing potential Pregnant or breast-feeding women Women of childbearing potential with no effective contraceptive method 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: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Q2W<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.<br>Drug: Atorvastatin<br>* Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.<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: REGN727;Drug: Atorvastatin<br>* Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.<br>|
| Experimental: Alirocumab 100 mg Q2W<br>Alirocumab 100 mg Q2W for 12-weeks in combination with atorvastatin stable dose. | Drug: Alirocumab<br>* Two SC injections in the abdomen only.<br>* Other names: REGN727;Drug: Atorvastatin<br>* Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.<br>|
| Experimental: 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: REGN727;Drug: Atorvastatin<br>* Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.<br>|
| Experimental: Alirocumab 200 mg Q4W<br>Alirocumab 200 mg every 4 weeks (Q4W) and alternating placebo Q2W for 12-weeks in combination with atorvastatin stable dose. | Drug: Alirocumab<br>* Two SC injections in the abdomen only.<br>* Other names: REGN727;Drug: Placebo (for alirocumab)<br>* Two subcutaneous (SC) injections in the abdomen only.<br>Drug: Atorvastatin<br>* Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.<br>|
| Experimental: Alirocumab 300 mg Q4W<br>Alirocumab 300 mg Q4W and alternating placebo Q2W for 12-weeks in combination with atorvastatin stable dose. | Drug: Alirocumab<br>* Two SC injections in the abdomen only.<br>* Other names: REGN727;Drug: Placebo (for alirocumab)<br>* Two subcutaneous (SC) injections in the abdomen only.<br>Drug: Atorvastatin<br>* Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.<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 study drug injection up to 21 days after last study drug 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 in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 12 - On-Treatment Analysis | Adjusted LS mean and standard errors were estimated using the same ANCOVA as for primary endpoint. | Baseline to Week 12 (LOCF) |