Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) When Co-administered With High Dose of Atorvastatin in Patients With Primary Hypercholesterolemia

Study Overview
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Brief Summary
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Primary Objective: To evaluate the effect of alirocumab (SAR236553/REGN727) on low-density lipoprotein cholesterol (LDL-C) levels compared with placebo when co-administered with 80 mg of atorvastatin after 8 weeks of treatment in participants with LDL-C ≥ 100mg/dL (≥ 2.59 mmol/L) on atorvastatin 10 mg. Secondary Objectives: To evaluate the effects of alirocumab on other lipid levels in comparison with placebo, when co-administered with 80 mg of atorvastatin after 8 weeks of treatment. To evaluate the efficacy of alirocumab when co-administered with a high dose of atorvastatin (80 mg) versus atorvastatin 10 mg. To evaluate the safety and tolerability of alirocumab when co-administered with 2 different doses of atorvastatin. To evaluate the development of anti-alirocumab antibodies. To evaluate the pharmacokinetics of alirocumab.

Detailed Description
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The duration of study participation depended on the status of the patient at screening: For participants receiving atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening, the study participation was to be approximately 17 weeks including a screening period of 1 week, a double-blind treatment period of 8 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 for at least 6 weeks prior to screening, or drug naive participants, the study participation was to be approximately 23 weeks with a screening period of 1 week, a run-in treatment period with atorvastatin 10 mg of 6 weeks, a double-blind treatment period of 8 weeks and a follow-up period of 8 weeks.

Official Title
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A Randomized, Double-blind, Parallel-group, Placebo-controlled, Fixed Dose/Dose Regimen, Multicenter Study Evaluating the Efficacy and Safety of SAR236553 When Co-administered With 80 mg of Atorvastatin Over 8 Weeks in Patients With Primary Hypercholesterolemia and LDL-cholesterol ≥ 100 mg/dL (≥2.59 mmol/L) on Atorvastatin 10 mg

Conditions
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Hypercholesterolemia

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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: - Participants receiving a lipid-lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening, or drug naive participants with primary hypercholesterolemia 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 stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening and likely to have low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥ 2.59 mmol/L) at the screening visit. Exclusion criteria: LDL-C < 100 mg/dL (< 2.59 mmol/L) at Week -1 (V1): After the run-in period on atorvastatin 10 mg for participants receiving a lipid lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg for at least 6 weeks prior to the screening period, or drug naive participants. OR At the first visit for participants who are being treated with atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening visit. 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 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
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Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Placebo Comparator: Placebo + Atorvastatin 80 mg<br>Placebo (for alirocumab) subcutaneous (SC) administration every 2 weeks (Q2W) in combination with atorvastatin 80 mg orally once daily for 8 weeks. | Drug: Placebo (for alirocumab)<br>* One SC injection in the abdomen only.<br>Drug: Atorvastatin<br>* Over-encapsulated tablet orally once daily in the evening with dinner.<br>|
| Experimental: Alirocumab + Atorvastatin 10 mg<br>Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks. | Drug: Alirocumab<br>* One subcutaneous (SC) injection in the abdomen only.<br>* Other names: REGN727;Drug: Atorvastatin<br>* Over-encapsulated tablet orally once daily in the evening with dinner.<br>Drug: Placebo (for atorvastatin)<br>* One over-encapsulated tablet of placebo for atorvastatin orally once daily in the evening with dinner.<br>|
| Experimental: Alirocumab + Atorvastatin 80 mg<br>Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks. | Drug: Alirocumab<br>* One subcutaneous (SC) injection in the abdomen only.<br>* Other names: REGN727;Drug: Atorvastatin<br>* Over-encapsulated tablet orally once daily in the evening with dinner.<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 LDL-C at Week 8 - 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 8 data were imputed by last observation carried forward [LOCF] method. | From Baseline to Week 8 (LOCF) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis | Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint. | From baseline to Week 8 (LOCF) | 
| Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis | Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint. | From baseline to Week 8 (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 8 - On-treatment Analysis |  | Week 8 (LOCF) | 
| Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - 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 (interquartile range). | From baseline to Week 8 (LOCF) | 
| Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis | Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint. | From Baseline to Week 8 (LOCF) | 
| Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis | Adjusted LS means and standard errors were estimated using the same ANCOVA as for primary endpoint. | From Baseline to Week 8 (LOCF) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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10020603