Study of Alirocumab (REGN727/SAR236553) in Patients With Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular (CV) Risk, Who Are Intolerant to Statins (ODYSSEY ALTERNATIVE)

Study Overview
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Brief Summary
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This is a randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-national, multi-center study to compare alirocumab (REGN727/SAR236553) versus ezetimibe in participants with primary hypercholesterolemia and moderate, high, or very high CV risk, who are intolerant to statins. An atorvastatin arm is added to determine that the population selected in the study is a truly statin intolerant population by assessing skeletal muscle-related adverse events.

Official Title
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A Randomized, Double-Blind, Double-Dummy, Active-Controlled Study to Evaluate the Efficacy and Safety of REGN727/SAR236553 in Patients With Primary Hypercholesterolemia Who Are Intolerant to Statins

Conditions
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Hypercholesterolemia

Intervention / Treatment
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* Drug: Atorvastatin
* Drug: Ezetimibe
* Drug: Alirocumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion: Patients with primary hypercholesterolemia [Heterozygous Familial Hypercholesterolemia (heFH) or non-FH] with moderate, high or very high CV risk and a history of statin intolerance Provide signed informed consent Exclusion: Calculated serum LDL-C <70 mg/dL (1.81 mmol/L) and very high CV risk at the screening visit Calculated serum LDL-C <100 mg/dL (2.59 mmol/L) and high or moderate CV risk at the screening visit A 10-year fatal cardiovascular disease risk score <1% at the screening visit (The inclusion/ exclusion criteria provided above is not intended to contain all considerations relevant to a patient's potential participation in this 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 |
| --- | --- |
| Other: Atorvastatin (statin rechallenge arm)<br>Atorvastatin 20 mg over-encapsulated tablets orally once daily (QD) for 24 weeks and placebo (for alirocumab) subcutaneous (SC) injection every two weeks (Q2W) for 24 weeks added to stable lipid-modifying therapy (LMT). | Drug: Atorvastatin<br>* Atorvastatin over-encapsulated tablets.<br>Drug: Placebo<br>* Placebo for alirocumab, ezitimibe and atorvastatin.<br>|
| Active Comparator: Ezetimibe<br>Ezetimibe 10 mg over-encapsulated tablets orally QD for 24 weeks and placebo (for alirocumab) SC injection Q2W for 24 weeks added to stable LMT. | Drug: Ezetimibe<br>* Ezetimibe over-encapsulated tablet.<br>* Other names: Zetia;Drug: Placebo<br>* Placebo for alirocumab, ezitimibe and atorvastatin.<br>|
| Experimental: Alirocumab 75 mg/ up to 150 mg<br>Alirocumab 75 mg SC injection Q2W for 24 weeks and placebo (for atorvastatin/ezetimibe) over-encapsulated tablets orally QD for 24 weeks added to stable LMT. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on cardiovascular risk. | Drug: Alirocumab<br>* Alirocumab SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.<br>* Other names: REGN727/SAR236553;Drug: Placebo<br>* Placebo for alirocumab, ezitimibe and atorvastatin.<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 24 - Intent--To-Treat (ITT) Analysis | Calculated LDL-C values were obtained from Friedewald formula. 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 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 LDL-C at Week 24 - On--Treatment Analysis | Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including 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 LDL--C at Week 12 -- ITT Analysis | Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 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 LDL-C at Week 12 - On--Treatment Analysis | Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including 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 (Apo) B at Week 24 -- ITT Analysis | Adjusted LS means and standard errors at Week 24 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 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 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). | 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 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--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 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). | 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 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 Apo B at Week 12 -- ITT Analysis | Adjusted LS means and standard errors at Week 12 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-HDL-C at Week 12 - ITT Analysis | Adjusted LS means and standard errors at Week 12 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-C at Week 12 - ITT Analysis | Adjusted LS means and standard errors at Week 12 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 Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | Adjusted percentages at Week 24 were obtained from a multiple imputation approach model 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 (ITT analysis). | Up to Week 24 | 
| Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis | Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including 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 | 
| 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 a multiple imputation approach model 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 (ITT analysis). | Up 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 a multiple imputation approach model including 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) at Week 24 - ITT Analysis | Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression 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 HDL-C at Week 24 - ITT Analysis | Adjusted LS means and standard errors at Week 24 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 at Week 24 - ITT Analysis | Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression 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 Apo A-1 at Week 24 - ITT Analysis | Adjusted LS means and standard errors at Week 24 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 | Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression 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 in HDL-C From Baseline to Week 12 -- ITT Analysis | Least-squares (LS) means and standard errors (SE) taken from MMRM (mixed-effect model with repeated measures) analysis | From Baseline to Week 12 | 
| Percent Change in Fasting Triglycerides From Baseline to Week 12 -- ITT Analysis | Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression 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 Apo A--1 at Week 12 -- ITT Analysis | Least squares (LS) means and standard errors (SE) taken from MMRM (mixed effect model with repeated measures) analysis. | From Baseline to Week 12 |