Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With High Cardiovascular Risk and Hypercholesterolemia (ODYSSEY COMBO I)

Study Overview
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Brief Summary
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Alirocumab (SAR236553/REGN727) is a fully human monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9). Primary Objective of the study: 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 (CV) risk participants with hypercholesterolemia Secondary Objectives: To evaluate the effect of alirocumab in comparison with placebo on LDL-C at other time points To evaluate the effect of alirocumab on other lipid parameters To evaluate the safety and tolerability of alirocumab

Detailed Description
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The maximum study duration was 62 weeks per participant, including a 2-week screening period, 52-week randomized treatment period, and 8-week follow-up period.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy

Conditions
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Hypercholesterolemia

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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants with hypercholesterolemia and established coronary heart disease (CHD) or CHD risk equivalents who were 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 to 6 weeks prior to screening (Week -2) Exclusion criteria: Age <18 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) and participants with a history of documented cardiovascular disease LDL-C <100 mg/dL (<2.59 mmol/L) and participants without a history of documented cardiovascular disease Not on a stable dose of LMT (including statin) for at least 4 weeks and/or fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (Week -2) and from screening to randomization Fasting serum triglycerides > 400 mg/dL (>4.52 mmol/L) 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

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 Q2W<br>Placebo (for alirocumab) every 2 weeks (Q2W) added to stable Lipid-Modifying Therapy (LMT) for 52 weeks. | Drug: Placebo (for alirocumab)<br>* Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector (also known as pre-filled pen).<br>Drug: Lipid-Modifying Therapy (LMT)<br>* Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose with or without other LMT as clinically indicated.<br>|
| Experimental: Alirocumab<br>Alirocumab 75 mg Q2W added to stable LMT for 52 weeks. Alirocumab dose up-titrated to 150 mg 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, thigh, or outer area of upper arm with a disposable auto-injector (also known as pre-filled pen).<br>* Other names: REGN727;Drug: Lipid-Modifying Therapy (LMT)<br>* Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose with or without other LMT as clinically indicated.<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 | 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 52 regardless of status on- or off-treatment were used in the model (ITT analysis). | From Baseline to Week 52 | 

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 from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis). | From Baseline to Week 52 | 
| Percent Change From Baseline in Calculated LDL-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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis | Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). | From Baseline to Week 52 | 
| 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 52 regardless of status on- or off-treatment. | From baseline to Week 52 | 
| Percent Change From Baseline in Apo B at Week 24 - On-treatment Analysis | Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). | From Baseline to Week 52 | 
| 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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| Percent Change From Baseline in Non-HDL-C at Week 24 - On-treatment Analysis | Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection). | From Baseline to Week 52 | 
| 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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| 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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| 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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| 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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis | Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| 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 from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model. | Up to Week 52 | 
| 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 from multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection. | Up to Week 52 | 
| 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 from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model. | From baseline to Week 52 | 
| 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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis | Adjusted means and standard errors at Week 24 from multiple imputation approach followed be robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| Percent Change From Baseline in Apolipoprotein 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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| Percent Change From Baseline in Lipoprotein(a) at Week 12- ITT Analysis | Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| Percent Change From Baseline in 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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis | Adjusted means and standard errors at Week 12 from multiple imputation approach followed by a robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment. | From Baseline to Week 52 | 
| Percent Change From Baseline in Apo A-1 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 52 regardless of status on- or off-treatment. | From Baseline to Week 52 |