Long-term Safety and Tolerability of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY Long Term)

Study Overview
=================
Brief Summary
-----------------
Alirocumab (SAR236553/REGN727) is a fully human monoclonal antibody that binds PCSK9 (proprotein convertase subtilisin/kexin type 9). Primary Objective of the study: To evaluate the long-term safety and tolerability of alirocumab in high cardiovascular risk participants with hypercholesterolemia not adequately controlled with their current lipid modifying therapy (LMT). Secondary Objectives: To evaluate the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels after 24 weeks of treatment in comparison with placebo. To evaluate the effect of alirocumab in comparison with placebo on LDL-C at other time points. To evaluate the effects of alirocumab on other lipid parameters.

Detailed Description
-----------------
The maximum study duration was to be 89 weeks per participant, including a 3-week screening period, a 78-week randomized treatment period and 8-week follow-up period.

Official Title
-----------------
Long-term Safety and Tolerability of SAR236553 (REGN727) in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid Modifying Therapy: A Randomized, Double-Blind, Placebo-Controlled Study

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Either A or B below and who were not adequately controlled with their lipid-modifying therapy: A) Participants with heterozygous familial hypercholesterolemia (heFH) with or without established coronary heart disease (CHD) or CHD risk equivalents OR B) Participants with hypercholesterolemia together with established CHD or CHD risk equivalents. Exclusion criteria: Age < 18 years LDL-C <70 mg/dL (< 1.81 mmol/L) Fasting serum triglycerides > 400 mg/dL (>4.52 mmol/L) The above information was 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

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<br>Placebo (for alirocumab) every 2 weeks (Q2W) added to stable Lipid-Modifying Therapy (LMT) for 78 weeks. | Drug: Placebo (for alirocumab)<br>* Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a pre-filled syringe.<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 150 mg Q2W added to stable LMT for 78 weeks. | Drug: Alirocumab<br>* Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a pre-filled syringe.<br>* Other names: Praluent;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?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced Adverse Events (AEs) | Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the 'treatment-emergent period' (the time from the first dose of study drug up to the last dose of study drug +70 days). | Up to 10 weeks after last study drug administration (maximum of 86 weeks) | 

Secondary 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 | 
| 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 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 Measured LDL-C at Week 24 - ITT Analysis | Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including 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 (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 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). | 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 | 
| Percentage of Very High Cardiovascular (CV) Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis | Very high CV risk: Heterozygous Familial Hypercholesterolemia (heFH) participants with coronary heart disease (CHD) or CHD risk equivalents or non- Familial Hypercholesterolemia (FH). High CV risk: heFH participants without CHD or CHD risk equivalents. CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (estimated glomerular filtration rate, 30 to <60 ml/minute/1.73 m^2 of body-surface area), or diabetes mellitus plus 2 or more additional risk factors (hypertension; ankle-brachial index of ≤0.90; microalbuminuria, macroalbuminuria, or a urinary dipstick result of >2+ protein; preproliferative or proliferative retinopathy or laser treatment for retinopathy; or family history of premature CHD). 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 imputation model. | Up to Week 52 | 
| Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) 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 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 | 
| 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 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 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 Apo A1 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 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 A1 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 |