Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia (ODYSSEY HIGH FH)

Study Overview
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Brief Summary
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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 effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels after 24 weeks of treatment in comparison with placebo. Secondary Objectives: 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 To evaluate the safety and tolerability of alirocumab

Detailed Description
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The maximum study duration was planned to be 89 weeks per participant including participants who successfully completed the 78-week treatment period had the possibility to join an open-label extension study (LTS13463, NCT01954394) at the end of the treatment 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 Patients With Heterozygous Familial Hypercholesterolemia and LDL-C Higher or Equal to 160mg/dL With Their Lipid-Modifying Therapy

Conditions
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Hypercholesterolaemia

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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants with heterozygous familial hypercholesterolemia who were not adequately controlled with their lipid-modifying therapy. Exclusion criteria: Age < 18 years LDL-C < 160 mg/dL (< 4.14 mmol/L) at the screening visit (Week-3). Fasting serum triglycerides > 400 mg/dL (> 4.52 mmol/L) during the screening period. Known history of homozygous familial hypercholesterolemia. 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 subcutaneous (SC) injection every two weeks (Q2W) on top of stable lipid-modifying therapy (LMT) for 78 weeks. | Drug: Placebo (for alirocumab)<br>* Solution for subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using 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 150 mg Q2W<br>Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks. | Drug: Alirocumab<br>* Solution for subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre filled pen).<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?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Calculated LDL-C at Week 24 - 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 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 B (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 Very High Cardiovascular (CV) Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis | Very high CV risk participants: Heterozygous Familial Hypercholesterolemia (heFH) participants with coronary heart disease (CHD) or CHD risk equivalents. High CV risk participants: 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 a family history of premature CHD). 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 52 regardless of status on- or off-treatment were included in the imputation model. | Up to Week 52 | 
| Percentage of Very High CV Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - On-Treatment Analysis | Adjusted percentages at Week 24 from a 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 from a 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 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 Apolipoprotein A-1 (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 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 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 | 
| Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis | Adjusted percentages at Week 24 from multiple imputation approach including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment. | Up to Week 52 | 
| Percentage of Participants Achieving 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 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 |