Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy
- Conditions
- Hypercholesterolemia
- Interventions
- Registration Number
- NCT01623115
- Lead Sponsor
- Sanofi
- 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 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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 486
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo (for alirocumab) Placebo for alirocumab every 2 weeks (Q2W) on top of stable lipid-modifying therapy (LMT) for 78 weeks. Placebo Lipid Modifying Therapy (LMT) Placebo for alirocumab every 2 weeks (Q2W) on top of stable lipid-modifying therapy (LMT) for 78 weeks. Alirocumab 75 mg/Up to 150 mg Q2W Alirocumab Alirocumab 75 mg Q2W on top of stable LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥ 70 mg/dL (1.81 mmol/L) at Week 8. Alirocumab 75 mg/Up to 150 mg Q2W Lipid Modifying Therapy (LMT) Alirocumab 75 mg Q2W on top of stable LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥ 70 mg/dL (1.81 mmol/L) at Week 8.
- Primary Outcome Measures
Name Time Method Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis From Baseline to Week 52 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).
- Secondary Outcome Measures
Name Time Method Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis From Baseline to Week 52 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).
Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis From Baseline to Week 52 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).
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis From Baseline to Week 52 Adjusted LS means and standard errors at Week 12 from MMRM including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis From Baseline to Week 52 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).
Percent Change From Baseline in Apo B at Week 12 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis From Baseline to Week 52 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).
Percent Change From Baseline in Total-C at Week 12 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis From Baseline to Week 52 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.
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 Up to Week 52 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 multiple imputation approach 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.
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 Up to Week 52 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.
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis Up to Week 52 Adjusted percentages at Week 24 from multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis Up to Week 52 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.
Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis From Baseline to Week 52 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.
Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis From Baseline to Week 52 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.
Trial Locations
- Locations (91)
Investigational Site Number 840421
🇺🇸Mission Viejo, California, United States
Investigational Site Number 840452
🇺🇸Washington, District of Columbia, United States
Investigational Site Number 840425
🇺🇸Auburn, Maine, United States
Investigational Site Number 040405
🇦🇹Wien, Austria
Investigational Site Number 840407
🇺🇸Morristown, New Jersey, United States
Investigational Site Number 840429
🇺🇸Long Beach, California, United States
Investigational Site Number 840417
🇺🇸Bell Gardens, California, United States
Investigational Site Number 840461
🇺🇸Northridge, California, United States
Investigational Site Number 124403
🇨🇦Quebec, Canada
Investigational Site Number 840401
🇺🇸Charlotte, North Carolina, United States
Investigational Site Number 528402
🇳🇱Groningen, Netherlands
Investigational Site Number 710402
🇿🇦Cape Town, South Africa
Investigational Site Number 840415
🇺🇸Kansas City, Kansas, United States
Investigational Site Number 710405
🇿🇦Bloemfontein, South Africa
Investigational Site Number 710406
🇿🇦Cap Town, South Africa
Investigational Site Number 840418
🇺🇸Ponte Vedra, Florida, United States
Investigational Site Number 752404
🇸🇪Goteborg, Sweden
Investigational Site Number 643404
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 840422
🇺🇸Bountiful, Utah, United States
Investigational Site Number 376404
🇮🇱Safed, Israel
Investigational Site Number 376402
🇮🇱Holon, Israel
Investigational Site Number 826409
🇬🇧London, United Kingdom
Investigational Site Number 710404
🇿🇦Rondebosch, South Africa
Investigational Site Number 724403
🇪🇸A Coruna, Spain
Investigational Site Number 724402
🇪🇸Zaragoza, Spain
Investigational Site Number 376405
🇮🇱Jerusalem, Israel
Investigational Site Number 124401
🇨🇦Montreal, Canada
Investigational Site Number 124404
🇨🇦Chicoutimi, Canada
Investigational Site Number 250402
🇫🇷Saint Herblain, France
Investigational Site Number 840408
🇺🇸New York, New York, United States
Investigational Site Number 643406
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 710403
🇿🇦Parow, South Africa
Investigational Site Number 643407
🇷🇺Kazan, Russian Federation
Investigational Site Number 528411
🇳🇱Leiden, Netherlands
Investigational Site Number 643412
🇷🇺Novisibirsk, Russian Federation
Investigational Site Number 643408
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 752401
🇸🇪Stockholm, Sweden
Investigational Site Number 643410
🇷🇺Yaroslavl, Russian Federation
Investigational Site Number 124406
🇨🇦Sherbrooke, Canada
Investigational Site Number 376401
🇮🇱Tel Hashomer, Israel
Investigational Site Number 124407
🇨🇦Toronto, Canada
Investigational Site Number 710407
🇿🇦Parktown, South Africa
Investigational Site Number 250403
🇫🇷Dijon, France
Investigational Site Number 826403
🇬🇧London, United Kingdom
Investigational Site Number 710408
🇿🇦Pretoria, South Africa
Investigational Site Number 724409
🇪🇸Madrid, Spain
Investigational Site Number 643409
🇷🇺Moscow, Russian Federation
Investigational Site Number 826408
🇬🇧London, United Kingdom
Investigational Site Number 643413
🇷🇺Moscow, Russian Federation
Investigational Site Number 643401
🇷🇺Moscow, Russian Federation
Investigational Site Number 250401
🇫🇷Paris Cedex 13, France
Investigational Site Number 710401
🇿🇦Bloemfontein, South Africa
Investigational Site Number 826405
🇬🇧Manchester, United Kingdom
Investigational Site Number 724408
🇪🇸Barcelona, Spain
Investigational Site Number 840412
🇺🇸Newport Beach, California, United States
Investigational Site Number 840455
🇺🇸Evanston, Illinois, United States
Investigational Site Number 840411
🇺🇸Boston, Massachusetts, United States
Investigational Site Number 840404
🇺🇸Philadelphia, Pennsylvania, United States
Investigational Site Number 840419
🇺🇸Los Angeles, California, United States
Investigational Site Number 840428
🇺🇸Newport Beach, California, United States
Investigational Site Number 840426
🇺🇸Philadelphia, Pennsylvania, United States
Investigational Site Number 840460
🇺🇸Dallas, Texas, United States
Investigational Site Number 528410
🇳🇱Amsterdam, Netherlands
Investigational Site Number 528408
🇳🇱Den Helder, Netherlands
Investigational Site Number 528409
🇳🇱Nieuwegein, Netherlands
Investigational Site Number 528412
🇳🇱Sliedrecht, Netherlands
Investigational Site Number 840410
🇺🇸Durham, North Carolina, United States
Investigational Site Number 840456
🇺🇸Miami, Florida, United States
Investigational Site Number 840430
🇺🇸Cincinnati, Ohio, United States
Investigational Site Number 840406
🇺🇸Nashville, Tennessee, United States
Investigational Site Number 040403
🇦🇹Graz, Austria
Investigational Site Number 203401
🇨🇿Praha, Czech Republic
Investigational Site Number 040402
🇦🇹Wien, Austria
Investigational Site Number 203405
🇨🇿Uherske Hradiste, Czech Republic
Investigational Site Number 203402
🇨🇿Zlin, Czech Republic
Investigational Site Number 578401
🇳🇴Bodø, Norway
Investigational Site Number 203403
🇨🇿Praha, Czech Republic
Investigational Site Number 208403
🇩🇰Esbjerg, Denmark
Investigational Site Number 208401
🇩🇰Copenhagen, Denmark
Investigational Site Number 840424
🇺🇸Portland, Oregon, United States
Investigational Site Number 724405
🇪🇸Madrid, Spain
Investigational Site Number 528406
🇳🇱Amsterdam, Netherlands
Investigational Site Number 643402
🇷🇺Arkhangelsk, Russian Federation
Investigational Site Number 528416
🇳🇱Maastricht, Netherlands
Investigational Site Number 724406
🇪🇸Córdoba, Spain
Investigational Site Number 724401
🇪🇸Madrid, Spain
Investigational Site Number 724407
🇪🇸Hospitalet De Llobregat, Spain
Investigational Site Number 710409
🇿🇦Somerset West, South Africa
Investigational Site Number 724404
🇪🇸Reus, Spain
Investigational Site Number 826402
🇬🇧London, United Kingdom
Investigational Site Number 840409
🇺🇸St Louis, Missouri, United States