Clinical trial NCT01623115: 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
Official title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Keywords: PCSK9
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Regeneron Pharmaceuticals
First posted: 2012-06-19
Enrollment: 486
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion criteria:

* Participants with heterozygous familial hypercholesterolemia who were not adequately controlled with their lipid-modifying therapy

Exclusion criteria:

* Age \< 18 years or legal age of adulthood, whichever is greater
* LDL-C \< 70 mg/dL (1.81 mmol/L) and with cardiovascular disease
* LDL-C \< 100 mg/dL (2.59 mmol/L) and without cardiovascular disease
* Fasting serum triglycerides \> 400 mg/dL (4.52 mmol/L)
* 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.

Primary outcomes:
measure: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis
timeFrame: From Baseline to Week 52
Secondary outcomes:
measure: Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apo B at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: 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
timeFrame: Up to Week 52
measure: 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
timeFrame: Up to Week 52
measure: Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
timeFrame: Up to Week 52
measure: Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
timeFrame: Up to Week 52
measure: Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
Other outcomes:
measure: Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis
timeFrame: From Baseline to Week 78
measure: Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis
timeFrame: From Baseline to Week 78
Locations:
city: Bell Gardens
country: United States
facility: Investigational Site Number 840417
state: California
city: Long Beach
country: United States
facility: Investigational Site Number 840429
state: California
city: Los Angeles
country: United States
facility: Investigational Site Number 840419
state: California
city: Mission Viejo
country: United States
facility: Investigational Site Number 840421
state: California
city: Newport Beach
country: United States
facility: Investigational Site Number 840412
state: California
city: Newport Beach
country: United States
facility: Investigational Site Number 840428
state: California
city: Northridge
country: United States
facility: Investigational Site Number 840461
state: California
city: Washington
country: United States
facility: Investigational Site Number 840452
state: District of Columbia
city: Miami
country: United States
facility: Investigational Site Number 840456
state: Florida
city: Ponte Vedra
country: United States
facility: Investigational Site Number 840418
state: Florida
city: Evanston
country: United States
facility: Investigational Site Number 840455
state: Illinois
city: Kansas City
country: United States
facility: Investigational Site Number 840415
state: Kansas
city: Auburn
country: United States
facility: Investigational Site Number 840425
state: Maine
city: Boston
country: United States
facility: Investigational Site Number 840411
state: Massachusetts
city: St Louis
country: United States
facility: Investigational Site Number 840409
state: Missouri
city: Morristown
country: United States
facility: Investigational Site Number 840407
state: New Jersey
city: New York
country: United States
facility: Investigational Site Number 840408
state: New York
city: Charlotte
country: United States
facility: Investigational Site Number 840401
state: North Carolina
city: Durham
country: United States
facility: Investigational Site Number 840410
state: North Carolina
city: Cincinnati
country: United States
facility: Investigational Site Number 840430
state: Ohio
city: Portland
country: United States
facility: Investigational Site Number 840424
state: Oregon
city: Philadelphia
country: United States
facility: Investigational Site Number 840404
state: Pennsylvania
city: Philadelphia
country: United States
facility: Investigational Site Number 840426
state: Pennsylvania
city: Nashville
country: United States
facility: Investigational Site Number 840406
state: Tennessee
city: Dallas
country: United States
facility: Investigational Site Number 840460
state: Texas
city: Bountiful
country: United States
facility: Investigational Site Number 840422
state: Utah
city: Graz
country: Austria
facility: Investigational Site Number 040403
city: Wien
country: Austria
facility: Investigational Site Number 040402
city: Wien
country: Austria
facility: Investigational Site Number 040405
city: Chicoutimi
country: Canada
facility: Investigational Site Number 124404
city: Montreal
country: Canada
facility: Investigational Site Number 124401
city: Quebec
country: Canada
facility: Investigational Site Number 124403
city: Sherbrooke
country: Canada
facility: Investigational Site Number 124406
city: Toronto
country: Canada
facility: Investigational Site Number 124407
city: Praha
country: Czech Republic
facility: Investigational Site Number 203401
city: Praha
country: Czech Republic
facility: Investigational Site Number 203403
city: Uherske Hradiste
country: Czech Republic
facility: Investigational Site Number 203405
city: Zlin
country: Czech Republic
facility: Investigational Site Number 203402
city: Copenhagen
country: Denmark
facility: Investigational Site Number 208401
city: Esbjerg
country: Denmark
facility: Investigational Site Number 208403
city: Dijon
country: France
facility: Investigational Site Number 250403
city: Paris Cedex 13
country: France
facility: Investigational Site Number 250401
city: Saint Herblain
country: France
facility: Investigational Site Number 250402
city: Holon
country: Israel
facility: Investigational Site Number 376402
city: Jerusalem
country: Israel
facility: Investigational Site Number 376405
city: Safed
country: Israel
facility: Investigational Site Number 376404
city: Tel Hashomer
country: Israel
facility: Investigational Site Number 376401
city: Amsterdam
country: Netherlands
facility: Investigational Site Number 528406
city: Amsterdam
country: Netherlands
facility: Investigational Site Number 528410
city: Den Helder
country: Netherlands
facility: Investigational Site Number 528408
city: Groningen
country: Netherlands
facility: Investigational Site Number 528402
city: Leiden
country: Netherlands
facility: Investigational Site Number 528411
city: Maastricht
country: Netherlands
facility: Investigational Site Number 528416
city: Nieuwegein
country: Netherlands
facility: Investigational Site Number 528409
city: Sliedrecht
country: Netherlands
facility: Investigational Site Number 528412
city: Bodø
country: Norway
facility: Investigational Site Number 578401
city: Arkhangelsk
country: Russian Federation
facility: Investigational Site Number 643402
city: Kazan
country: Russian Federation
facility: Investigational Site Number 643407
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643409
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643413
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643401
city: Novisibirsk
country: Russian Federation
facility: Investigational Site Number 643412
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643408
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643406
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643404
city: Yaroslavl
country: Russian Federation
facility: Investigational Site Number 643410
city: Bloemfontein
country: South Africa
facility: Investigational Site Number 710401
city: Bloemfontein
country: South Africa
facility: Investigational Site Number 710405
city: Cap Town
country: South Africa
facility: Investigational Site Number 710406
city: Cape Town
country: South Africa
facility: Investigational Site Number 710402
city: Parktown
country: South Africa
facility: Investigational Site Number 710407
city: Parow
country: South Africa
facility: Investigational Site Number 710403
city: Pretoria
country: South Africa
facility: Investigational Site Number 710408
city: Rondebosch
country: South Africa
facility: Investigational Site Number 710404
city: Somerset West
country: South Africa
facility: Investigational Site Number 710409
city: A Coruna
country: Spain
facility: Investigational Site Number 724403
city: Barcelona
country: Spain
facility: Investigational Site Number 724408
city: Córdoba
country: Spain
facility: Investigational Site Number 724406
city: Hospitalet De Llobregat
country: Spain
facility: Investigational Site Number 724407
city: Madrid
country: Spain
facility: Investigational Site Number 724409
city: Madrid
country: Spain
facility: Investigational Site Number 724401
city: Madrid
country: Spain
facility: Investigational Site Number 724405
city: Reus
country: Spain
facility: Investigational Site Number 724404
city: Zaragoza
country: Spain
facility: Investigational Site Number 724402
city: Goteborg
country: Sweden
facility: Investigational Site Number 752404
city: Stockholm
country: Sweden
facility: Investigational Site Number 752401
city: London
country: United Kingdom
facility: Investigational Site Number 826402
city: London
country: United Kingdom
facility: Investigational Site Number 826403
city: London
country: United Kingdom
facility: Investigational Site Number 826408
city: London
country: United Kingdom
facility: Investigational Site Number 826409
city: Manchester
country: United Kingdom
facility: Investigational Site Number 826405
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Kastelein JJ, Robinson JG, Farnier M, Krempf M, Langslet G, Lorenzato C, Gipe DA, Baccara-Dinet MT. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014 Jun;28(3):281-9. doi: 10.1007/s10557-014-6523-z.
citation: Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F, Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe DA, Geiger MJ, Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015 Nov 14;36(43):2996-3003. doi: 10.1093/eurheartj/ehv370. Epub 2015 Sep 1.
citation: Mahmood T, Minnier J, Ito MK, Li QH, Koren A, Kam IW, Fazio S, Shapiro MD. Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies. Eur J Prev Cardiol. 2021 Jul 23;28(8):816-822. doi: 10.1177/2047487320915803. Epub 2020 Apr 10.
citation: Leiter LA, Tinahones FJ, Karalis DG, Bujas-Bobanovic M, Letierce A, Mandel J, Samuel R, Jones PH. Alirocumab safety in people with and without diabetes mellitus: pooled data from 14 ODYSSEY trials. Diabet Med. 2018 Dec;35(12):1742-1751. doi: 10.1111/dme.13817. Epub 2018 Oct 9.
citation: Defesche JC, Stefanutti C, Langslet G, Hopkins PN, Seiz W, Baccara-Dinet MT, Hamon SC, Banerjee P, Kastelein JJP. Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. J Clin Lipidol. 2017 Nov-Dec;11(6):1338-1346.e7. doi: 10.1016/j.jacl.2017.08.016. Epub 2017 Sep 4.
citation: Kastelein JJ, Hovingh GK, Langslet G, Baccara-Dinet MT, Gipe DA, Chaudhari U, Zhao J, Minini P, Farnier M. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017 Jan-Feb;11(1):195-203.e4. doi: 10.1016/j.jacl.2016.12.004. Epub 2016 Dec 28.
citation: Ray KK, Ginsberg HN, Davidson MH, Pordy R, Bessac L, Minini P, Eckel RH, Cannon CP. Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control. Circulation. 2016 Dec 13;134(24):1931-1943. doi: 10.1161/CIRCULATIONAHA.116.024604. Epub 2016 Oct 24.