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

Hypercholesterolemia Clinical Trial

— ODYSSEY FH I  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01623115
• Other study ID #: EFC12492
• Secondary ID: U1111-1121-42752
• Status: Completed
• Phase: Phase 3
• First received: June 15, 2012
• Last updated: January 11, 2016
• Start date: July 2012
• Est. completion date: December 2014

Study information

• Verified date: January 2016
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Completed
• Enrollment: 486
• Est. completion date: December 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

Drug:
• Alirocumab
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).
• Placebo (for alirocumab)
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).
• Lipid Modifying Therapy (LMT)
Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose with or without other LMT as clinically indicated.

Locations

Country	Name	City	State
Austria	Investigational Site Number 040403	Graz
Austria	Investigational Site Number 040402	Wien
Austria	Investigational Site Number 040405	Wien
Canada	Investigational Site Number 124404	Chicoutimi
Canada	Investigational Site Number 124401	Montreal
Canada	Investigational Site Number 124403	Quebec
Canada	Investigational Site Number 124406	Sherbrooke
Canada	Investigational Site Number 124407	Toronto
Czech Republic	Investigational Site Number 203401	Praha
Czech Republic	Investigational Site Number 203403	Praha
Czech Republic	Investigational Site Number 203405	Uherske Hradiste
Czech Republic	Investigational Site Number 203402	Zlin
Denmark	Investigational Site Number 208401	Copenhagen
Denmark	Investigational Site Number 208403	Esbjerg
France	Investigational Site Number 250403	Dijon
France	Investigational Site Number 250401	Paris Cedex 13
France	Investigational Site Number 250402	Saint Herblain
Israel	Investigational Site Number 376402	Holon
Israel	Investigational Site Number 376405	Jerusalem
Israel	Investigational Site Number 376404	Safed
Israel	Investigational Site Number 376401	Tel Hashomer
Netherlands	Investigational Site Number 528406	Amsterdam
Netherlands	Investigational Site Number 528410	Amsterdam
Netherlands	Investigational Site Number 528408	Den Helder
Netherlands	Investigational Site Number 528402	Groningen
Netherlands	Investigational Site Number 528411	Leiden
Netherlands	Investigational Site Number 528416	Maastricht
Netherlands	Investigational Site Number 528409	Nieuwegein
Netherlands	Investigational Site Number 528412	Sliedrecht
Norway	Investigational Site Number 578401	Bodø
Russian Federation	Investigational Site Number 643402	Arkhangelsk
Russian Federation	Investigational Site Number 643407	Kazan
Russian Federation	Investigational Site Number 643401	Moscow
Russian Federation	Investigational Site Number 643409	Moscow
Russian Federation	Investigational Site Number 643413	Moscow
Russian Federation	Investigational Site Number 643412	Novisibirsk
Russian Federation	Investigational Site Number 643404	St-Petersburg
Russian Federation	Investigational Site Number 643406	St-Petersburg
Russian Federation	Investigational Site Number 643408	St-Petersburg
Russian Federation	Investigational Site Number 643410	Yaroslavl
South Africa	Investigational Site Number 710401	Bloemfontein
South Africa	Investigational Site Number 710405	Bloemfontein
South Africa	Investigational Site Number 710406	Cap Town
South Africa	Investigational Site Number 710402	Cape Town
South Africa	Investigational Site Number 710407	Parktown
South Africa	Investigational Site Number 710403	Parow
South Africa	Investigational Site Number 710408	Pretoria
South Africa	Investigational Site Number 710404	Rondebosch
South Africa	Investigational Site Number 710409	Somerset West
Spain	Investigational Site Number 724403	A Coruna
Spain	Investigational Site Number 724408	Barcelona
Spain	Investigational Site Number 724406	Córdoba
Spain	Investigational Site Number 724407	Hospitalet De Llobregat
Spain	Investigational Site Number 724401	Madrid
Spain	Investigational Site Number 724405	Madrid
Spain	Investigational Site Number 724409	Madrid
Spain	Investigational Site Number 724404	Reus
Spain	Investigational Site Number 724402	Zaragoza
Sweden	Investigational Site Number 752404	Goteborg
Sweden	Investigational Site Number 752401	Stockholm
United Kingdom	Investigational Site Number 826402	London
United Kingdom	Investigational Site Number 826403	London
United Kingdom	Investigational Site Number 826408	London
United Kingdom	Investigational Site Number 826409	London
United Kingdom	Investigational Site Number 826405	Manchester
United States	Investigational Site Number 840425	Auburn	Maine
United States	Investigational Site Number 840417	Bell Gardens	California
United States	Investigational Site Number 840411	Boston	Massachusetts
United States	Investigational Site Number 840422	Bountiful	Utah
United States	Investigational Site Number 840401	Charlotte	North Carolina
United States	Investigational Site Number 840430	Cincinnati	Ohio
United States	Investigational Site Number 840460	Dallas	Texas
United States	Investigational Site Number 840410	Durham	North Carolina
United States	Investigational Site Number 840455	Evanston	Illinois
United States	Investigational Site Number 840415	Kansas City	Kansas
United States	Investigational Site Number 840429	Long Beach	California
United States	Investigational Site Number 840419	Los Angeles	California
United States	Investigational Site Number 840456	Miami	Florida
United States	Investigational Site Number 840421	Mission Viejo	California
United States	Investigational Site Number 840407	Morristown	New Jersey
United States	Investigational Site Number 840406	Nashville	Tennessee
United States	Investigational Site Number 840408	New York	New York
United States	Investigational Site Number 840412	Newport Beach	California
United States	Investigational Site Number 840428	Newport Beach	California
United States	Investigational Site Number 840461	Northridge	California
United States	Investigational Site Number 840404	Philadelphia	Pennsylvania
United States	Investigational Site Number 840426	Philadelphia	Pennsylvania
United States	Investigational Site Number 840418	Ponte Vedra	Florida
United States	Investigational Site Number 840424	Portland	Oregon
United States	Investigational Site Number 840409	St Louis	Missouri
United States	Investigational Site Number 840452	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Austria,  Canada,  Czech Republic,  Denmark,  France,  Israel,  Netherlands,  Norway,  Russian Federation,  South Africa,  Spain,  Sweden,  United Kingdom, 

References & Publications (2)

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 pati — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis	Adjusted LS means and standard errors at Week 52 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	No
Other	Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis	Adjusted LS means and standard errors at Week 78 from MMRM including all available post-baseline data from Week 4 to Week 78 regardless of status on-or off-treatment.	From Baseline to Week 78	No
Other	Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis	Adjusted LS means and standard errors at Week 78 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 78 (i.e. up to 21 days after last injection).	From Baseline to Week 78	No
Primary	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	No
Secondary	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	No
Secondary	Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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 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.	Up to Week 52	No
Secondary	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 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	No
Secondary	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 model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.	Up to Week 52	No
Secondary	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 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	No
Secondary	Percent Change From Baseline in Lipoprotein (a) 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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No