Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY COMBO II)

Hypercholesterolemia Clinical Trial

Official title:

A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 Versus Ezetimibe in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Statin Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01644188
• Other study ID #: EFC11569
• Secondary ID: U1111-1121-43152
• Status: Completed
• Phase: Phase 3
• First received: July 16, 2012
• Last updated: October 7, 2015
• Start date: August 2012
• Est. completion date: July 2015

Study information

• Verified date: October 2015
• 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 demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to stable maximally tolerated daily statin therapy in comparison with ezetimibe after 24 weeks of treatment in participants with hypercholesterolemia at high cardiovascular (CV) risk.

Secondary Objectives:

• To evaluate the effect of alirocumab in comparison with ezetimibe on LDL-C at other time points

• To evaluate the effect of alirocumab on other lipid parameters

• To evaluate the safety and tolerability of alirocumab

Description:

The maximum study duration was 115 weeks per participant, including a 3-week screening period, 104-week randomized treatment period and 8-week follow-up period.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 720
• Est. completion date: July 2015
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

Participants with hypercholesterolemia and established coronary heart disease (CHD) or CHD risk equivalents who were not adequately controlled with a maximally tolerated daily dose of statin at stable dose for at least 4 weeks prior to the screening visit (Week -2).

Exclusion criteria:

• Age < 18 or legal age of adulthood, whichever was greater

• Participants without established CHD or CHD risk equivalents

• LDL-C <70 mg/dL (<1.81 mmol/L) and participants with a history of documented cardiovascular disease

• LDL-C <100 mg/dL (<2.59 mmol/L) and participants without a history of documented CV disease

• Fasting serum triglycerides >400 mg/dL (>4.52 mmol/L)

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

Intervention

Drug:
• Alirocumab
1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using the autoinjector.
• Placebo (for alirocumab)
1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using the autoinjector.
• Ezetimibe
One over-encapsulated tablet orally once daily at approximately the same time of the day with or without food.
• Placebo (for ezetimibe)
One capsule once daily orally at approximately the same time of the day with or without food.
• Lipid Modifying Therapy (LMT)
Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose.

Locations

Country	Name	City	State
Canada	Investigational Site Number 124902	Brampton
Canada	Investigational Site Number 124914	Mirabel
Canada	Investigational Site Number 124903	Montreal
Canada	Investigational Site Number 124918	Toronto
Denmark	Investigational Site Number 208913	Esbjerg
Denmark	Investigational Site Number 208914	Glostrup
Denmark	Investigational Site Number 208905	Hellerup
Denmark	Investigational Site Number 208911	Herlev
Denmark	Investigational Site Number 208907	Hvidovre
Denmark	Investigational Site Number 208901	København S
Denmark	Investigational Site Number 208906	Køge
Denmark	Investigational Site Number 208908	Roskilde
Denmark	Investigational Site Number 208903	Silkeborg
France	Investigational Site Number 250906	Dijon
France	Investigational Site Number 250907	Montpellier Cedex 5
France	Investigational Site Number 250903	Nantes
France	Investigational Site Number 250905	Nimes
Hungary	Investigational Site Number 348901	Budapest
Hungary	Investigational Site Number 348903	Budapest
Hungary	Investigational Site Number 348908	Budapest
Hungary	Investigational Site Number 348905	Debrecen
Hungary	Investigational Site Number 348906	Szekesfehervar
Israel	Investigational Site Number 376908	Holon
Israel	Investigational Site Number 376903	Kfar Saba
Israel	Investigational Site Number 376906	Ofakim
Israel	Investigational Site Number 376902	Petach Tikva
Israel	Investigational Site Number 376904	Rehovot
Israel	Investigational Site Number 376907	Safed
Israel	Investigational Site Number 376901	Tel Aviv
Korea, Republic of	Investigational Site Number 410908	Anyang-Si
Korea, Republic of	Investigational Site Number 410920	Busan
Korea, Republic of	Investigational Site Number 410926	Daegu
Korea, Republic of	Investigational Site Number 410923	Gwangju
Korea, Republic of	Investigational Site Number 410901	Seoul
Korea, Republic of	Investigational Site Number 410905	Seoul
Korea, Republic of	Investigational Site Number 410909	Seoul
Korea, Republic of	Investigational Site Number 410914	Seoul
Korea, Republic of	Investigational Site Number 410921	Seoul
Korea, Republic of	Investigational Site Number 410922	Seoul
Korea, Republic of	Investigational Site Number 410924	Seoul
Korea, Republic of	Investigational Site Number 410915	Suwon
Korea, Republic of	Investigational Site Number 410913	Uijeongbu
Korea, Republic of	Investigational Site Number 410927	Wonju
Russian Federation	Investigational Site Number 643906	Barnaul
Russian Federation	Investigational Site Number 643903	Kemerovo
Russian Federation	Investigational Site Number 643904	Moscow
Russian Federation	Investigational Site Number 643908	Moscow
Russian Federation	Investigational Site Number 643924	Moscow
Russian Federation	Investigational Site Number 643927	Moscow
Russian Federation	Investigational Site Number 643928	Moscow
Russian Federation	Investigational Site Number 643931	Moscow
Russian Federation	Investigational Site Number 643932	Moscow
Russian Federation	Investigational Site Number 643911	Orenburg
Russian Federation	Investigational Site Number 643921	Ryazan
Russian Federation	Investigational Site Number 643922	Saint-Petersburg
Russian Federation	Investigational Site Number 643925	Saint-Petersburg
Russian Federation	Investigational Site Number 643929	Saratov
Russian Federation	Investigational Site Number 643914	St-Petersburg
South Africa	Investigational Site Number 710917	Alberton
South Africa	Investigational Site Number 710909	Bloemfontein
South Africa	Investigational Site Number 710914	Bloemfontein
South Africa	Investigational Site Number 710904	Cape Town
South Africa	Investigational Site Number 710905	Cape Town
South Africa	Investigational Site Number 710918	Middelburg
South Africa	Investigational Site Number 710913	Pretoria
South Africa	Investigational Site Number 710915	Somerset West
Ukraine	Investigational Site Number 804905	Kiev
Ukraine	Investigational Site Number 804902	Uzhhorod
United States	Investigational Site Number 840949	Albuquerque	New Mexico
United States	Investigational Site Number 840959	Anaheim	California
United States	Investigational Site Number 840301	Beverly Hills	California
United States	Investigational Site Number 840980	Birmingham	Alabama
United States	Investigational Site Number 840962	Boynton Beach	Florida
United States	Investigational Site Number 840987	Bradenton	Florida
United States	Investigational Site Number 840932	Bristol	Tennessee
United States	Investigational Site Number 840946	Butte	Montana
United States	Investigational Site Number 840913	Charleston	South Carolina
United States	Investigational Site Number 840933	Chino	California
United States	Investigational Site Number 840963	Cincinnati	Ohio
United States	Investigational Site Number 840302	Clearwater	Florida
United States	Investigational Site Number 840902	Evansville	Indiana
United States	Investigational Site Number 840966	Fall River	Massachusetts
United States	Investigational Site Number 840994	Fort Worth	Texas
United States	Investigational Site Number 840955	Greenville	North Carolina
United States	Investigational Site Number 840912	Greer	South Carolina
United States	Investigational Site Number 840939	Houston	Texas
United States	Investigational Site Number 840973	Houston	Texas
United States	Investigational Site Number 840935	Jacksonville	Florida
United States	Investigational Site Number 840917	Kansas City	Missouri
United States	Investigational Site Number 840938	Lexington	North Carolina
United States	Investigational Site Number 840914	Lincoln	Nebraska
United States	Investigational Site Number 840991	Lincoln	California
United States	Investigational Site Number 840979	Los Angeles	California
United States	Investigational Site Number 840970	Lyndhust	Ohio
United States	Investigational Site Number 840906	Marion	Ohio
United States	Investigational Site Number 840997	Marion	Ohio
United States	Investigational Site Number 840995	Meridian	Idaho
United States	Investigational Site Number 840903	Miami	Florida
United States	Investigational Site Number 840920	Miami	Florida
United States	Investigational Site Number 840944	Nashville	Tennessee
United States	Investigational Site Number 840974	New Windsor	New York
United States	Investigational Site Number 840931	Norfolk	Virginia
United States	Investigational Site Number 840943	Ocala	Florida
United States	Investigational Site Number 840982	Orem	Utah
United States	Investigational Site Number 840981	Oveido	Florida
United States	Investigational Site Number 840940	Oxon Hill	Maryland
United States	Investigational Site Number 840952	Palm Springs	California
United States	Investigational Site Number 840964	Perrysburg	Ohio
United States	Investigational Site Number 840918	Phoenix	Arizona
United States	Investigational Site Number 840961	Port Orange	Florida
United States	Investigational Site Number 840928	Renton	Washington
United States	Investigational Site Number 840984	Richmond	Virginia
United States	Investigational Site Number 840303	Sarasota	Florida
United States	Investigational Site Number 840976	Smithfield	North Carolina
United States	Investigational Site Number 840990	Spokane	Washington
United States	Investigational Site Number 840998	St. Louis	Missouri
United States	Investigational Site Number 840986	St. Petersburg	Florida
United States	Investigational Site Number 840988	St. Petersburg	Florida
United States	Investigational Site Number 840945	Sugar Land	Texas
United States	Investigational Site Number 840992	Summerville	South Carolina
United States	Investigational Site Number 840930	Thousand Oaks	California
United States	Investigational Site Number 840971	Tomball	Texas
United States	Investigational Site Number 840960	Topeka	Kansas
United States	Investigational Site Number 840925	Tucson	Arizona
United States	Investigational Site Number 840921	Vista	California
United States	Investigational Site Number 840985	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  France,  Hungary,  Israel,  Korea, Republic of,  Russian Federation,  South Africa,  Ukraine, 

References & Publications (2)

Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM; ODYSSEY COMBO II Investigators. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally — View Citation

Colhoun HM, Robinson JG, Farnier M, Cariou B, Blom D, Kereiakes DJ, Lorenzato C, Pordy R, Chaudhari U. Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials. BMC Cardiovasc Disord. 2014 Sep 20;14:121. doi: 10.1186/1471-2261-14-121. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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 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 or 3 days after the last capsule, whichever came first) (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 a 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 or 3 days after the last capsule, whichever came first) (on-treatment analysis).	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 or 3 days after the last capsule, whichever came first).	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 or 3 days after the last capsule, whichever came first).	From Baseline up 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 a 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 Participants Achieving 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 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 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 or 3 days after the last capsule, whichever came first.	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 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	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