Trial Outcomes & Findings for Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY COMBO II) (NCT NCT01644188)

Last Updated: 2016-08-04

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

720 participants

Primary outcome timeframe

From Baseline to Week 52

Results posted on

2016-08-04

Participant Flow

The study was conducted at 126 centers in 10 countries. Overall, 1112 participants were screened between August 2012 and May 2013, 392 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.

Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, intensity of statin treatment and geographical region. Assignment to arms was done centrally using Interactive Voice/Web Response System in 2:1 ratio (alirocumab: ezetimibe) after confirmation of selection criteria. 720 participants were randomized.

Participant milestones

Participant milestones
Measure	Alirocumab 75 /up to 150 mg Q2W Subcutaneous injection of alirocumab 75 mg every 2 weeks (Q2W) and oral placebo capsule for ezetimibe daily added to stable Lipid- Modifying Therapy (LMT) for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when low density lipoprotein cholesterol (LDL-C) level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Overall Study STARTED	479	241
Overall Study Treated	479	241
Overall Study COMPLETED	357	166
Overall Study NOT COMPLETED	122	75

Reasons for withdrawal

Reasons for withdrawal
Measure	Alirocumab 75 /up to 150 mg Q2W Subcutaneous injection of alirocumab 75 mg every 2 weeks (Q2W) and oral placebo capsule for ezetimibe daily added to stable Lipid- Modifying Therapy (LMT) for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when low density lipoprotein cholesterol (LDL-C) level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Overall Study Adverse Event	44	20
Overall Study Poor compliance to protocol	26	14
Overall Study Physician Decision	1	3
Overall Study Participant moved	7	2
Overall Study Related to auto-injector administration	2	2
Overall Study Consent withdrawn by participant	14	7
Overall Study Selection criteria finally not met	2	0
Overall Study Lost to Follow-up	1	0
Overall Study Death	4	3
Overall Study Last visit outside protocol visit window	14	16
Overall Study Site closure	1	1
Overall Study Other than specified above	6	7

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Alirocumab 75 /up to 150 mg Q2W n=479 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=241 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.	Total n=720 Participants Total of all reporting groups
Age, Continuous	61.7 years STANDARD_DEVIATION 9.4 • n=5 Participants	61.3 years STANDARD_DEVIATION 9.2 • n=7 Participants	61.6 years STANDARD_DEVIATION 9.3 • n=5 Participants
Sex: Female, Male Female	119 Participants n=5 Participants	71 Participants n=7 Participants	190 Participants n=5 Participants
Sex: Female, Male Male	360 Participants n=5 Participants	170 Participants n=7 Participants	530 Participants n=5 Participants
Calculated LDL-C in mg/dL	108.6 mg/dL STANDARD_DEVIATION 36.5 • n=5 Participants	104.6 mg/dL STANDARD_DEVIATION 34.1 • n=7 Participants	107.3 mg/dL STANDARD_DEVIATION 35.7 • n=5 Participants
Calculated LDL-C in mmol/L	2.812 mmol/L STANDARD_DEVIATION 0.945 • n=5 Participants	2.710 mmol/L STANDARD_DEVIATION 0.884 • n=7 Participants	2.778 mmol/L STANDARD_DEVIATION 0.926 • n=5 Participants

PRIMARY outcome

Timeframe: From Baseline to Week 52

Population: ITT population: all randomized participants with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis	-50.6 percent change Standard Error 1.4	-20.7 percent change Standard Error 1.9

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Modified ITT population (mITT): all randomized and treated participants with one baseline and at least one post-baseline calculated LDL-C value on-treatment.

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).

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=464 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=235 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Calculated LDL--C at Week 24 - On--Treatment Analysis	-52.4 percent change Standard Error 1.3	-21.8 percent change Standard Error 1.8

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis	-51.2 percent change Standard Error 1.3	-21.8 percent change Standard Error 1.8

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: mITT population.

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).

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=464 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=235 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis	-52.4 percent change Standard Error 1.2	-22.7 percent change Standard Error 1.7

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants of the ITT population with one baseline and at least one post-baseline Apo-B value on-or off-treatment (Apo-B ITT population).

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=452 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=228 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT Analysis	-40.7 percent change Standard Error 1.1	-18.3 percent change Standard Error 1.5

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment (Apo-B mITT population).

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).

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=442 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=221 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis	-42.1 percent change Standard Error 1	-19.1 percent change Standard Error 1.4

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment (non-HDL-C ITT population).

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis	-42.1 percent change Standard Error 1.2	-19.2 percent change Standard Error 1.7

SECONDARY outcome

Timeframe: From Baseline up to Week 52

Population: Participants of the mITT population with one baseline and at least one post-baseline non-HDL-C value on-treatment (non-HDL-C mITT population).

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=464 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=235 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis	-43.7 percent change Standard Error 1.1	-20.2 percent change Standard Error 1.6

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants of the ITT population with one baseline and at least one post-baseline Total-C value on- or off-treatment (Total-C ITT population).

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis	-29.3 percent change Standard Error 0.9	-14.6 percent change Standard Error 1.2

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Apo-B ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=452 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=228 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Apo-B at Week 12 - ITT Analysis	-39.7 percent change Standard Error 1	-17.2 percent change Standard Error 1.3

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Non-HDL-C ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis	-42.6 percent change Standard Error 1.1	-20.6 percent change Standard Error 1.5

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Total-C ITT population

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Total-C at Week 12 - ITT Analysis	-29.4 percent change Standard Error 0.8	-15.1 percent change Standard Error 1.1

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis	-49.5 percent change Standard Error 1.5	-18.3 percent change Standard Error 2.1

SECONDARY outcome

Timeframe: Up to Week 52

Population: ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis	77 percentage of participants	45.6 percentage of participants

SECONDARY outcome

Timeframe: Up to Week 52

Population: mITT population.

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).

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=464 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=235 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis	78.9 percentage of participants	47.4 percentage of participants

SECONDARY outcome

Timeframe: From baseline to Week 52

Population: ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis	-27.8 percent change Standard Error 1.4	-6.1 percent change Standard Error 2

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment (HDL-C ITT population).

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis	8.6 percent change Standard Error 0.8	0.5 percent change Standard Error 1.1

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis	-13 percent change Standard Error 1.5	-12.8 percent change Standard Error 2

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants of the ITT population with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment (Apo A-1 ITT population).

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=452 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=228 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis	5 percent change Standard Error 0.6	-1.3 percent change Standard Error 0.8

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis	-22.1 percent change Standard Error 1.2	1.1 percent change Standard Error 1.7

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: HDL-C ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis	8.7 percent change Standard Error 0.7	2.8 percent change Standard Error 1

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: ITT population.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis	-13 percent change Standard Error 1.5	-12.8 percent change Standard Error 2.0

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Apo A-1 ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis	1.5 percent change Standard Error 0.5	-2.9 percent change Standard Error 0.7

OTHER_PRE_SPECIFIED outcome

Timeframe: From Baseline to Week 52

Population: mITT population.

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 or 3 days after the last capsule, whichever came first).

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=464 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=235 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis	-51.8 Percent change Standard Error 1.5	-19.7 Percent change Standard Error 2.1

OTHER_PRE_SPECIFIED outcome

Timeframe: From Baseline to Week 104

Population: ITT population.

Adjusted LS means and standard errors at Week 104 from MMRM including all available post-baseline data from Week 4 to Week 104 regardless of status on-or off-treatment.

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=467 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=240 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Calculated LDL-C at Week 104 - ITT Analysis	-44.2 Percent change Standard Error 1.7	-15.2 Percent change Standard Error 2.4

OTHER_PRE_SPECIFIED outcome

Timeframe: From Baseline to Week 104

Population: mITT population.

Adjusted LS means and standard errors at Week 104 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 104 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).

Outcome measures

Outcome measures
Measure	Alirocumab 75 /up to 150 mg Q2W n=464 Participants Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.	Ezetimibe 10 mg n=235 Participants Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Percent Change From Baseline in Calculated LDL-C at Week 104 - On-Treatment Analysis	-48.9 Percent change Standard Error 1.7	-17.0 Percent change Standard Error 2.4

Adverse Events

Alirocumab 75/Up to 150 mg Q2W

Serious events: 124 serious events

Other events: 185 other events

Deaths: 0 deaths

Ezetimibe 10 mg

Serious events: 60 serious events

Other events: 90 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Alirocumab 75/Up to 150 mg Q2W n=479 participants at risk Participants exposed to Alirocumab 75 /up to 150 mg Q2W added to stable LMT (mean exposition of 90 weeks).	Ezetimibe 10 mg n=241 participants at risk Participants exposed to Ezetimibe 10 mg added to stable LMT (mean exposition of 90 weeks).
Infections and infestations Upper respiratory tract infection	8.8% 42/479 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).	7.1% 17/241 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).
Infections and infestations Nasopharyngitis	4.8% 23/479 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).	6.2% 15/241 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).
Infections and infestations Influenza	4.6% 22/479 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).	6.6% 16/241 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).
Nervous system disorders Dizziness	5.8% 28/479 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).	7.5% 18/241 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).
Nervous system disorders Headache	6.1% 29/479 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).	5.4% 13/241 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).
Vascular disorders Hypertension	6.5% 31/479 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).	5.8% 14/241 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).
Musculoskeletal and connective tissue disorders Myalgia	5.2% 25/479 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).	5.4% 13/241 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).
Injury, poisoning and procedural complications Accidental overdose	9.8% 47/479 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).	7.9% 19/241 • All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs. Reported AEs are treatment emergent that is AEs that developed/worsened during 'the treatment emergent period' (from the first dose of double-blind study drug administration \[capsule or injection, whichever came first\] up the day of the last double blind injection + 70 days).

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Publication restrictions are in place

Restriction type: OTHER