Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe in Patients With Hypercholesterolemia (ODYSSEY MONO)

• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Hypercholesterolemia
Interventions	Drug: Alirocumab; Drug: Ezetimibe; Drug: Placebo (for Alirocumab); Drug: Placebo (for Ezetimibe)
Enrollment	103

Participant Flow

Recruitment Details	The study was conducted at 8 centers in 4 countries. A total of 204 participants were screened between July 2012 and November 2012, 101 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Details	Randomization was stratified according to the diabetes mellitus status. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1 ratio ( alirocumab:ezetimibe) after confirmation of selection criteria. 103 participants were randomized.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description	Oral ezetimibe 10 mg capsule daily and subcutaneous (SC) placebo injection for alirocumab every 2 weeks (Q2W) for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when low density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Period Title: Overall Study
Started	51 [1]	52 [1]
Treated	51	52
Completed	44	44
Not Completed	7	8
Reason Not Completed
Poor compliance to protocol	1	0
Consent withdrawn by participant	0	1
Participant moved	0	1
Adverse Event	4	5
Site scheduling error	1	1
Protocol Violation	1	0
[1] Randomized

Baseline Characteristics

Arm/Group Title		Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W	Total
Arm/Group Description		Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.	Total of all reporting groups
Overall Number of Baseline Participants		51	52	103
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	51 participants	52 participants	103 participants
		59.6 (5.3)	60.8 (4.6)	60.2 (5.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	51 participants	52 participants	103 participants
	Female	24 47.1%	24 46.2%	48 46.6%
	Male	27 52.9%	28 53.8%	55 53.4%
Calculated LDL-C in mmol/L [1]; Mean (Standard Deviation); Unit of measure: mmol/L
	Number Analyzed	51 participants	52 participants	103 participants
		3.58 (0.6)	3.65 (0.7)	3.62 (0.7)
		[1] Measure Description: Calculated LDL-C in mmol/L from Friedewald formula (LDL cholesterol = Total cholesterol - HDL cholesterol - [Triglyceride/2.2]).
Calculated LDL-C in mg/dL [1]; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	51 participants	52 participants	103 participants
		138.3 (24.5)	141.1 (27.1)	139.7 (25.8)
		[1] Measure Description: Calculated LDL-C in mg/dL from Friedewald formula (LDL cholesterol = Total cholesterol - HDL cholesterol - [Triglyceride/5]).

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis
Description	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 24 regardless of status on­ or off-treatment were used in the model (ITT analysis).
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-15.6 (3.1)	-47.2 (3.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Alirocumab group was compared to ezetimibe group using an appropriate contrast statement.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-31.6
	Confidence Interval	(2-Sided) 95%; -40.2 to -23.0
	Estimation Comments	Alirocumab vs Ezetimibe

2. Secondary Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 12 from MMRM including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-19.6 (2.6)	-48.1 (2.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-28.5
	Confidence Interval	(2-Sided) 95%; -35.7 to -21.2
	Estimation Comments	Alirocumab vs Ezetimibe

3. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	46	48
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-11.0 (2.4)	-36.7 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-25.8
	Confidence Interval	(2-Sided) 95%; -32.3 to -19.2
	Estimation Comments	Alirocumab vs Ezetimibe

4. Secondary Outcome

Title	Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-15.1 (2.9)	-40.6 (2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-25.5
	Confidence Interval	(2-Sided) 95%; -33.5 to -17.4
	Estimation Comments	Alirocumab vs Ezetimibe

5. Secondary Outcome

Title	Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-10.9 (2.2)	-29.6 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-18.7
	Confidence Interval	(2-Sided) 95%; -24.7 to -12.7
	Estimation Comments	Alirocumab vs Ezetimibe

6. Secondary Outcome

Title	Percent Change From Baseline in Apo B at Week 12 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Apo-B ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	46	48
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-11.7 (2.1)	-37.3 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-25.7
	Confidence Interval	(2-Sided) 95%; -31.5 to -19.8
	Estimation Comments	Alirocumab vs Ezetimibe

7. Secondary Outcome

Title	Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

non-HDL-C ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-16.7 (2.4)	-42.5 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-25.8
	Confidence Interval	(2-Sided) 95%; -32.4 to -19.2
	Estimation Comments	Alirocumab vs Ezetimibe

8. Secondary Outcome

Title	Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Total-C ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-12.0 (1.7)	-30.3 (1.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-18.3
	Confidence Interval	(2-Sided) 95%; -23.1 to -13.5
	Estimation Comments	Alirocumab vs Ezetimibe

9. Secondary Outcome

Title	Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis
Description	Adjusted percentages at Week 24 were obtained from multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment were included in the imputation model.
Time Frame	Up to Week 24

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Measure Type: Number; Unit of Measure: percentage of participants
	32.2	88.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance ≤ 0.05.
	Method	Regression, Logistic
	Comments	Multiple imputation approach followed by logistic regression model.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	34.8
	Confidence Interval	(2-Sided) 95%; 8.7 to 139.0
	Estimation Comments	Alirocumab vs Ezetimibe

10. Secondary Outcome

Title	Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
Description	Adjusted percentages at Week 24 from multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	Up to Week 24

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Measure Type: Number; Unit of Measure: percentage of participants
	2.4	59.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	Threshold for significance was ≤ 0.05.
	Method	Regression, Logistic
	Comments	Multiple imputation approach followed by logistic regression model.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	69.8
	Confidence Interval	(2-Sided) 95%; 8.8 to 556.0
	Estimation Comments	Alirocumab vs Ezetimibe

11. Secondary Outcome

Title	Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis
Description	Adjusted means and standard errors at Week 24 from a multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Mean (Standard Error); Unit of Measure: percent change
	-12.3 (3.8)	-16.7 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ezetimibe 10 mg, Alirocumab 75/Up to 150 mg Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4013
	Comments	Threshold for significance ≤ 0.05.
	Method	Regression, Robust
	Comments	Multiple imputation approach followed by robust regression model.
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-4.4
	Confidence Interval	(2-Sided) 95%; -14.8 to 5.9
	Estimation Comments	Alirocumab vs Ezetimibe

12. Secondary Outcome

Title	Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Least Squares Mean (Standard Error); Unit of Measure: percent change
	1.6 (1.9)	6.0 (1.9)

13. Secondary Outcome

Title	Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

HDL-C ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Least Squares Mean (Standard Error); Unit of Measure: percent change
	1.6 (2.0)	9.0 (2.0)

14. Secondary Outcome

Title	Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis
Description	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 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Mean (Standard Error); Unit of Measure: percent change
	-14.2 (3.7)	-17.2 (3.7)

15. Secondary Outcome

Title	Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
Description	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 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Mean (Standard Error); Unit of Measure: percent change
	-10.8 (4.3)	-11.9 (4.2)

16. Secondary Outcome

Title	Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
Description	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 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	51	52
Mean (Standard Error); Unit of Measure: percent change
	-2.3 (3.5)	-12.2 (3.4)

17. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	46	48
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-0.6 (1.6)	4.7 (1.6)

18. Secondary Outcome

Title	Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on­ or off-treatment.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Apo A-1 ITT population.

Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description:	Oral ezetimibe 10 mg capsule daily and SC placebo injection for alirocumab Q2W for 24 weeks.	SC injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily for 24 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	46	48
Mean (Standard Error); Unit of Measure: percent change
	-2.2 (1.4)	2.3 (1.4)

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 32 post-treatment follow-up visit) regardless of seriousness or relationship to study drug.
Adverse Event Reporting Description	Reported adverse events are treatment-emergent adverse events 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 to the day of the last double-blind injection + 70 days).
Arm/Group Title	Ezetimibe 10 mg	Alirocumab 75/Up150 mg Q2W
Arm/Group Description	Participants exposed to Ezetimibe 10 mg (mean exposure of 22 weeks).	Participants exposed to Alirocumab 75 mg/Up to 150 mg Q2W (mean exposure of 22 weeks).
All-Cause Mortality
	Ezetimibe 10 mg	Alirocumab 75/Up150 mg Q2W
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Ezetimibe 10 mg	Alirocumab 75/Up150 mg Q2W
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/51 (1.96%)	1/52 (1.92%)
Musculoskeletal and connective tissue disorders
Bone erosion † 1	1/51 (1.96%)	0/52 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism † 1	0/51 (0.00%)	1/52 (1.92%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDra 16.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Ezetimibe 10 mg	Alirocumab 75/Up150 mg Q2W
	Affected / at Risk (%)	Affected / at Risk (%)
Total	27/51 (52.94%)	25/52 (48.08%)
Gastrointestinal disorders
Diarrhoea † 1	2/51 (3.92%)	6/52 (11.54%)
Nausea † 1	3/51 (5.88%)	3/52 (5.77%)
Infections and infestations
Nasopharyngitis † 1	8/51 (15.69%)	12/52 (23.08%)
Influenza † 1	3/51 (5.88%)	6/52 (11.54%)
Upper respiratory tract infection † 1	5/51 (9.80%)	2/52 (3.85%)
Urinary tract infection † 1	3/51 (5.88%)	0/52 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	2/51 (3.92%)	3/52 (5.77%)
Back pain † 1	3/51 (5.88%)	1/52 (1.92%)
Nervous system disorders
Headache † 1	2/51 (3.92%)	3/52 (5.77%)
Dizziness † 1	3/51 (5.88%)	1/52 (1.92%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDra 16.0

Limitations and Caveats

Due to administrative error in the automated process (which was detected after database lock), planned dose up­titration criteria for LDL­C levels was changed from ≥100 mg/dL to ≥70 mg/dL.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

Name/Title: Trial Transparency Team

Organization: Sanofi

EMail: Contact-US@sanofi.com

Publications of Results:

Roth EM, Taskinen MR, Ginsberg HN, Kastelein JJ, Colhoun HM, Robinson JG, Merlet L, Pordy R, Baccara-Dinet MT. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014 Sep;176(1):55-61. doi: 10.1016/j.ijcard.2014.06.049. Epub 2014 Jul 2.

Roth EM, McKenney JM. ODYSSEY MONO: effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks. Future Cardiol. 2015;11(1):27-37. doi: 10.2217/fca.14.82.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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. Epub 2016 Oct 24.

Responsible Party:	Sanofi
ClinicalTrials.gov Identifier:	NCT01644474 History of Changes
Other Study ID Numbers:	EFC11716; U1111-1124-1167 ( Other Identifier: UTN ); 2011-001424-38 ( EudraCT Number )
First Submitted:	July 17, 2012
First Posted:	July 19, 2012
Results First Submitted:	August 20, 2015
Results First Posted:	November 6, 2015
Last Update Posted:	November 6, 2015