Evaluation of Alirocumab in Addition to Lipid-Modifying Therapy in Patients With High Cardiovascular Risk and Hypercholesterolemia in South Korea and Taiwan

• 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: Placebo (for Alirocumab); Drug: Alirocumab; Drug: Lipid-Modifying Therapy (LMT)
Enrollment	199

Participant Flow

Recruitment Details	The study was conducted at 27 centers in South Korea and Taiwan. Overall 316 participants were screened between January and September 2015, of whom 117 were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Details	Randomization was stratified according to prior history of myocardial infarction (MI) or ischemic stroke, intensity of statin treatment and country. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1 ratio (Placebo:Alirocumab). A total of 199 participants were randomized.

Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description	Placebo (for alirocumab) subcutaneous (SC) injection every 2 weeks (Q2W) added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W 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	102 [1]	97 [1]
Treated	102	97
Completed	97	87
Not Completed	5	10
Reason Not Completed
Adverse Event	1	2
Poor compliance to protocol	1	0
Withdrawal by Subject	1	0
Last injection missed	2	2
End treatment visit outside visit window	0	4
Other than specified above	0	2
[1] Randomized

Baseline Characteristics

Arm/Group Title		Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W	Total
Arm/Group Description		Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W 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		102	97	199
Baseline Analysis Population Description		Baseline population included all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	102 participants	97 participants	199 participants
		60.1 (9.1)	61.2 (10.4)	60.6 (9.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	102 participants	97 participants	199 participants
	Female	21 20.6%	14 14.4%	35 17.6%
	Male	81 79.4%	83 85.6%	164 82.4%
Calculated LDL-C in mmol/L [1]; Mean (Standard Deviation); Unit of measure: mmol/L
	Number Analyzed	102 participants	97 participants	199 participants
		2.572 (0.653)	2.513 (0.721)	2.543 (0.686)
		[1] Measure Description: Calculated LDL-C in mmol/L from Friedewald formula (LDL-C = Total cholesterol - High-density lipoprotein cholesterol [HDL-C] - [Triglyceride/2.2]).

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 up 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 that included all randomized participants with one baseline and at least one post-baseline calculated LDL-C on- or off-treatment.

Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Least Squares Mean (Standard Error); Unit of Measure: percent change
	6.3 (2.9)	-57.1 (3.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/Up to 150 mg Q2W
	Comments	Alirocumab group was compared to placebo group using an appropriate contrast statement.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	-63.4
	Confidence Interval	(2-Sided) 95%; -71.6 to -55.2
	Estimation Comments	Alirocumab 75 mg Q2W/ Up to 150 mg Q2W vs. Placebo Q2W

2. Secondary Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
Description	Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data up to Week 24 (i.e. up to 21 days after last injection) (on-treatment analysis).
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	100	97
Least Squares Mean (Standard Error); Unit of Measure: Percent Change
	6.0 (2.7)	-60.2 (2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance was at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-66.2
	Confidence Interval	(2-Sided) 95%; -73.9 to -58.4
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

3. 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 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Least Squares Mean (Standard Error); Unit of Measure: percent change
	4.7 (2.2)	-57.9 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-62.5
	Confidence Interval	(2-Sided) 95%; -68.8 to -56.3
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

4. Secondary Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
Description	Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data up to Week 24 (i.e. up to 21 days after last injection).
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	100	97
Least Squares Mean (Standard Error); Unit of Measure: percent change
	4.7 (2.2)	-58.4 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-63.1
	Confidence Interval	(2-Sided) 95%; -69.2 to -57.0
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

5. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	100	96
Least Squares Mean (Standard Error); Unit of Measure: percent change
	4.1 (2.3)	-42.3 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-46.3
	Confidence Interval	(2-Sided) 95%; -53.0 to -39.7
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

6. Secondary Outcome

Title	Percent Change From Baseline in Apo B at Week 24 - On-treatment Analysis
Description	Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data up to Week 24 (i.e. up to 21 days after last injection).
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	99	95
Least Squares Mean (Standard Error); Unit of Measure: percent change
	3.8 (2.1)	-45.4 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-49.2
	Confidence Interval	(2-Sided) 95%; -55.3 to -43.1
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

7. 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 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Least Squares Mean (Standard Error); Unit of Measure: percent change
	4.3 (2.4)	-47.2 (2.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-51.5
	Confidence Interval	(2-Sided) 95%; -58.4 to -44.6
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

8. Secondary Outcome

Title	Percent Change From Baseline in Non-HDL-C at Week 24 - On-treatment Analysis
Description	Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data up to Week 24 (i.e. up to 21 days after last injection).
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	100	97
Least Squares Mean (Standard Deviation); Unit of Measure: percent change
	4.1 (2.2)	-50.1 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-54.2
	Confidence Interval	(2-Sided) 95%; -60.6 to -47.8
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

9. 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 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Least Squares Mean (Standard Deviation); Unit of Measure: percent change
	4.0 (1.8)	-31.2 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-35.2
	Confidence Interval	(2-Sided) 95%; -40.3 to -30.1
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

10. 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 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	100	96
Least Squares Mean (Standard Error); Unit of Measure: percent change
	5.2 (1.8)	-40.9 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-46.1
	Confidence Interval	(2-Sided) 95%; -51.2 to -41.0
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

11. 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 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Least Squares Mean (Standard Deviation); Unit of Measure: percent change
	3.9 (1.8)	-47.3 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-51.2
	Confidence Interval	(2-Sided) 95%; -56.4 to -46.1
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

12. 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 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.8 (1.4)	-32.9 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-35.8
	Confidence Interval	(2-Sided) 95%; -39.7 to -31.9
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

13. Secondary Outcome

Title	Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 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 up to Week 24 regardless of status on- or off-treatment were included in the imputation model.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Measure Type: Number; Unit of Measure: percentage of participants
	14.2	85.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Regression, Logistic
	Comments	Multiple imputation approach followed by logistic regression model.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	46.9
	Confidence Interval	(2-Sided) 95%; 18.4 to 119.4
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

14. Secondary Outcome

Title	Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-treatment Analysis
Description	Adjusted percentages at Week 24 were obtained from multiple imputation approach model including available post-baseline on-treatment data up to Week 24 (i.e. up to 21 days after last injection).
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	100	97
Measure Type: Number; Unit of Measure: percentage of participants
	14.1	88.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Regression, Logistic
	Comments	Multiple imputation approach followed by logistic regression model
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	70.0
	Confidence Interval	(2-Sided) 95%; 23.3 to 210.8
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Mean (Standard Error); Unit of Measure: percent change
	-2.251 (2.962)	-35.862 (3.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	Regression, Robust
	Comments	Multiple imputation approach followed by a robust regression model.
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-33.611
	Confidence Interval	(2-Sided) 95%; -41.883 to -25.338
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

16. Secondary Outcome

Title	Percent Change From Baseline in High Density Lipoprotein (HDL-C) at Week 24 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Least Squares Mean (Standard Error); Unit of Measure: percent change
	6.2 (1.7)	13.8 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0029
	Comments	Threshold for significance at 0.05 level.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	7.5
	Confidence Interval	(2-Sided) 95%; 2.6 to 12.4
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

17. Secondary Outcome

Title	Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
Description	Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Mean (Standard Error); Unit of Measure: percent change
	-3.627 (3.111)	-8.143 (3.204)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Q2W, Alirocumab 75 mg Q2W/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
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3110
	Comments	Threshold for significance at 0.05 level.
	Method	Regression, Robust
	Comments	Multiple imputation approach followed by a robust regression model.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.515
	Confidence Interval	(2-Sided) 95%; -13.250 to 4.219
	Estimation Comments	Alirocumab 75 mg Q2W/Up to 150 mg Q2W vs. Placebo Q2W

18. 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 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	100	96
Least Squares Mean (Standard Error); Unit of Measure: percent change
	3.2 (1.2)	4.5 (1.2)

19. Secondary Outcome

Title	Percent Change From Baseline in Lipoprotein(a) at Week 12- ITT Analysis
Description	Adjusted means and standard errors at Week 12 were obtained from multiple imputation approach followed by robust regression model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Mean (Standard Error); Unit of Measure: percent change
	-1.676 (2.732)	-33.601 (2.778)

20. 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 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.0 (1.5)	7.1 (1.6)

21. Secondary Outcome

Title	Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
Description	Adjusted means and standard errors at Week 12 were obtained from multiple imputation approach followed by a robust regression model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	102	97
Mean (Standard Error); Unit of Measure: percent change
	2.113 (3.192)	-6.999 (3.252)

22. 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 were obtained from MMRM model including all available post-baseline data up 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	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W added to stable LMT for 24 weeks.	Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Overall Number of Participants Analyzed	100	96
Least Squares Mean (Standard Error); Unit of Measure: percent change
	1.5 (1.1)	4.5 (1.1)

Adverse Events

Time Frame	All Adverse Events (AEs) 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 investigational product.
Adverse Event Reporting Description	Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘treatment emergent period’ (the time from the first dose of study drug up to the last dose of study drug +70 days).
Arm/Group Title	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
Arm/Group Description	Participants exposed to Placebo (for Alirocumab) SC injection Q2W added to stable LMT (mean exposure of 23 weeks).	Participants exposed to Alirocumab 75 mg Q2W/up to 150 mg Q2W SC injection added to stable LMT (mean exposure of 24 weeks).
All-Cause Mortality
	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/102 (0.00%)	1/97 (1.03%)
Serious Adverse Events
	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
	Affected / at Risk (%)	Affected / at Risk (%)
Total	10/102 (9.80%)	17/97 (17.53%)
Cardiac disorders
Angina pectoris † 1	0/102 (0.00%)	2/97 (2.06%)
Coronary artery disease † 1	1/102 (0.98%)	2/97 (2.06%)
Angina unstable † 1	1/102 (0.98%)	1/97 (1.03%)
Supraventricular tachycardia † 1	0/102 (0.00%)	1/97 (1.03%)
Acute myocardial infarction † 1	1/102 (0.98%)	0/97 (0.00%)
Coronary artery stenosis † 1	1/102 (0.98%)	0/97 (0.00%)
Infections and infestations
Influenza † 1	0/102 (0.00%)	1/97 (1.03%)
Diarrhoea infectious † 1	1/102 (0.98%)	0/97 (0.00%)
Pulmonary tuberculosis † 1	1/102 (0.98%)	0/97 (0.00%)
Injury, poisoning and procedural complications
Ligament sprain † 1	0/102 (0.00%)	1/97 (1.03%)
Loss of anatomical alignment after fracture reduction † 1	0/102 (0.00%)	1/97 (1.03%)
Muscle strain † 1	0/102 (0.00%)	1/97 (1.03%)
Patella fracture † 1	0/102 (0.00%)	1/97 (1.03%)
Post procedural haematoma † 1	0/102 (0.00%)	1/97 (1.03%)
Radius fracture † 1	0/102 (0.00%)	1/97 (1.03%)
Road traffic accident † 1	1/102 (0.98%)	0/97 (0.00%)
Traumatic fracture † 1	0/102 (0.00%)	1/97 (1.03%)
Arterial injury † 1	1/102 (0.98%)	0/97 (0.00%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion † 1	0/102 (0.00%)	1/97 (1.03%)
Myopathy † 1	0/102 (0.00%)	1/97 (1.03%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm of spinal cord † 1	0/102 (0.00%)	1/97 (1.03%)
Rectal adenocarcinoma † 1	0/102 (0.00%)	1/97 (1.03%)
Nervous system disorders
Cerebellar haemorrhage † 1	0/102 (0.00%)	1/97 (1.03%)
Cervical myelopathy † 1	0/102 (0.00%)	1/97 (1.03%)
Ischaemic stroke † 1	1/102 (0.98%)	1/97 (1.03%)
Neuromuscular pain † 1	1/102 (0.98%)	0/97 (0.00%)
Product Issues
Device failure † 1	0/102 (0.00%)	1/97 (1.03%)
Respiratory, thoracic and mediastinal disorders
Epistaxis † 1	1/102 (0.98%)	0/97 (0.00%)
Vascular disorders
Brachiocephalic artery stenosis † 1	0/102 (0.00%)	1/97 (1.03%)
Peripheral arterial occlusive disease † 1	1/102 (0.98%)	0/97 (0.00%)
1 Term from vocabulary, MedDRA 19.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo Q2W	Alirocumab 75 mg Q2W/Up to 150 mg Q2W
	Affected / at Risk (%)	Affected / at Risk (%)
Total	15/102 (14.71%)	19/97 (19.59%)
Gastrointestinal disorders
Diarrhoea † 1	1/102 (0.98%)	5/97 (5.15%)
Infections and infestations
Nasopharyngitis † 1	4/102 (3.92%)	6/97 (6.19%)
Upper respiratory tract infection † 1	6/102 (5.88%)	3/97 (3.09%)
Nervous system disorders
Dizziness † 1	3/102 (2.94%)	6/97 (6.19%)
Headache † 1	3/102 (2.94%)	5/97 (5.15%)
1 Term from vocabulary, MedDRA 19.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

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

Chao TH, Hsiao PJ, Liu ME, Wu CJ, Chiang FT, Chen ZC, Chen CP, Yeh HI, Lee TH, Chiang CE. A subanalysis of Taiwanese patients from ODYSSEY South Korea and Taiwan study evaluating the efficacy and safety of alirocumab. J Chin Med Assoc. 2019 Apr;82(4):265-271. doi: 10.1097/JCMA.0000000000000062.

Koh KK, Nam CW, Chao TH, Liu ME, Wu CJ, Kim DS, Kim CJ, Li I, Li J, Baccara-Dinet MT, Hsiao PJ, Chiang CE. A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). J Clin Lipidol. 2018 Jan - Feb;12(1):162-172.e6. doi: 10.1016/j.jacl.2017.09.007. Epub 2017 Oct 19.

Responsible Party:	Sanofi
ClinicalTrials.gov Identifier:	NCT02289963 History of Changes
Other Study ID Numbers:	EFC14074; U1111-1157-3294 ( Other Identifier: UTN )
First Submitted:	November 10, 2014
First Posted:	November 13, 2014
Results First Submitted:	April 24, 2017
Results First Posted:	June 26, 2017
Last Update Posted:	June 26, 2017