Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy (ODYSSEY FH I)

• ClinicalTrials.gov Identifier: NCT01623115
• Recruitment Status: Completed
• First Posted: June 19, 2012
• Results First Posted: November 4, 2015
• Last Update Posted: February 8, 2016
• 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: Placebo (for alirocumab); Drug: Lipid Modifying Therapy (LMT)
• Enrollment: 486

Participant Flow

Recruitment Details	The study was conducted at 89 centers in 14 countries. A total of 597 participants were screened between July 2012 and April 2013, 111 of whom were screen failures.
Pre-assignment Details	Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, intensity of statin treatment & geographic region. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in 1:2 (placebo:alirocumab) after confirmation of selection criteria. 486 participants were randomized.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description	Placebo for alirocumab subcutaneous (SC) injection every 2 weeks (Q2W) on top of stable lipid-modifying therapy (LMT) for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163 [1]	323 [1]
Treated	163	322
Completed	130	246
Not Completed	33	77
Reason Not Completed
Randomized but not treated	0	1
Physician Decision	1	0
Participants moved	1	5
Adverse Event	10	13
Poor compliance to protocol	4	10
Consent withdrawn by participant	2	6
Related to study drug administration	0	2
Last visit outside protocol visit window	14	26
Site closure	1	7
Death	0	4
Other than specified above	0	3
[1] Randomized

Baseline Characteristics

Arm/Group Title		Placebo	Alirocumab 75 mg/Up to 150 mg Q2W	Total
Arm/Group Description		Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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		163	323	486
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	163 participants	323 participants	486 participants
		51.7 (12.3)	52.1 (12.9)	51.9 (12.7)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	163 participants	323 participants	486 participants
	Female	69 42.3%	143 44.3%	212 43.6%
	Male	94 57.7%	180 55.7%	274 56.4%
Calculated LDL-C in mg/dL [1]; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	163 participants	323 participants	486 participants
		144.4 (46.8)	144.8 (51.1)	144.6 (49.7)
		[1] Measure Description: Calculated LDL-C from Friedewald formula (LDL cholesterol = Total cholesterol - HDL cholesterol - [Triglyceride/5]).
Calculated LDL-C in mmol/L; Mean (Standard Deviation); Unit of measure: mmol/L
	Number Analyzed	163 participants	323 participants	486 participants
		3.739 (1.213)	3.749 (1.325)	3.746 (1.287)

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 52 regardless of status on- or off-treatment were used in the model (ITT analysis).
Time Frame	From Baseline to Week 52

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	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	9.1 (2.2)	-48.8 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/Up to 150 mg Q2W
	Comments	Alirocumab group was compared to placebo 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	-57.9
	Confidence Interval	(2-Sided) 95%; -63.3 to -52.6
	Estimation Comments	Alirocumab vs Placebo

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 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis).
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	321
Least Squares Mean (Standard Error); Unit of Measure: percent change
	8.8 (2.2)	-49.3 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-58.1
	Confidence Interval	(2-Sided) 95%; -63.5 to -52.7
	Estimation Comments	Alirocumab vs Placebo

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 from MMRM including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	5.7 (2)	-43.5 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-49.2
	Confidence Interval	(2-Sided) 95%; -53.9 to -44.5
	Estimation Comments	Alirocumab vs Placebo

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 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).
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	321
Least Squares Mean (Standard Error); Unit of Measure: percent change
	5.7 (2)	-43.9 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-49.5
	Confidence Interval	(2-Sided) 95%; -54.2 to -44.8
	Estimation Comments	Alirocumab vs Placebo

5. 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 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

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	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	160	309
Least Squares Mean (Standard Error); Unit of Measure: percent change
	4.7 (1.6)	-41.1 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-45.8
	Confidence Interval	(2-Sided) 95%; -49.8 to -41.8
	Estimation Comments	Alirocumab vs Placebo

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 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).
Time Frame	From Baseline to Week 52

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	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	159	308
Least Squares Mean (Standard Error); Unit of Measure: percent change
	4.5 (1.7)	-41.4 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-45.9
	Confidence Interval	(2-Sided) 95%; -49.9 to -41.8
	Estimation Comments	Alirocumab vs Placebo

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 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame	From Baseline to Week 52

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	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	9.6 (2)	-42.8 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-52.4
	Confidence Interval	(2-Sided) 95%; -57.2 to -47.6
	Estimation Comments	Alirocumab vs Placebo

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 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).
Time Frame	From Baseline to Week 52

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	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	321
Least Squares Mean (Standard Error); Unit of Measure: percent change
	9.4 (2)	-43.3 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-52.6
	Confidence Interval	(2-Sided) 95%; -57.5 to -47.8
	Estimation Comments	Alirocumab vs Placebo

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 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame	From Baseline to Week 52

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	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	7.3 (1.5)	-31.4 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-38.7
	Confidence Interval	(2-Sided) 95%; -42.4 to -35
	Estimation Comments	Alirocumab vs Placebo

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 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Apo B ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	160	309
Least Squares Mean (Standard Error); Unit of Measure: percent change
	3.1 (1.5)	-34.5 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-37.5
	Confidence Interval	(2-Sided) 95%; -41.2 to -33.9
	Estimation Comments	Alirocumab vs Placebo

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 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

non-HDL-C ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	5.3 (1.8)	-38.4 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-43.7
	Confidence Interval	(2-Sided) 95%; -48 to -39.4
	Estimation Comments	Alirocumab vs Placebo

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 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Total-C ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	4.1 (1.4)	-28.3 (1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-32.5
	Confidence Interval	(2-Sided) 95%; -35.7 to -29.2
	Estimation Comments	Alirocumab vs Placebo

13. Secondary Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	9 (2.6)	-47.1 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	-56.2
	Confidence Interval	(2-Sided) 95%; -62.4 to -50
	Estimation Comments	Alirocumab vs Placebo

14. Secondary Outcome

Title	Percentage of Very High Cardiovascular (CV) Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis
Description	Very high CV risk participants: Heterozygous Familial Hypercholesterolemia (heFH) participants with coronary heart disease (CHD) or CHD risk equivalents. High CV risk participants: heFH participants without CHD or CHD risk equivalents. CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (estimated glomerular filtration rate, 30 to <60 ml/minute/1.73 m^2 of body-surface area), or diabetes mellitus plus 2 or more additional risk factors (hypertension; ankle-brachial index of ≤0.90; microalbuminuria, macroalbuminuria, or a urinary dipstick result of >2+ protein; preproliferative or proliferative retinopathy or laser treatment for retinopathy; or a family history of premature CHD). Adjusted percentages at Week 24 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Measure Type: Number; Unit of Measure: percentage of participants
	2.4	72.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	156
	Confidence Interval	(2-Sided) 95%; 48.9 to 498.1
	Estimation Comments	Alirocumab vs Placebo

15. Secondary Outcome

Title	Percentage of Very High CV Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - On- Treatment Analysis
Description	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.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	321
Measure Type: Number; Unit of Measure: percentage of participants
	2.4	73

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	156.6
	Confidence Interval	(2-Sided) 95%; 49.7 to 493.7
	Estimation Comments	Alirocumab vs Placebo

16. 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 52 regardless of status on- or off-treatment.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Measure Type: Number; Unit of Measure: percentage of participants
	0.8	59.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	244.9
	Confidence Interval	(2-Sided) 95%; 34.4 to 1744.4
	Estimation Comments	Alirocumab vs Placebo

17. Secondary Outcome

Title	Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
Description	Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	321
Measure Type: Number; Unit of Measure: percentage of participants
	0.8	60.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	240
	Confidence Interval	(2-Sided) 95%; 33.9 to 1700.7
	Estimation Comments	Alirocumab vs Placebo

18. 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 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.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Mean (Standard Error); Unit of Measure: percent change
	-7.5 (2)	-25.2 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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, Robust
	Comments	Multiple imputation approach followed by robust regression model.
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-17.7
	Confidence Interval	(2-Sided) 95%; -22.6 to -12.9
	Estimation Comments	Alirocumab vs Placebo

19. 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 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

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	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	0.8 (1.2)	8.8 (0.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	8
	Confidence Interval	(2-Sided) 95%; 5 to 11
	Estimation Comments	Alirocumab vs Placebo

20. 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 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Mean (Standard Error); Unit of Measure: percent change
	6.3 (2.2)	-9.6 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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, Robust
	Comments	Multiple imputation approach followed by robust regression model.
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-16
	Confidence Interval	(2-Sided) 95%; -21.3 to -10.6
	Estimation Comments	Alirocumab vs Placebo

21. 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 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

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	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	160	309
Least Squares Mean (Standard Error); Unit of Measure: percent change
	0.3 (1)	5 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	= 0.0002
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; 2.3 to 7.2
	Estimation Comments	Alirocumab vs Placebo

22. 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 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Mean (Standard Error); Unit of Measure: percent change
	-3.9 (1.8)	-21.2 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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, Robust
	Comments	Multiple imputation approach followed by robust regression model.
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-17.3
	Confidence Interval	(2-Sided) 95%; -21.5 to -13
	Estimation Comments	Alirocumab vs Placebo

23. 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 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

HDL-C ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	2.1 (1.2)	6.4 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	0.0031
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	4.3
	Confidence Interval	(2-Sided) 95%; 1.5 to 7.2
	Estimation Comments	Alirocumab vs Placebo

24. 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 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Mean (Standard Error); Unit of Measure: percent change
	1.7 (2.2)	-8 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	0.0003
	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	-9.7
	Confidence Interval	(2-Sided) 95%; -15 to -4.4
	Estimation Comments	Alirocumab vs Placebo

25. 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 52 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

Apo A-1 ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	160	309
Least Squares Mean (Standard Error); Unit of Measure: percent change
	0.1 (1)	2.9 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Alirocumab 75 mg/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	0.0187
	Comments	Threshold for significance ≤ 0.05.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 95%; 0.5 to 5.2
	Estimation Comments	Alirocumab vs Placebo

26. Other Pre-specified Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis
Description	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).
Time Frame	From Baseline to Week 52

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	321
Least Squares Mean (Standard Error); Unit of Measure: percent change
	9.1 (2.6)	-48.1 (1.9)

27. Other Pre-specified Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis
Description	Adjusted LS means and standard errors at Week 78 from MMRM including all available post-baseline data from Week 4 to Week 78 regardless of status on-or off-treatment.
Time Frame	From Baseline to Week 78

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	322
Least Squares Mean (Standard Error); Unit of Measure: percent change
	11.5 (2.8)	-40.3 (2.0)

28. Other Pre-specified Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis
Description	Adjusted LS means and standard errors at Week 78 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 78 (i.e. up to 21 days after last injection).
Time Frame	From Baseline to Week 78

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo	Alirocumab 75 mg/Up to 150 mg Q2W
Arm/Group Description:	Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.	Alirocumab 75 mg SC injection Q2W on top of stable LMT for 78 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	163	321
Least Squares Mean (Standard Error); Unit of Measure: percent change
	14.0 (2.8)	-43.7 (2.0)

Adverse Events

Time Frame	All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit in the study regardless of seriousness or relationship to study drug.
Adverse Event Reporting Description	Reported adverse events are treatment-emergent that is AEs that developed/worsened during the 'treatment-emergent period' (from the first double-blind injection up to the day of the last injection + 70 days or up to first intake in the extension study, whichever came first).
Arm/Group Title	Placebo	Alirocumab 75/Up to 150 mg Q2W
Arm/Group Description	Participants exposed to placebo Q2W on top of stable LMT (mean exposure of 72 weeks).	Participants exposed to Alirocumab 75 mg/Up to 150 mg Q2W on top of stable LMT (mean exposure of 72 weeks).
All-Cause Mortality
	Placebo	Alirocumab 75/Up to 150 mg Q2W
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Placebo	Alirocumab 75/Up to 150 mg Q2W
	Affected / at Risk (%)	Affected / at Risk (%)
Total	22/163 (13.50%)	44/322 (13.66%)
Blood and lymphatic system disorders
Lymphoid tissue hyperplasia † 1	0/163 (0.00%)	1/322 (0.31%)
Cardiac disorders
Angina pectoris † 1	1/163 (0.61%)	2/322 (0.62%)
Coronary artery disease † 1	0/163 (0.00%)	4/322 (1.24%)
Acute myocardial infarction † 1	1/163 (0.61%)	3/322 (0.93%)
Cardiac failure congestive † 1	1/163 (0.61%)	2/322 (0.62%)
Ventricular extrasystoles † 1	1/163 (0.61%)	0/322 (0.00%)
Angina unstable † 1	2/163 (1.23%)	2/322 (0.62%)
Atrial fibrillation † 1	2/163 (1.23%)	1/322 (0.31%)
Bradycardia † 1	0/163 (0.00%)	2/322 (0.62%)
Atrial flutter † 1	0/163 (0.00%)	1/322 (0.31%)
Atrioventricular block † 1	0/163 (0.00%)	1/322 (0.31%)
Cardiac failure chronic † 1	0/163 (0.00%)	1/322 (0.31%)
Myocardial infarction † 1	0/163 (0.00%)	1/322 (0.31%)
Cardio-respiratory arrest † 1	1/163 (0.61%)	0/322 (0.00%)
Coronary artery occlusion † 1	1/163 (0.61%)	0/322 (0.00%)
Intracardiac thrombus † 1	1/163 (0.61%)	0/322 (0.00%)
Left ventricular dysfunction † 1	1/163 (0.61%)	0/322 (0.00%)
Mitral valve incompetence † 1	1/163 (0.61%)	0/322 (0.00%)
Ventricular fibrillation † 1	1/163 (0.61%)	0/322 (0.00%)
Eye disorders
Cataract † 1	0/163 (0.00%)	1/322 (0.31%)
Retinal artery embolism † 1	0/163 (0.00%)	1/322 (0.31%)
Retinal degeneration † 1	0/163 (0.00%)	1/322 (0.31%)
Gastrointestinal disorders
Gastrooesophageal reflux disease † 1	0/163 (0.00%)	1/322 (0.31%)
Colonic pseudo-obstruction † 1	0/163 (0.00%)	1/322 (0.31%)
Umbilical hernia † 1	0/163 (0.00%)	1/322 (0.31%)
Gastrointestinal haemorrhage † 1	1/163 (0.61%)	0/322 (0.00%)
Pancreatitis † 1	1/163 (0.61%)	0/322 (0.00%)
General disorders
Non-cardiac chest pain † 1	0/163 (0.00%)	1/322 (0.31%)
Pyrexia † 1	1/163 (0.61%)	0/322 (0.00%)
Gait disturbance † 1	1/163 (0.61%)	0/322 (0.00%)
Hepatobiliary disorders
Hepatitis alcoholic † 1	0/163 (0.00%)	1/322 (0.31%)
Bile duct stone † 1	1/163 (0.61%)	0/322 (0.00%)
Cholecystitis acute † 1	1/163 (0.61%)	0/322 (0.00%)
Infections and infestations
Influenza † 1	1/163 (0.61%)	0/322 (0.00%)
Pneumonia † 1	0/163 (0.00%)	1/322 (0.31%)
Cellulitis † 1	1/163 (0.61%)	0/322 (0.00%)
Pilonidal cyst † 1	0/163 (0.00%)	1/322 (0.31%)
Pyelonephritis † 1	0/163 (0.00%)	1/322 (0.31%)
Septic shock † 1	0/163 (0.00%)	1/322 (0.31%)
Clostridium difficile colitis † 1	1/163 (0.61%)	0/322 (0.00%)
Injury, poisoning and procedural complications
Fall † 1	1/163 (0.61%)	0/322 (0.00%)
Post lumbar puncture syndrome † 1	0/163 (0.00%)	1/322 (0.31%)
Radius fracture † 1	0/163 (0.00%)	1/322 (0.31%)
Thoracic vertebral fracture † 1	0/163 (0.00%)	1/322 (0.31%)
Toxicity to various agents † 1	0/163 (0.00%)	1/322 (0.31%)
Spinal compression fracture † 1	1/163 (0.61%)	0/322 (0.00%)
Investigations
Hepatic enzyme increased † 1	0/163 (0.00%)	1/322 (0.31%)
International normalised ratio increased † 1	0/163 (0.00%)	1/322 (0.31%)
Metabolism and nutrition disorders
Fluid retention † 1	1/163 (0.61%)	0/322 (0.00%)
Musculoskeletal and connective tissue disorders
Muscle spasms † 1	0/163 (0.00%)	1/322 (0.31%)
Osteoarthritis † 1	0/163 (0.00%)	3/322 (0.93%)
Bursitis † 1	0/163 (0.00%)	1/322 (0.31%)
Tendonitis † 1	1/163 (0.61%)	0/322 (0.00%)
Arthritis † 1	0/163 (0.00%)	1/322 (0.31%)
Lumbar spinal stenosis † 1	0/163 (0.00%)	1/322 (0.31%)
Musculoskeletal chest pain † 1	1/163 (0.61%)	1/322 (0.31%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acinic cell carcinoma of salivary gland † 1	0/163 (0.00%)	1/322 (0.31%)
Bladder transitional cell carcinoma † 1	0/163 (0.00%)	1/322 (0.31%)
Lung neoplasm † 1	0/163 (0.00%)	1/322 (0.31%)
Non-small cell lung cancer metastatic † 1	0/163 (0.00%)	1/322 (0.31%)
Pancreatic carcinoma metastatic † 1	0/163 (0.00%)	1/322 (0.31%)
Prostate cancer recurrent † 1	0/163 (0.00%)	1/322 (0.31%)
Renal cancer metastatic † 1	0/163 (0.00%)	1/322 (0.31%)
Thyroid adenoma † 1	0/163 (0.00%)	1/322 (0.31%)
Benign neoplasm of thyroid gland † 1	1/163 (0.61%)	0/322 (0.00%)
Breast cancer † 1	1/163 (0.61%)	0/322 (0.00%)
Prostate cancer † 1	1/163 (0.61%)	0/322 (0.00%)
Nervous system disorders
Presyncope † 1	0/163 (0.00%)	1/322 (0.31%)
Syncope † 1	1/163 (0.61%)	2/322 (0.62%)
Carotid artery stenosis † 1	1/163 (0.61%)	0/322 (0.00%)
Cerebrovascular accident † 1	0/163 (0.00%)	1/322 (0.31%)
Transient ischaemic attack † 1	1/163 (0.61%)	0/322 (0.00%)
Psychiatric disorders
Depression † 1	0/163 (0.00%)	1/322 (0.31%)
Renal and urinary disorders
Urinary bladder polyp † 1	0/163 (0.00%)	1/322 (0.31%)
Respiratory, thoracic and mediastinal disorders
Epistaxis † 1	0/163 (0.00%)	1/322 (0.31%)
Asthma † 1	1/163 (0.61%)	0/322 (0.00%)
Chronic obstructive pulmonary disease † 1	1/163 (0.61%)	0/322 (0.00%)
Hyperventilation † 1	1/163 (0.61%)	0/322 (0.00%)
Skin and subcutaneous tissue disorders
Eczema nummular † 1	0/163 (0.00%)	1/322 (0.31%)
Social circumstances
Pregnancy of partner † 1	0/163 (0.00%)	1/322 (0.31%)
Miscarriage of partner † 1	0/163 (0.00%)	2/322 (0.62%)
Vascular disorders
Arteriovenous fistula † 1	0/163 (0.00%)	1/322 (0.31%)
Trousseau's syndrome † 1	0/163 (0.00%)	1/322 (0.31%)
Aortic stenosis † 1	1/163 (0.61%)	0/322 (0.00%)
Hypertensive crisis † 1	1/163 (0.61%)	0/322 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 17.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Alirocumab 75/Up to 150 mg Q2W
	Affected / at Risk (%)	Affected / at Risk (%)
Total	70/163 (42.94%)	142/322 (44.10%)
General disorders
Injection site reaction † 1	18/163 (11.04%)	40/322 (12.42%)
Infections and infestations
Nasopharyngitis † 1	12/163 (7.36%)	36/322 (11.18%)
Upper respiratory tract infection † 1	14/163 (8.59%)	22/322 (6.83%)
Influenza † 1	9/163 (5.52%)	20/322 (6.21%)
Sinusitis † 1	7/163 (4.29%)	17/322 (5.28%)
Bronchitis † 1	9/163 (5.52%)	10/322 (3.11%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	9/163 (5.52%)	20/322 (6.21%)
Back pain † 1	7/163 (4.29%)	18/322 (5.59%)
Myalgia † 1	11/163 (6.75%)	6/322 (1.86%)
Nervous system disorders
Headache † 1	9/163 (5.52%)	15/322 (4.66%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 17.1

Limitations and Caveats

Manual reclassification was done by the Sponsor for the "other reasons" of non-completion of study as specified in the electronic case report form (eCRF).

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:

Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F, Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe DA, Geiger MJ, Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015 Nov 14;36(43):2996-3003. doi: 10.1093/eurheartj/ehv370. Epub 2015 Sep 1.

Other Publications:

Kastelein JJ, Robinson JG, Farnier M, Krempf M, Langslet G, Lorenzato C, Gipe DA, Baccara-Dinet MT. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014 Jun;28(3):281-9. doi: 10.1007/s10557-014-6523-z.

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.

Defesche JC, Stefanutti C, Langslet G, Hopkins PN, Seiz W, Baccara-Dinet MT, Hamon SC, Banerjee P, Kastelein JJP. Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. J Clin Lipidol. 2017 Nov - Dec;11(6):1338-1346.e7. doi: 10.1016/j.jacl.2017.08.016. Epub 2017 Sep 4. Erratum in: J Clin Lipidol. 2020 Sep - Oct;14(5):742.

Kastelein JJ, Hovingh GK, Langslet G, Baccara-Dinet MT, Gipe DA, Chaudhari U, Zhao J, Minini P, Farnier M. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017 Jan - Feb;11(1):195-203.e4. doi: 10.1016/j.jacl.2016.12.004. Epub 2016 Dec 28.

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: NCT01623115
• Other Study ID Numbers: EFC12492; U1111-1121-4275 ( Other Identifier: UTN ); 2011-005109-56 ( EudraCT Number )
• First Submitted: June 15, 2012
• First Posted: June 19, 2012
• Results First Submitted: August 20, 2015
• Results First Posted: November 4, 2015
• Last Update Posted: February 8, 2016