Efficacy and Safety of Alirocumab in Patients With Hypercholesterolemia Not Adequately Controlled With Non-statin Lipid Modifying Therapy or the Lowest Strength of Statin (ODYSSEY-NIPPON)

• ClinicalTrials.gov Identifier: NCT02584504
• Recruitment Status: Completed
• First Posted: October 22, 2015
• Results First Posted: May 7, 2018
• Last Update Posted: January 23, 2019
• 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; Drug: Atorvastatin; Drug: Non-statin Lipid-Modifying Therapy; Other: Diet Alone
• Enrollment: 163

Participant Flow

Recruitment Details	The study was conducted at 30 active centers in Japan. Overall 241 participants were screened between 30 November 2015 and 19 October 2016, of whom 78 were screen failures and 163 were randomized. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Details	Randomization stratified per background statin therapy (Yes/No). "No statin" also stratified per background fibrate/ezetimibe therapy (Yes/No), 'Yes' =fibrate/ezetimibe, 'No' =diet therapy alone. Randomization followed 1:1:1 ratio (Alirocumab 150 mg Q4W: Alirocumab 150 mg Q2W: Placebo Q2W).

Arm/Group Title	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description	In double-blind treatment period (DBTP), participants received Alirocumab 150 mg subcutaneous (SC) injection every 4 weeks (Q4W) alternating with placebo (for alirocumab) Q4W added to lowest-strength statin therapy (atorvastatin 5 mg daily), stable non-statin Lipid-Modifying Therapy (LMT) or diet therapy alone for 12 weeks. Participants who completed DBTP, entered in open-label treatment period (OLTP) and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg every 2 weeks (Q2W) at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.	In DBTP, participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.	In DBTP, participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
Period Title: Double-blind Treatment
Started	54 [1]	53 [1]	56 [1]
ITT Population	54	53	56
mITT Population	54	53	56
Safety Population	54	53	56
Completed	54	51	55
Not Completed	0	2	1
Reason Not Completed
Participant withdrew consent	0	0	1
Adverse Event	0	1	0
Family Matter	0	1	0
[1] Randomized
Period Title: Open-label Treatment
Started	54	51	55
Treated	54	50	54
Completed	52	47	47
Not Completed	2	4	8
Reason Not Completed
Participant withdrew consent	0	0	4
Adverse Event	2	2	3
Physician Decision	0	1	0
Entered but not treated	0	1	1

Baseline Characteristics

Arm/Group Title		Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W	Total
Arm/Group Description		In DBTP, participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.	In DBTP, participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.	In DBTP, participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.	Total of all reporting groups
Overall Number of Baseline Participants		54	53	56	163
Baseline Analysis Population Description		Baseline population included all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	54 participants	53 participants	56 participants	163 participants
		62.6 (9.8)	63.6 (10.4)	64.6 (10.0)	63.6 (10.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	54 participants	53 participants	56 participants	163 participants
	Female	21 38.9%	20 37.7%	19 33.9%	60 36.8%
	Male	33 61.1%	33 62.3%	37 66.1%	103 63.2%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Asian	Number Analyzed	54 participants	53 participants	56 participants	163 participants
		54 100.0%	53 100.0%	56 100.0%	163 100.0%
Calculated LDL-C in mg/dL [1]; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	54 participants	53 participants	56 participants	163 participants
		154.2 (59.5)	149.2 (31.1)	149.4 (32.6)	150.9 (42.8)
		[1] Measure Description: Calculated LDL-C in mg/dL from Friedewald formula (LDL cholesterol = Total cholesterol - high density lipoprotein [HDL] cholesterol - [Triglyceride/5]).
Calculated LDL-C in mmol/L; Mean (Standard Deviation); Unit of measure: mmol/L
	Number Analyzed	54 participants	53 participants	56 participants	163 participants
		3.993 (1.541)	3.865 (0.806)	3.870 (0.844)	3.909 (1.109)

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 12- Intent to Treat (ITT) Analysis
Description	Adjusted Least-squares (LS) means and standard errors at Week 12 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 12 regardless of status on- or off-treatment were used in the model (ITT analysis).
Time Frame	From Baseline to Week 12

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	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-43.8 (2.2)	-70.1 (2.3)	-4.3 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Alirocumab 150 mg Q4W 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 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	Threshold for significance at 0.025 level.
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	-39.5
	Confidence Interval	(2-Sided) 97.5%; -46.5 to -32.4
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Alirocumab 150 mg Q2W 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 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-65.8
	Confidence Interval	(2-Sided) 97.5%; -72.9 to -58.7
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Alirocumab 150 mg Q2W
	Comments	Alirocumab 150 mg Q4W group was compared to Alirocumab 150 mg Q2W group using an appropriate contrast statement.
	Type of Statistical Test	Other
	Comments	Statistical test was not planned because this comparison was for a descriptive purpose.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-26.3
	Confidence Interval	(2-Sided) 95%; -32.5 to -20.0
	Estimation Comments	Alirocumab 150 mg Q4W group vs Alirocumab 150 mg Q2W

2. 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 from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time Frame	From Baseline to Week 12

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	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-43.4 (2.1)	-70.1 (2.2)	-2.8 (2.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo 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 0.025 level. Hierarchical procedure for comparisons of Alirocumab 150 mg Q4W versus Placebo Q2W and Alirocumab 150 mg Q2W versus Placebo Q2W were processed separately.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-40.6
	Confidence Interval	(2-Sided) 97.5%; -47.4 to -33.8
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-67.4
	Confidence Interval	(2-Sided) 97.5%; -74.2 to -60.5
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

3. Secondary Outcome

Title	Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 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 12 regardless of status on- or off-treatment and assigning a weight of 0.5 for Week 10 and 12 time points.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-54.2 (1.9)	-69.9 (1.9)	-3.7 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-50.5
	Confidence Interval	(2-Sided) 97.5%; -56.6 to -44.5
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-66.2
	Confidence Interval	(2-Sided) 97.5%; -72.3 to -60.1
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

4. Secondary Outcome

Title	Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 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 from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection) and assigning a weight of 0.5 for Week 10 and 12 time points.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-54.0 (1.9)	-69.9 (1.9)	-2.6 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-51.4
	Confidence Interval	(2-Sided) 97.5%; -57.4 to -45.4
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-67.3
	Confidence Interval	(2-Sided) 97.5%; -73.3 to -61.3
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

5. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein B (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 12 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 12

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	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-32.2 (2.0)	-57.9 (2.0)	-6.0 (2.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-26.2
	Confidence Interval	(2-Sided) 97.5%; -32.5 to -19.9
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-51.9
	Confidence Interval	(2-Sided) 97.5%; -58.3 to -45.5
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

6. Secondary Outcome

Title	Percent Change From Baseline in Apo-B 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 at from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time Frame	From Baseline to Week 12

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	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	55
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-31.8 (2.0)	-58.0 (2.0)	-4.6 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-27.2
	Confidence Interval	(2-Sided) 97.5%; -33.5 to -20.9
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-53.4
	Confidence Interval	(2-Sided) 97.5%; -59.7 to -47.1
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

7. Secondary Outcome

Title	Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (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 12 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 12

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	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-36.2 (2.0)	-61.1 (2.0)	-4.9 (2.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-31.3
	Confidence Interval	(2-Sided) 97.5%; -37.7 to -25.0
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-56.2
	Confidence Interval	(2-Sided) 97.5%; -62.5 to -49.8
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

8. Secondary Outcome

Title	Percent Change From Baseline in Non-HDL-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 from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time Frame	From Baseline to Week 12

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	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-35.9 (1.9)	-61.1 (2.0)	-3.5 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-32.4
	Confidence Interval	(2-Sided) 97.5%; -38.6 to -26.3
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-57.6
	Confidence Interval	(2-Sided) 97.5%; -63.8 to -51.4
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

9. Secondary Outcome

Title	Percent Change From Baseline in Total Cholesterol (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 12 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 12

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	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-25.8 (1.5)	-44.7 (1.6)	-3.3 (1.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-22.5
	Confidence Interval	(2-Sided) 97.5%; -27.4 to -17.6
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-41.4
	Confidence Interval	(2-Sided) 97.5%; -46.4 to -36.5
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

10. Secondary Outcome

Title	Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- ITT Analysis
Description	Calculated LDL-C goal was defined as calculated LDL-C <100 mg/dL (2.59 mmol/L) for heterozygous familiar hypercholesterolemia (heFH) participants or non-familial hypercholesterolemia (non-FH) participants who had a history of documented CHD, or <120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model.
Time Frame	Up to Week 12

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Measure Type: Number; Unit of Measure: percentage of participants
	85.2	96.2	14.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Regression, Logistic
	Comments	Multiple imputation approach followed by logistic regression model.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	61.2
	Confidence Interval	(2-Sided) 97.5%; 13.9 to 268.9
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Regression, Logistic
	Comments	Multiple imputation approach followed by logistic regression model.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	281.4
	Confidence Interval	(2-Sided) 97.5%; 33.3 to 2382.2
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

11. Secondary Outcome

Title	Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- On-Treatment Analysis
Description	Calculated LDL-C goal was defined as calculated LDL-C <100 mg/dL (2.59 mmol/L) for heFH participants or non-FH participants who had a history of documented CHD, or <120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time Frame	Up to Week 12

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Measure Type: Number; Unit of Measure: percentage of participants
	85.2	96.2	10.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Regression, Logistic
	Comments	Multiple imputation approach followed by logistic regression model.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	102.8
	Confidence Interval	(2-Sided) 97.5%; 19.0 to 556.8
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Regression, Logistic
	Comments	Multiple imputation approach followed by logistic regression model.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	500.8
	Confidence Interval	(2-Sided) 97.5%; 47.9 to 5230.9
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

12. 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 for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Mean (Standard Error); Unit of Measure: percent change
	-31.7 (3.3)	-49.6 (3.3)	1.3 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Regression, Robust
	Comments	Multiple imputation approach followed by robust regression model.
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-32.9
	Confidence Interval	(2-Sided) 97.5%; -43.4 to -22.5
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Regression, Robust
	Comments	Multiple imputation approach followed by robust regression model.
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-50.9
	Confidence Interval	(2-Sided) 97.5%; -61.5 to -40.3
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

13. Secondary Outcome

Title	Percent Change From Baseline in High Density Lipoprotein Cholesterol (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 12 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 12

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	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	7.7 (1.8)	9.9 (1.8)	2.0 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0241
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	5.7
	Confidence Interval	(2-Sided) 97.5%; 0.0 to 11.3
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0022
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	7.8
	Confidence Interval	(2-Sided) 97.5%; 2.1 to 13.5
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

14. Secondary Outcome

Title	Percent Change From Baseline in Fasting Triglycerides (TGs) 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 12 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Mean (Standard Error); Unit of Measure: percent change
	-0.6 (3.7)	-18.0 (3.8)	-6.4 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q4W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2645
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Regression, Robust
	Comments	Multiple imputation approach followed by robust regression model.
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	5.9
	Confidence Interval	(2-Sided) 97.5%; -5.9 to 17.7
	Estimation Comments	Alirocumab 150 mg Q4W vs. Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Alirocumab 150 mg Q2W, Placebo Q2W
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0299
	Comments	Threshold for significance at 0.025 level for Bonferroni adjustment.
	Method	Regression, Robust
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Adjusted Mean Difference
	Estimated Value	-11.6
	Confidence Interval	(2-Sided) 97.5%; -23.5 to 0.4
	Estimation Comments	Alirocumab 150 mg Q2W vs. Placebo

15. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein A-1 (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 12 regardless of status on- or off-treatment.
Time Frame	From Baseline to Week 12

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	Alirocumab 150 mg Q4W	Alirocumab 150 mg Q2W	Placebo Q2W
Arm/Group Description:	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed	54	53	56
Least Squares Mean (Standard Error); Unit of Measure: percent change
	6.8 (1.6)	9.1 (1.7)	2.9 (1.6)

16. Other Pre-specified Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis
Description	[Not Specified]
Time Frame	Baseline, Weeks 20, 24, 36, 48 and 64

Outcome Measure Data

Analysis Population Description

Open-label treatment (OLT) population included all randomized participants who received at least one dose or part of dose of open-label investigational medicinal product. Here, "number analyzed" signifies participants with available data at each specified time-point.

Arm/Group Title		Alirocumab 150mgQ4W/Up Q2W(After Alirocumab 150mgQ4W in DBTP)	Alirocumab 150mgQ4W/Up Q2W(After Alirocumab 150mgQ2W in DBTP)	Alirocumab 150mg Q4W/Up Q2W (After Placebo Q2W in DBTP)
Arm/Group Description:		Participants who received alirocumab 150 mg Q4W during DBTP and completed DBTP, entered in OLTP and received alirocumab 150 mg Q4W from Week 12 up to Week 64. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.	Participants who received alirocumab 150 mg Q2W during DBTP and completed DBTP, entered in OLTP and received alirocumab 150 mg Q4W from Week 12 up to Week 64. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.	Participants who received Placebo Q2W during DBTP and completed DBTP, entered in OLTP and received alirocumab 150 mg Q4W from Week 12 up to Week 64. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
Overall Number of Participants Analyzed		54	50	54
Mean (Standard Deviation); Unit of Measure: Percent change
Week 20	Number Analyzed	53 participants	50 participants	53 participants
		-42.1 (20.1)	-47.8 (24.2)	-45.5 (20.5)
Week 24	Number Analyzed	53 participants	49 participants	51 participants
		-39.7 (20.4)	-46.0 (20.0)	-47.8 (21.7)
Week 36	Number Analyzed	52 participants	49 participants	51 participants
		-49.2 (19.4)	-51.5 (19.6)	-56.2 (18.8)
Week 48	Number Analyzed	52 participants	48 participants	48 participants
		-48.6 (21.6)	-53.9 (17.6)	-57.8 (17.4)
Week 64	Number Analyzed	51 participants	48 participants	47 participants
		-44.3 (22.8)	-55.2 (17.5)	-58.1 (19.6)

Adverse Events

Time Frame	All Adverse Events (AEs) were collected from signature of the informed consent form up to the end of study (up to Week 64) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported AEs and deaths are TEAEs that is AEs that developed/ worsened and death that occurred during 'treatment-emergent period' (time from first dose of study drug up to last dose of study drug +70 days). Analysis performed on safety population which included randomized participants who actually received at least 1 dose or partial dose of double-blind IMP injection for double-blind treatment period and at least 1 dose or partial dose of open-label IMP injection for open-label treatment period.
Arm/Group Title	Double-blind Treatment Period: Placebo Q2W	Double-blind Treatment Period: Alirocumab 150 mg Q4W	Double-blind Treatment Period: Alirocumab 150 mg Q2W	Open-label Treatment Period: Alirocumab 150 mg Q4W/Up Q2W
Arm/Group Description	Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks.	Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily) stable non-statin LMT or diet therapy alone for 12 weeks.	Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks.	All participants received alirocumab 150 mg Q4W from the start of the open-label treatment period. Alirocumab dose up-titrated from 150 mg Q4W to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥ 100 mg/dL (2.59 mmol/L) or ≥ 120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
All-Cause Mortality
	Double-blind Treatment Period: Placebo Q2W	Double-blind Treatment Period: Alirocumab 150 mg Q4W	Double-blind Treatment Period: Alirocumab 150 mg Q2W	Open-label Treatment Period: Alirocumab 150 mg Q4W/Up Q2W
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/56 (0.00%)	0/54 (0.00%)	1/53 (1.89%)	0/158 (0.00%)
Serious Adverse Events
	Double-blind Treatment Period: Placebo Q2W	Double-blind Treatment Period: Alirocumab 150 mg Q4W	Double-blind Treatment Period: Alirocumab 150 mg Q2W	Open-label Treatment Period: Alirocumab 150 mg Q4W/Up Q2W
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/56 (1.79%)	1/54 (1.85%)	2/53 (3.77%)	12/158 (7.59%)
Blood and lymphatic system disorders
Anaemia † 1	0/56 (0.00%)	0/54 (0.00%)	1/53 (1.89%)	0/158 (0.00%)
Cardiac disorders
Acute myocardial infarction † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Angina unstable † 1	1/56 (1.79%)	0/54 (0.00%)	0/53 (0.00%)	0/158 (0.00%)
Coronary artery stenosis † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	2/158 (1.27%)
Injury, poisoning and procedural complications
Multiple fractures † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Subdural haematoma † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Metabolism and nutrition disorders
Diabetes mellitus inadequate control † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Musculoskeletal and connective tissue disorders
Osteoarthritis † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Metastases to stomach † 1	0/56 (0.00%)	0/54 (0.00%)	1/53 (1.89%)	0/158 (0.00%)
Non-small cell lung cancer † 1	0/56 (0.00%)	0/54 (0.00%)	1/53 (1.89%)	0/158 (0.00%)
Pituitary tumour benign † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Nervous system disorders
Dizziness postural † 1	0/56 (0.00%)	0/54 (0.00%)	1/53 (1.89%)	0/158 (0.00%)
Facial spasm † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Loss of consciousness † 1	0/56 (0.00%)	0/54 (0.00%)	1/53 (1.89%)	0/158 (0.00%)
Psychiatric disorders
Schizophrenia † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis † 1	0/56 (0.00%)	0/54 (0.00%)	0/53 (0.00%)	1/158 (0.63%)
Interstitial lung disease † 1	0/56 (0.00%)	1/54 (1.85%)	0/53 (0.00%)	0/158 (0.00%)
1 Term from vocabulary, MedDra 20.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Double-blind Treatment Period: Placebo Q2W	Double-blind Treatment Period: Alirocumab 150 mg Q4W	Double-blind Treatment Period: Alirocumab 150 mg Q2W	Open-label Treatment Period: Alirocumab 150 mg Q4W/Up Q2W
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	14/56 (25.00%)	11/54 (20.37%)	13/53 (24.53%)	72/158 (45.57%)
General disorders
Non-cardiac chest pain † 1	1/56 (1.79%)	0/54 (0.00%)	4/53 (7.55%)	3/158 (1.90%)
Infections and infestations
Pharyngitis † 1	0/56 (0.00%)	3/54 (5.56%)	0/53 (0.00%)	5/158 (3.16%)
Viral upper respiratory tract infection † 1	9/56 (16.07%)	8/54 (14.81%)	8/53 (15.09%)	54/158 (34.18%)
Injury, poisoning and procedural complications
Fall † 1	3/56 (5.36%)	0/54 (0.00%)	1/53 (1.89%)	11/158 (6.96%)
Musculoskeletal and connective tissue disorders
Back pain † 1	0/56 (0.00%)	0/54 (0.00%)	1/53 (1.89%)	8/158 (5.06%)
Nervous system disorders
Dizziness † 1	3/56 (5.36%)	0/54 (0.00%)	0/53 (0.00%)	2/158 (1.27%)
1 Term from vocabulary, MedDra 20.0; † 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
• Phone: 800-633-1610 ext 1#
• EMail: Contact-US@sanofi.com

Publications:

Teramoto T, Kondo A, Kiyosue A, Harada-Shiba M, Ishigaki Y, Tobita K, Kawabata Y, Ozaki A, Baccara-Dinet MT, Sata M. Efficacy and safety of alirocumab in patients with hypercholesterolemia not adequately controlled with non-statin lipid-lowering therapy or the lowest strength of statin: ODYSSEY NIPPON study design and rationale. Lipids Health Dis. 2017 Jun 17;16(1):121. doi: 10.1186/s12944-017-0513-7.

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

Teramoto T, Kiyosue A, Ishigaki Y, Harada-Shiba M, Kawabata Y, Ozaki A, Baccara-Dinet MT, Sata M. Efficacy and safety of alirocumab 150mg every 4 weeks in hypercholesterolemic patients on non-statin lipid-lowering therapy or lowest strength dose of statin: ODYSSEY NIPPON. J Cardiol. 2019 Mar;73(3):218-227. doi: 10.1016/j.jjcc.2018.10.004. Epub 2018 Nov 30.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT02584504
• Other Study ID Numbers: EFC14305; U1111-1170-7697 ( Other Identifier: UTN )
• First Submitted: October 21, 2015
• First Posted: October 22, 2015
• Results First Submitted: April 3, 2018
• Results First Posted: May 7, 2018
• Last Update Posted: January 23, 2019