Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) When Co-administered With High Dose of Atorvastatin in Patients With Primary Hypercholesterolemia

• 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: Atorvastatin; Drug: Placebo (for atorvastatin)
Enrollment	92

Participant Flow

Recruitment Details	The study was conducted at 20 centers in the United States of America. Overall, 214 participants were screened between January 2011 and April 2011. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Details	Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1:1 ratio after confirmation of selection criteria. 92 participants were randomized.

Arm/Group Title	Placebo + Atorvastatin 80 mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
Arm/Group Description	Placebo (for alirocumab) subcutaneous (SC) injection every two weeks (Q2W) in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Period Title: Overall Study
Started	31 [1]	31 [1]	30 [1]
Treated	31	31	30
Completed	24	28	28
Not Completed	7	3	2
Reason Not Completed
Adverse Event	4	1	1
Poor compliance to protocol	0	1	0
Participant Moved	1	0	0
Consent withdrawn by subject	1	1	1
Exclusion criteria finally met	1	0	0
[1] Randomized

Baseline Characteristics

Arm/Group Title		Placebo + Atorvastatin 80 mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg	Total
Arm/Group Description		Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		31	31	30	92
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	31 participants	31 participants	30 participants	92 participants
		55.3 (10.3)	57.9 (10.0)	57.6 (9.3)	56.9 (9.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	31 participants	31 participants	30 participants	92 participants
	Female	18 58.1%	17 54.8%	20 66.7%	55 59.8%
	Male	13 41.9%	14 45.2%	10 33.3%	37 40.2%
Low-Density Lipoprotein Cholesterol (LDL-C) in mmol/L; Mean (Standard Deviation); Unit of measure: mmol/L
	Number Analyzed	31 participants	31 participants	30 participants	92 participants
		3.138 (0.469)	3.101 (0.402)	3.288 (0.564)	3.174 (0.484)
LDL-C in mg/dL; Mean (Standard Deviation); Unit of measure: mg/dL
	Number Analyzed	31 participants	31 participants	30 participants	92 participants
		121.2 (18.1)	119.7 (15.5)	126.9 (21.8)	122.6 (18.7)

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Calculated LDL-C at Week 8 - On-treatment Analysis
Description	Calculated LDL-C values were obtained using the Friedewald formula. Baseline adjusted least squares (LS) means and standard errors were estimated using an analysis of covariance (ANCOVA) model including available post-baseline data on treatment from first investigational product (IP) injection up to 21 days after last IP injection (on-treatment analysis). Missing Week 8 data were imputed by last observation carried forward [LOCF] method.
Time Frame	From Baseline to Week 8 (LOCF)

Outcome Measure Data

Analysis Population Description

Modified Intent-To-Treat (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 + Atorvastatin 80 mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed	29	29	30
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-17.3 (3.5)	-66.2 (3.5)	-73.2 (3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo + Atorvastatin 80 mg, Alirocumab + Atorvastatin 80 mg
	Comments	Throughout the ANCOVA model, the Alirocumab + atorvastatin 80 mg group was compared to the placebo + atorvastatin 80 mg group using appropriate contrast and the 95% confidence interval (CI) of the difference was provided.
	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	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-55.82
	Confidence Interval	(2-Sided) 95%; -65.62 to -46.03
	Estimation Comments	Alirocumab vs. placebo

2. Secondary Outcome

Title	Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis
Description	Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time Frame	From baseline to Week 8 (LOCF)

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo + Atorvastatin 80 mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed	29	29	30
Least Squares Mean (Standard Error); Unit of Measure: mmol/L
	-0.56 (0.11)	-2.09 (0.11)	-2.31 (0.11)

3. Secondary Outcome

Title	Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis
Description	Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time Frame	From baseline to Week 8 (LOCF)

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo + Atorvastatin 80 mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed	29	29	30
Least Squares Mean (Standard Error); Unit of Measure: mg/dL
	-21.5 (4.2)	-80.7 (4.2)	-89.3 (4.1)

4. Secondary Outcome

Title	Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis
Description	[Not Specified]
Time Frame	Week 8 (LOCF)

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo + Atorvastatin 80 mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed	29	29	30
Measure Type: Number; Unit of Measure: percentage of participants
LDL-C < 100 mg/dL (2.59 mmol/L)	51.7	100.0	100.0
LDL-C < 70 mg/dL (1.81 mmol/L)	17.2	96.6	90.0

5. Secondary Outcome

Title	Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis
Description	Since the assumptions of normal distribution and equality of variances were not verified for the lipid parameters, percent changes were expressed as median (interquartile range).
Time Frame	From baseline to Week 8 (LOCF)

Outcome Measure Data

Analysis Population Description

Participants of the mITT population with one baseline and at least one post-baseline on treatment value for lipid parameters analyzed. Here, n signifies number of participants analysed for each lipid parameter.

Arm/Group Title	Placebo + Atorvastatin 80 mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed	29	29	30
Median (Inter-Quartile Range); Unit of Measure: percent change
Total Cholesterol (n=29, 29, 30)	-16.6; (-25.1 to -3.2)	-40.5; (-44.8 to -36.0)	-47.2; (-51.5 to -37.8)
Fasting Triglycerides (n=29, 29, 30)	-11.9; (-30.4 to 14.3)	-4.0; (-30.5 to 17.4)	-24.7; (-40.3 to -4.4)
Non-HDL-C (n= 29, 29, 30)	-22.3; (-31.4 to -3.7)	-58.3; (-63.9 to -50.2)	-63.9; (-73.9 to -56.1)
Apo-B (n = 29, 28, 29)	-12.0; (-23.6 to -3.5)	-54.4; (-60.2 to -48.3)	-58.0; (-67.1 to -46.1)
Lipoprotein(a) (n= 29, 28, 29)	-2.7; (-19.5 to 16.7)	-34.7; (-50.0 to -24.7)	-31.0; (-50.0 to -15.4)

6. Secondary Outcome

Title	Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis
Description	Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time Frame	From Baseline to Week 8 (LOCF)

Outcome Measure Data

Analysis Population Description

Participants of the mITT population with one baseline and at least one post-baseline on treatment HDL-C value.

Arm/Group Title	Placebo + Atorvastatin 80 mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed	29	29	30
Least Squares Mean (Standard Error); Unit of Measure: percent change
	-3.6 (2.3)	2.6 (2.3)	5.8 (2.3)

7. Secondary Outcome

Title	Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis
Description	Adjusted LS means and standard errors were estimated using the same ANCOVA as for primary endpoint.
Time Frame	From Baseline to Week 8 (LOCF)

Outcome Measure Data

Analysis Population Description

Participants of the mITT population with one baseline and at least one post-baseline on treatment value for lipid parameter analyzed

Arm/Group Title	Placebo + Atorvastatin 80 mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
Arm/Group Description:	Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed	29	28	29
Median (Inter-Quartile Range); Unit of Measure: ratio
	-0.03; (-0.12 to 0.08)	-0.34; (-0.44 to -0.27)	-0.36; (-0.40 to -0.29)

Adverse Events

Time Frame	All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 16) regardless of seriousness or relationship to investigational medicianal product (IMP).
Adverse Event Reporting Description	Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘treatment emergent period’ (the time from the first dose to the last dose of IMP + 70 days). Safety population: participants received at least one dose or partial dose of IMP.
Arm/Group Title	Placebo + Atorvastatin 80mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
Arm/Group Description	Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
All-Cause Mortality
	Placebo + Atorvastatin 80mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Placebo + Atorvastatin 80mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/31 (0.00%)	0/31 (0.00%)	1/30 (3.33%)
Metabolism and nutrition disorders
Dehydration † 1	0/31 (0.00%)	0/31 (0.00%)	1/30 (3.33%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 14.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo + Atorvastatin 80mg	Alirocumab + Atorvastatin 10 mg	Alirocumab + Atorvastatin 80 mg
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	13/31 (41.94%)	4/31 (12.90%)	10/30 (33.33%)
Gastrointestinal disorders
Diarrhoea † 1	3/31 (9.68%)	1/31 (3.23%)	3/30 (10.00%)
General disorders
Injection site pruritus † 1	2/31 (6.45%)	0/31 (0.00%)	1/30 (3.33%)
Infections and infestations
Upper respiratory tract infection † 1	2/31 (6.45%)	2/31 (6.45%)	1/30 (3.33%)
Injury, poisoning and procedural complications
Accidental overdose † 1	0/31 (0.00%)	2/31 (6.45%)	2/30 (6.67%)
Musculoskeletal and connective tissue disorders
Pain in extremity † 1	5/31 (16.13%)	0/31 (0.00%)	1/30 (3.33%)
Nervous system disorders
Dizziness † 1	0/31 (0.00%)	0/31 (0.00%)	3/30 (10.00%)
Headache † 1	2/31 (6.45%)	0/31 (0.00%)	3/30 (10.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 14.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

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

Results Point of Contact

Name/Title: Trial Transparency Team

Organization: Sanofi

EMail: Contact ­-US@sanofi.com

Publications of Results:

Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012 Nov 15;367(20):1891-900. doi: 10.1056/NEJMoa1201832. Epub 2012 Oct 31.

Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol. 2014 Sep 1;114(5):711-5. doi: 10.1016/j.amjcard.2014.05.060. Epub 2014 Jun 18.

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.

Toth PP, Hamon SC, Jones SR, Martin SS, Joshi PH, Kulkarni KR, Banerjee P, Hanotin C, Roth EM, McKenney JM. Effect of alirocumab on specific lipoprotein non-high-density lipoprotein cholesterol and subfractions as measured by the vertical auto profile method: analysis of 3 randomized trials versus placebo. Lipids Health Dis. 2016 Feb 13;15:28. doi: 10.1186/s12944-016-0197-4.

Responsible Party:	Sanofi
ClinicalTrials.gov Identifier:	NCT01288469 History of Changes
Other Study ID Numbers:	DFI11566; U1111-1117-9994 ( Other Identifier: UTN )
First Submitted:	February 1, 2011
First Posted:	February 2, 2011
Results First Submitted:	August 21, 2015
Results First Posted:	September 24, 2015
Last Update Posted:	September 24, 2015