Trial Outcomes & Findings for Study of Alirocumab (REGN727/SAR236553) in Patients With heFH (Heterozygous Familial Hypercholesterolemia) Who Are Not Adequately Controlled With Their LMT (Lipid-Modifying Therapy) (NCT NCT01709500)

Results Overview

Calculated LDL-C values were obtained using the Friedewald formula. 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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

249 participants

Primary outcome timeframe

From Baseline to Week 52

Results posted on

2015-10-28

Participant Flow

The study was conducted at 26 sites in 4 countries. Overall, 322 participants were screened between 28 Nov 2012 and 26 Apr 2013, 73 of whom were screen failures.

Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, and intensity of statin treatment. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 2:1 (alirocumab: placebo) ratio after confirmation of selection criteria.

Participant milestones

Participant milestones
Measure	Alirocumab 75 mg/up to 150 mg Alirocumab 75 mg SC injection every two weeks (Q2W) added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo Placebo matched to alirocumab SC injection for 78-week treatment duration.
Overall Study STARTED	167	82
Overall Study Treated	167	81
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	167	82

Reasons for withdrawal

Reasons for withdrawal
Measure	Alirocumab 75 mg/up to 150 mg Alirocumab 75 mg SC injection every two weeks (Q2W) added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo Placebo matched to alirocumab SC injection for 78-week treatment duration.
Overall Study Randomized but not treated	0	1
Overall Study Adverse Event	5	1
Overall Study Poor compliance to protocol	2	1
Overall Study Other	3	1
Overall Study Related to IMP administration	1	0
Overall Study Treatment ongoing	156	78

Baseline Characteristics

Study of Alirocumab (REGN727/SAR236553) in Patients With heFH (Heterozygous Familial Hypercholesterolemia) Who Are Not Adequately Controlled With Their LMT (Lipid-Modifying Therapy)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Alirocumab 75 mg/up to 150 mg n=167 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=82 Participants Placebo matched to alirocumab SC injection for 78--week treatment duration.	Total n=249 Participants Total of all reporting groups
Age, Continuous	53.2 years STANDARD_DEVIATION 12.93 • n=5 Participants	53.2 years STANDARD_DEVIATION 12.55 • n=7 Participants	53.2 years STANDARD_DEVIATION 12.8 • n=5 Participants
Sex: Female, Male Female	81 Participants n=5 Participants	37 Participants n=7 Participants	118 Participants n=5 Participants
Sex: Female, Male Male	86 Participants n=5 Participants	45 Participants n=7 Participants	131 Participants n=5 Participants
Calculated LDL-C in mmol/L	3.485 mmol/L STANDARD_DEVIATION 1.065 • n=5 Participants	3.471 mmol/L STANDARD_DEVIATION 1.071 • n=7 Participants	3.480 mmol/L STANDARD_DEVIATION 1.065 • n=5 Participants
Calculated LDL-C in mg/dL	134.6 mg/dL STANDARD_DEVIATION 41.1 • n=5 Participants	134.0 mg/dL STANDARD_DEVIATION 41.4 • n=7 Participants	134.4 mg/dL STANDARD_DEVIATION 41.1 • n=5 Participants

PRIMARY outcome

Timeframe: From Baseline to Week 52

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

Calculated LDL-C values were obtained using the Friedewald formula. 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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--to--Treat (ITT) Analysis	-48.7 percent change Standard Error 1.9	2.8 percent change Standard Error 2.8

SECONDARY outcome

Timeframe: From Baseline to Week 52

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

Calculated LDL-C values were obtained using the Friedewald formula. Adjusted LS means and standard errors at Week 24 were obtained 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).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis	-49.4 percent change Standard Error 1.9	2.7 percent change Standard Error 2.7

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: ITT population.

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 (ITT analysis).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis	-43.8 percent change Standard Error 1.8	4.6 percent change Standard Error 2.6

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: mITT population.

Calculated LDL-C values were obtained using the Friedewald formula. 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 52 (i.e. up to 21 days after last injection) (on-treatment analysis).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Calculated LDL-C at Week 12 - On- Treatment Analysis	-44.2 percent change Standard Error 1.8	4.6 percent change Standard Error 2.6

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=163 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis	-42.8 percent change Standard Error 1.4	-3.5 percent change Standard Error 2

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: mITT population

Adjusted LS means and standard errors at Week 24 were obtained 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).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=162 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=80 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis	-43.2 percent change Standard Error 1.4	-3.5 percent change Standard Error 2

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Non-High -Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis	-42.6 percent change Standard Error 1.8	3.1 percent change Standard Error 2.5

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: mITT population

Adjusted LS means and standard errors at Week 24 were obtained 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).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis	-43.2 percent change Standard Error 1.7	3.1 percent change Standard Error 2.5

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline total-C value on- or off-treatment.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis	-30.6 percent change Standard Error 1.4	2.1 percent change Standard Error 1.9

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Apo B ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=163 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Apo B at Week 12 - ITT Analysis	-35.4 percent change Standard Error 1.4	-0.9 percent change Standard Error 2

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Non-HDL-C ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis	-37.9 percent change Standard Error 1.7	4.1 percent change Standard Error 2.4

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Total--C ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Total-C at Week 12 - ITT Analysis	-26.6 percent change Standard Error 1.3	3.4 percent change Standard Error 1.9

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: ITT population.

Calculated LDL-C values were obtained using the Friedewald formula. 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 (ITT analysis).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis	-50.3 percent change Standard Error 2.3	8.4 percent change Standard Error 3.3

SECONDARY outcome

Timeframe: Up to Week 52

Population: ITT population.

Adjusted percentages at Week 24 were obtained from a multiple imputation approach model 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 (ITT analysis).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis	81.4 percentage of participants	11.3 percentage of participants

SECONDARY outcome

Timeframe: Up to week 52

Population: mITT population.

Adjusted percentages at Week 24 were obtained from a 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 (on-treatment analysis).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percentage of Very High CV Risk Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL--C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis	82.1 percentage of participants	11.6 percentage of participants

SECONDARY outcome

Timeframe: Up to Week 52

Population: ITT population.

Adjusted percentages at Week 24 were obtained from a multiple imputation approach model 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 (ITT analysis).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis	68.2 percentage of participants	1.2 percentage of participants

SECONDARY outcome

Timeframe: Up to Week 52

Population: mITT population.

Adjusted percentages at Week 52 were obtained from a 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 (on-treatment analysis).

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percentage of Participants Reaching Calculated LDL--C <70 mg/dL (1.81 mmol/L) at Week 52 - On-Treatment Analysis	68.8 percentage of participants	1.3 percentage of participants

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants analyzed: participants of the ITT population.

Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis	-30.3 percent change Standard Error 1.8	-10 percent change Standard Error 2.5

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis	6.0 percent change Standard Error 1.2	-0.8 percent change Standard Error 1.6

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants analyzed: participants of the ITT population.

Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis	-10.4 percent change Standard Error 2	0.5 percent change Standard Error 2.8

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=163 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis	2.8 percent change Standard Error 0.9	-1.6 percent change Standard Error 1.3

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Lipoprotein (a) ITT population.

Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis	-24.7 percent change Standard Deviation 1.7	-5.6 percent change Standard Deviation 2.5

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: HDL-C ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis	6.0 percent change Standard Error 1.0	-0.8 percent change Standard Error 1.6

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Fasting triglycerides ITT population.

Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=166 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis	-8.1 percent change Standard Error 2.2	0.6 percent change Standard Error 3.1

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Apo A-1 ITT population.

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.

Outcome measures

Outcome measures
Measure	Alirocumab 75 mg/up to 150 mg n=163 Participants Alirocumab 75 mg SC injection Q2W added to stable dose of statin with or without LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 Participants Placebo matched to alirocumab SC injection for 78-week treatment duration.
Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis	0.4 percent change Standard Error 0.9	-1.9 percent change Standard Error 1.3

Adverse Events

Alirocumab 75 mg/up to 150 mg

Serious events: 10 serious events

Other events: 65 other events

Deaths: 0 deaths

Placebo

Serious events: 7 serious events

Other events: 35 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Alirocumab 75 mg/up to 150 mg n=167 participants at risk Alirocumab 75 mg SC injection every two weeks (Q2W) added to stable dose of statin with or without LMT for 76 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 participants at risk Placebo matched to alirocumab SC injection for 78-week treatment duration.
Gastrointestinal disorders Diarrhoea	5.4% 9/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
General disorders Injection site reaction	10.8% 18/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	7.4% 6/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Infections and infestations Influenza	14.4% 24/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	7.4% 6/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Infections and infestations Nasopharyngitis	10.8% 18/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	19.8% 16/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Musculoskeletal and connective tissue disorders Myalgia	6.0% 10/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	6.2% 5/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Nervous system disorders Headache	8.4% 14/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	8.6% 7/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.

Additional Information

Clinical Trial Management

Regeneron Pharmaceuticals, Inc

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Not less than 45 days prior to submission for publication or presentation, the Institution shall, or cause the Principal Investigator to, provide the Sponsor with a copy of the Manuscript. The Institution shall consider in good faith any comments from the Sponsor regarding the content, and shall delete Confidential Information upon written request of the Sponsor. At the Sponsor's request, the Institution shall delay publication for an additional 60 days to allow patent applications to be filed.
Publication restrictions are in place

Restriction type: OTHER

Measure	Alirocumab 75 mg/up to 150 mg n=167 participants at risk Alirocumab 75 mg SC injection every two weeks (Q2W) added to stable dose of statin with or without LMT for 76 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL at Week 8.	Placebo n=81 participants at risk Placebo matched to alirocumab SC injection for 78-week treatment duration.
Cardiac disorders Acute coronary syndrome	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Cardiac disorders Angina pectoris	0.60% 1/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	0.00% 0/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Cardiac disorders Angina unstable	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Cardiac disorders Cardiogenic shock	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Cardiac disorders Coronary artery stenosis	0.60% 1/167 • Number of events 1 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	0.00% 0/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Cardiac disorders Myocardial infarction	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
General disorders Device dislocation	0.60% 1/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	0.00% 0/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
General disorders Non-Cardiac chest pain	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Infections and infestations Appendicitis	0.60% 1/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	0.00% 0/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Infections and infestations Endocarditis	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Infections and infestations Hepatitis a	0.60% 1/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	0.00% 0/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Infections and infestations Lower respiratory tract infection	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Infections and infestations Viral infection	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.60% 1/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	0.00% 0/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.60% 1/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.60% 1/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	0.00% 0/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal adenocarcinoma	0.60% 1/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	0.00% 0/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Nervous system disorders Syncope	0.00% 0/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	1.2% 1/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.60% 1/167 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.	0.00% 0/81 • From Baseline up to Week 78 Treatment emergent adverse events that developed during treatment emergent adverse events period (the time from the first dose of study drug to the last dose of study drug + 70 days (10 weeks) are reported.