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Study of Alirocumab (REGN727/SAR236553) added-on to Rosuvastatin Versus Other Lipid Modifying Treatments (LMT) (ODYSSEY OPTIONS II)

Sponsor
Regeneron Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01730053
Collaborator
Sanofi (Industry)
305
Enrollment
93
Locations
6
Arms
18
Actual Duration (Months)
3.3
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To evaluate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab (REGN727/SAR236553) as an add-on therapy to other LMT in patients with hypercholesterolemia at high cardiovascular (CV) risk.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
305 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double-Blind Study of the Efficacy and Safety of REGN727 Added-on to Rosuvastatin Versus Ezetimibe Added-on to Rosuvastatin Versus Rosuvastatin Dose Increase in Patients Who Are Not Controlled on Rosuvastatin
Actual Study Start Date :
Nov 30, 2012
Actual Primary Completion Date :
Apr 30, 2014
Actual Study Completion Date :
May 31, 2014

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Rosuvastatin 20 mg

Participants, who were receiving rosuvastatin 10 mg over-encapsulated tablet orally at baseline, received rosuvastatin 20 mg over-encapsulated tablet orally once daily (QD), placebo for alirocumab SC injection every two weeks (Q2W), and placebo for ezetimibe over-encapsulated tablet orally QD added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.

Drug: Rosuvastatin
Rosuvastatin over-encapsulated tablets orally.
Other Names:
  • Crestor

    • Drug: Placebo
    Placebo for alirocumab and ezetimibe.
    Active Comparator: Ezetimibe 10 mg + Rosuvastatin 10 mg

    Participants, who were receiving rosuvastatin 10 mg over-encapsulated tablet orally at baseline, received ezetimibe 10 mg over-encapsulated tablet orally QD, rosuvastatin 10 mg over-encapsulated tablet orally QD, and placebo for alirocumab SC injection Q2W added to stable LMT for 24 weeks.

    Drug: Rosuvastatin
    Rosuvastatin over-encapsulated tablets orally.
    Other Names:
  • Crestor

    • Drug: Ezetimibe
    Ezetimibe over-encapsulated tablets orally.
    Other Names:
  • Ezetrol

    • Drug: Placebo
    Placebo for alirocumab and ezetimibe.
    Experimental: Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg

    Participants, who were receiving rosuvastatin 10 mg over-encapsulated tablet orally at baseline, received alirocumab 75 mg SC injection Q2W, rosuvastatin 10 mg over-encapsulated tablet orally QD, and placebo for ezetimibe over-encapsulated tablet orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

    Drug: Alirocumab
    Alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.
    Other Names:
  • REGN727/SAR236553

    • Drug: Rosuvastatin
    Rosuvastatin over-encapsulated tablets orally.
    Other Names:
  • Crestor

    • Drug: Placebo
    Placebo for alirocumab and ezetimibe.
    Active Comparator: Rosuvastatin 40 mg

    Participants, who were receiving rosuvastatin 20 mg over-encapsulated tablet orally at baseline, received rosuvastatin 40 mg over-encapsulated tablet orally QD, placebo for alirocumab Q2W SC injection, and placebo for ezetimibe QD over-encapsulated tablet orally added to stable LMT for 24 weeks.

    Drug: Rosuvastatin
    Rosuvastatin over-encapsulated tablets orally.
    Other Names:
  • Crestor

    • Drug: Placebo
    Placebo for alirocumab and ezetimibe.
    Active Comparator: Ezetimibe 10 mg + Rosuvastatin 20 mg

    Participants, who were receiving rosuvastatin 20 mg over-encapsulated tablet orally at baseline, received ezetimibe 10 mg over-encapsulated tablet orally QD, rosuvastatin 20 mg over-encapsulated tablet orally QD, and placebo for alirocumab Q2W SC injection added to stable LMT for 24 weeks.

    Drug: Rosuvastatin
    Rosuvastatin over-encapsulated tablets orally.
    Other Names:
  • Crestor

    • Drug: Ezetimibe
    Ezetimibe over-encapsulated tablets orally.
    Other Names:
  • Ezetrol

    • Drug: Placebo
    Placebo for alirocumab and ezetimibe.
    Experimental: Alirocumab 75 mg/ up to 150 mg + Rosuvastatin 20 mg

    Participants, who were receiving rosuvastatin 20 mg over-encapsulated tablet orally at baseline, received alirocumab 75 mg Q2W SC injection, rosuvastatin 20 mg over-encapsulated tablet orally QD, and placebo for ezetimibe over-encapsulated tablet orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.

    Drug: Alirocumab
    Alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.
    Other Names:
  • REGN727/SAR236553

    • Drug: Rosuvastatin
    Rosuvastatin over-encapsulated tablets orally.
    Other Names:
  • Crestor

    • Drug: Placebo
    Placebo for alirocumab and ezetimibe.

    Outcome Measures

    Primary Outcome Measures

    1. Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis [From Baseline to Week 24]

      Calculated LDL-C values were obtained from 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 24 regardless of status on- or off-treatment were used in the model (ITT analysis).

    Secondary Outcome Measures

    1. Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis [From Baseline to Week 24]

      Calculated LDL-C values were obtained from 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 24 (ie. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis).

    2. Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis [From Baseline to Week 12]

      Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment (ITT analysis).

    3. Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis [From Baseline to Week 12]

      Calculated LDL-C values were obtained from 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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis).

    4. Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis [From Baseline to Week 24]

      Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    5. Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis [From Baseline to Week 24]

      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 24 (ie. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first).

    6. Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis [From Baseline to Week 24]

      Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    7. Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis [From Baseline to Week 24]

      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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first).

    8. Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis [From Baseline to Week 24]

      Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    9. Percent Change From Baseline in Apo B at Week 12 - ITT Analysis [From Baseline to Week 12]

      Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    10. Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis [From Baseline to Week 12]

      Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    11. Percent Change From Baseline in Total-C at Week 12 - ITT Analysis [From Baseline to Week 12]

      Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    12. 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 [Up to Week 24]

      Calculated LDL-C values were obtained from Friedewald formula. 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 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).

    13. 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 [Up to Week 24]

      Calculated LDL-C values were obtained from Friedewald formula. 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 24 i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first (on-treatment analysis).

    14. Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis [Up to Week 24]

      Calculated LDL-C values were obtained from Friedewald formula. 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 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).

    15. Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis [Up to Week 24]

      Calculated LDL-C values were obtained from Friedewald formula. 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 24 i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first (on-treatment analysis).

    16. Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis [From Baseline to Week 24]

      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 24 regardless of status on- or off-treatment.

    17. Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis [From Baseline to Week 24]

      Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    18. Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis [From Baseline to Week 24]

      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 24 regardless of status on- or off-treatment.

    19. Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis [From Baseline to Week 24]

      Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    20. Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis [From Baseline to Week 12]

      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 24 regardless of status on- or off-treatment.

    21. Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis [From Baseline to Week 12]

      Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    22. Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis [From Baseline to Week 12]

      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 24 regardless of status on- or off-treatment.

    23. Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis [From Baseline to Week 12]

      Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Patients with LDL-C greater than or equal to 70 mg/dL at the screening visit and who are not adequately controlled with a stable daily dose of rosuvastatin, with or without other LMT.

    OR

    1. Patients with screening LDL-C greater than or equal to 100 mg/dL who are not adequately controlled with a stable daily dose of rosuvastatin before the screening visit, with or without other LMT.
    Exclusion Criteria:

    1. LDL-C less than 70 mg/dL at the screening visit in patients with history of documented cardiovascular disease (CVD)

    2. LDL-C less than 100 mg/dL at the screening visit in patients without history of documented coronary heart disease (CHD) or non-CHD CVD, but with other risk factors

    3. Homozygous familial hypercholesterolemia (FH) (clinically or previous genotyping)

    4. Recent (within 3 months prior to the screening visit) myocardial infarction (MI), unstable angina leading to hospitalization, percutaneous coronary intervention (PCI), coronary bypass graft surgery (CABG), uncontrolled cardiac arrhythmia, stroke, transient ischemic attack, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease

    5. Newly diagnosed (within 3 months prior to randomization visit) or poorly controlled diabetes

    6. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins

    (The inclusion/ exclusion criteria provided above is not intended to contain all considerations relevant to a patient's potential participation in this clinical trial).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Chandler Arizona United States
    2 Tucson Arizona United States
    3 Anaheim California United States
    4 Beverly Hills California United States
    5 Fair Oaks California United States
    6 Newport Beach California United States
    7 Northridge California United States
    8 Sacramento California United States
    9 Walnut Creek California United States
    10 Milford Connecticut United States
    11 Atlantis Florida United States
    12 Bradenton Florida United States
    13 Clearwater Florida United States
    14 Fort Lauderdale Florida United States
    15 Jacksonville Florida United States
    16 Lakeland Florida United States
    17 (2 Locations) Miami Florida United States
    18 Oviedo Florida United States
    19 Pinellas Park Florida United States
    20 Port Orange Florida United States
    21 Sarasota Florida United States
    22 Tampa Florida United States
    23 West Palm Beach Florida United States
    24 Winter Park Florida United States
    25 Boise Idaho United States
    26 Morton Illinois United States
    27 Evansville Indiana United States
    28 Indianapolis Indiana United States
    29 Newton Kansas United States
    30 Overland Park Kansas United States
    31 Wichita Kansas United States
    32 Lexington Kentucky United States
    33 Louisville Kentucky United States
    34 Auburn Maine United States
    35 Bethesda Maryland United States
    36 Edina Minnesota United States
    37 Rochester Minnesota United States
    38 Olive Branch Mississippi United States
    39 Port Gibson Mississippi United States
    40 Saint Louis Missouri United States
    41 Butte Montana United States
    42 Williamsville New York United States
    43 Cincinnati Ohio United States
    44 Marion Ohio United States
    45 Portland Oregon United States
    46 Warwick Rhode Island United States
    47 Greer South Carolina United States
    48 Summerville South Carolina United States
    49 Kingsport Tennessee United States
    50 Dallas Texas United States
    51 Fort Worth Texas United States
    52 Houston Texas United States
    53 Bountiful Utah United States
    54 Salt Lake City Utah United States
    55 Herston Australia
    56 New Lambton Heights Australia
    57 Perth Australia
    58 Sherwood Australia
    59 Woolloongabba Australia
    60 Brampton Ontario Canada
    61 Burlington Ontario Canada
    62 Etobicoke Ontario Canada
    63 London Ontario Canada
    64 Newmarket Ontario Canada
    65 Thornhill Ontario Canada
    66 Toronto Ontario Canada
    67 Chicoutimi Quebec Canada
    68 Dijon France
    69 Lille France
    70 Bad Oeynhausen Germany
    71 Berlin Germany
    72 Koeln Germany
    73 Regensburg Germany
    74 Ulm Germany
    75 Chieti Italy
    76 Genova Italy
    77 Napoli Italy
    78 Palermo Italy
    79 (2 Locations) Roma Italy
    80 Baja California Mexico
    81 Distrito Federal Mexico
    82 (3 Locations) Guadalajara Mexico
    83 Monterrey Mexico
    84 Zapopan Jalisco Mexico
    85 (2 Locations) Barcelona Spain
    86 Madrid Spain
    87 Santiago Spain
    88 Sevilla Spain
    89 West Bromwich West Midlands United Kingdom
    90 Chester United Kingdom
    91 Peterborough United Kingdom
    92 Salford United Kingdom
    93 Stevenage United Kingdom

    Sponsors and Collaborators

    • Regeneron Pharmaceuticals
    • Sanofi

    Investigators

    • Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Regeneron Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01730053
    Other Study ID Numbers:
    • R727-CL-1118
    First Posted:
    Nov 21, 2012
    Last Update Posted:
    Apr 7, 2020
    Last Verified:
    Mar 1, 2020
    Additional relevant MeSH terms:
    Hypercholesterolemia
    Rosuvastatin Calcium
    Ezetimibe

    Study Results

    Participant Flow

    Recruitment Details The study was conducted at 79 sites in 8 countries. Overall, 672 participants were screened between 24 October 2012 and 27 September 2013, 367 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.
    Pre-assignment Detail Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, and intensity of statin treatment (rosuvastatin 10 or 20 mg). Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System (IVWRS) in a 1:1:1:1:1:1 ratio after confirmation of selection criteria.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Period Title: Overall Study
    STARTED 48 48 49 53 53 54
    Treated 48 48 49 53 53 54
    COMPLETED 43 34 38 45 44 41
    NOT COMPLETED 5 14 11 8 9 13

    Baseline Characteristics

    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75/up to 150 + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg Total
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants, who were receiving rosuvastatin 10 mg over-encapsulated tablet orally at baseline, received alirocumab 75 mg SC injection Q2W, rosuvastatin 10 mg over-encapsulated tablet orally QD, and placebo for ezetimibe over-encapsulated tablet orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Total of all reporting groups
    Overall Participants 48 48 49 53 53 54 305
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    61.5
    (11.15)
    60.4
    (10.38)
    62.2
    (11.11)
    60.6
    (10.11)
    63.1
    (10.2)
    57.9
    (8.86)
    60.9
    (10.4)
    Sex: Female, Male (Count of Participants)
    Female
    15
    31.3%
    22
    45.8%
    18
    36.7%
    15
    28.3%
    22
    41.5%
    26
    48.1%
    118
    38.7%
    Male
    33
    68.8%
    26
    54.2%
    31
    63.3%
    38
    71.7%
    31
    58.5%
    28
    51.9%
    187
    61.3%
    Low density lipoprotein cholesterol (LDL-C) in mg/dL (mg/dL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mg/dL]
    105.9
    (36.0)
    102.4
    (41.9)
    107.3
    (26.4)
    112.9
    (43.3)
    119.0
    (48.0)
    118.3
    (32.2)
    111.3
    (39.0)
    LDL-C in mmol/L (mmol/L) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [mmol/L]
    2.743
    (0.933)
    2.653
    (1.085)
    2.78
    (0.684)
    2.924
    (1.122)
    3.082
    (1.243)
    3.065
    (0.834)
    2.882
    (1.009)

    Outcome Measures

    1. Primary Outcome
    Title Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis
    Description Calculated LDL-C values were obtained from 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 24 regardless of status on- or off-treatment were used in the model (ITT analysis).
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    ITT population: all randomized participants with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Least Squares Mean (Standard Error) [percent change]
    -16.3
    (4.1)
    -14.4
    (4.4)
    -50.6
    (4.2)
    -15.9
    (7.1)
    -11.0
    (7.2)
    -36.3
    (7.1)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Alirocumab group was compared to the corresponding active control group using an appropriate contrast statement.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -34.2
    Confidence Interval (2-Sided) 98.75%
    -49.2 to -19.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments As described in statistical analysis 1 of the endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -36.1
    Confidence Interval (2-Sided) 98.75%
    -51.5 to -20.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 40 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Comments As described in statistical analysis 1 of the endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value =0.0453
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -20.3
    Confidence Interval (2-Sided) 98.75%
    -45.8 to 5.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Comments As described in statistical analysis 1 of the endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value =0.0136
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -25.3
    Confidence Interval (2-Sided) 98.75%
    -50.9 to 0.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
    Description Calculated LDL-C values were obtained from 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 24 (ie. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis).
    Time Frame From Baseline to Week 24

    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 Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 46 48 50 50 51
    Least Squares Mean (Standard Error) [percent change]
    -18.3
    (3.3)
    -20.3
    (3.6)
    -53.5
    (3.5)
    -17.0
    (6.9)
    -16.5
    (6.9)
    -41.5
    (6.9)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    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 1.25 % level.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -35.2
    Confidence Interval (2-Sided) 98.75%
    -47.4 to -23.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -33.2
    Confidence Interval (2-Sided) 98.75%
    -45.9 to -20.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 40 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value =0.0131
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -24.5
    Confidence Interval (2-Sided) 98.75%
    -49.2 to 0.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
    Description Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment (ITT analysis).
    Time Frame From Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Least Squares Mean (Standard Error) [percent change]
    -17.1
    (4.1)
    -17.4
    (4.2)
    -49.6
    (4.1)
    -22.1
    (5.3)
    -19.3
    (5.4)
    -32.3
    (5.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -35.2
    Confidence Interval (2-Sided) 98.75%
    -47.4 to -17.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -32.2
    Confidence Interval (2-Sided) 98.75%
    -47 to -17.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
    Description Calculated LDL-C values were obtained from 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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis).
    Time Frame From Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    mITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 46 48 50 50 51
    Least Squares Mean (Standard Error) [percent change]
    -17.2
    (3.6)
    -20.3
    (3.8)
    -52.6
    (3.6)
    -22.9
    (5.2)
    -21.8
    (5.2)
    -35.1
    (5.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -35.3
    Confidence Interval (2-Sided) 98.75%
    -48.2 to -22.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -32.3
    Confidence Interval (2-Sided) 98.75%
    -45.6 to -19.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 44 44 44 51 48 49
    Least Squares Mean (Standard Error) [percent change]
    -7.3
    (3.0)
    -9.7
    (3.1)
    -36.5
    (3.1)
    -9.8
    (4.1)
    -11.2
    (4.3)
    -28.3
    (4.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -29.2
    Confidence Interval (2-Sided) 98.75%
    -40.1 to -18.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -26.8
    Confidence Interval (2-Sided) 98.75%
    -37.9 to -15.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis
    Description Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (ie. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first).
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants analyzed: participants of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 44 42 43 50 47 48
    Least Squares Mean (Standard Error) [percent change]
    -8.8
    (2.6)
    -11.2
    (2.7)
    -39.5
    (2.6)
    -12.7
    (4.0)
    -12.6
    (4.1)
    -30.4
    (4.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -30.7
    Confidence Interval (2-Sided) 98.75%
    -40.1 to -21.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -28.3
    Confidence Interval (2-Sided) 98.75%
    -38.0 to -18.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Least Squares Mean (Standard Error) [percent change]
    -11.3
    (3.4)
    -13.4
    (3.7)
    -42.7
    (3.5)
    -11.2
    (5.1)
    -12.9
    (5.2)
    -31.4
    (5.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -31.4
    Confidence Interval (2-Sided) 98.75%
    -43.9 to -18.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -29.3
    Confidence Interval (2-Sided) 98.75%
    -42.1 to -16.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis
    Description Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first).
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants analyzed: participants of the mITT population with one baseline and at least one post-baseline Non-HDL-C value on-treatment.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 46 48 50 50 51
    Least Squares Mean (Standard Error) [percent change]
    -12.9
    (2.8)
    -17.5
    (3.1)
    -45.7
    (2.9)
    -14.9
    (4.2)
    -18.2
    (4.2)
    -35.6
    (4.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -32.8
    Confidence Interval (2-Sided) 98.75%
    -43.2 to -22.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -28.2
    Confidence Interval (2-Sided) 98.75%
    -39.1 to -17.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline Total-C value on- or off-treatment.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Least Squares Mean (Standard Error) [percent change]
    -8.3
    (2.4)
    -8.7
    (2.6)
    -28.9
    (2.5)
    -8.5
    (3.6)
    -12.4
    (3.6)
    -20.6
    (3.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -20.6
    Confidence Interval (2-Sided) 98.75%
    -29.4 to -11.8
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -20.3
    Confidence Interval (2-Sided) 98.75%
    -29.3 to -11.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Percent Change From Baseline in Apo B at Week 12 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    Apo B ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 44 44 44 51 48 49
    Least Squares Mean (Standard Error) [percent change]
    -8.1
    (3.2)
    -12.1
    (3.3)
    -36.1
    (3.2)
    -13.7
    (3.3)
    -14.3
    (3.3)
    -29.0
    (3.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -28.1
    Confidence Interval (2-Sided) 98.75%
    -39.7 to -16.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -24.0
    Confidence Interval (2-Sided) 98.75%
    -35.7 to -12.3
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    11. Secondary Outcome
    Title Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    Non-HDL-C ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Least Squares Mean (Standard Error) [percent change]
    -11.7
    (3.5)
    -16.3
    (3.6)
    -41.2
    (3.5)
    -18.0
    (3.6)
    -18.7
    (3.7)
    -29.8
    (3.6)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -29.5
    Confidence Interval (2-Sided) 98.75%
    -42.1 to -16.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -24.9
    Confidence Interval (2-Sided) 98.75%
    -37.7 to -12.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    Total-C ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/ up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants, who were receiving rosuvastatin 20 mg over-encapsulated tablet orally at baseline, received alirocumab 75 mg Q2W SC injection, rosuvastatin 20 mg over-encapsulated tablet orally QD, and placebo for ezetimibe over-encapsulated tablet orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Least Squares Mean (Standard Error) [percent change]
    -8.9
    (2.6)
    -11.8
    (2.7)
    -29.0
    (2.6)
    -13.8
    (2.8)
    -13.9
    (2.8)
    -19.4
    (2.7)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -20.1
    Confidence Interval (2-Sided) 98.75%
    -29.4 to -10.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -17.2
    Confidence Interval (2-Sided) 98.75%
    -26.7 to -7.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    13. Secondary Outcome
    Title 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
    Description Calculated LDL-C values were obtained from Friedewald formula. 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 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).
    Time Frame Up to Week 24

    Outcome Measure Data

    Analysis Population Description
    ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Number [percentage of participants]
    45.0
    93.8%
    57.2
    119.2%
    84.9
    173.3%
    40.1
    75.7%
    52.2
    98.5%
    66.7
    123.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 12.4
    Confidence Interval (2-Sided) 98.75%
    2.6 to 59.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value =0.0007
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 8.4
    Confidence Interval (2-Sided) 98.75%
    1.8 to 40.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    14. Secondary Outcome
    Title 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
    Description Calculated LDL-C values were obtained from Friedewald formula. 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 24 i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first (on-treatment analysis).
    Time Frame Up to Week 24

    Outcome Measure Data

    Analysis Population Description
    mITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 46 48 50 50 51
    Number [percentage of participants]
    47.0
    97.9%
    60.5
    126%
    86.4
    176.3%
    41.3
    77.9%
    54.8
    103.4%
    70.4
    130.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 15.6
    Confidence Interval (2-Sided) 98.75%
    2.58 to 88.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value =0.001
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 9.9
    Confidence Interval (2-Sided) 98.75%
    1.7 to 56.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    15. Secondary Outcome
    Title Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
    Description Calculated LDL-C values were obtained from Friedewald formula. 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 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).
    Time Frame Up to Week 24

    Outcome Measure Data

    Analysis Population Description
    ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Number [percentage of participants]
    31.3
    65.2%
    43.1
    89.8%
    77.8
    158.8%
    29.9
    56.4%
    43.6
    82.3%
    60.1
    111.3%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 18.6
    Confidence Interval (2-Sided) 98.75%
    3.6 to 96.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 11.6
    Confidence Interval (2-Sided) 98.75%
    2.5 to 53.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    16. Secondary Outcome
    Title Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
    Description Calculated LDL-C values were obtained from Friedewald formula. 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 24 i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first (on-treatment analysis).
    Time Frame Up to Week 24

    Outcome Measure Data

    Analysis Population Description
    mITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 46 48 50 50 51
    Number [percentage of participants]
    34.8
    72.5%
    46.7
    97.3%
    76.5
    156.1%
    30.6
    57.7%
    45.1
    85.1%
    66.1
    122.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a Logistic regression model.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 20.3
    Confidence Interval (2-Sided) 98.75%
    2.4 to 67.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value =0.0002
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Logistic
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 12.7
    Confidence Interval (2-Sided) 98.75%
    2.4 to 67.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    17. Secondary Outcome
    Title Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis
    Description Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants analyzed: participants of the ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/ up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants, who were receiving rosuvastatin 20 mg over-encapsulated tablet orally at baseline, received alirocumab 75 mg Q2W SC injection, rosuvastatin 20 mg over-encapsulated tablet orally QD, and placebo for ezetimibe over-encapsulated tablet orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Mean (Standard Error) [percent change]
    -4.0
    (4.3)
    -4.3
    (4.5)
    -27.9
    (4.1)
    -5.2
    (4.8)
    -5.8
    (4.6)
    -22.7
    (5.1)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a robust regression model.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Robust
    Comments
    Method of Estimation Estimation Parameter Adjusted Mean Difference
    Estimated Value -23.9
    Confidence Interval (2-Sided) 98.75%
    -38.6 to -9.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Ezetimibe 10 mg + Rosuvastatin 10 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Analysis description as per the statistical analysis 1 of this endpoint.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value =0.0001
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Robust
    Comments
    Method of Estimation Estimation Parameter Adjusted Mean Difference
    Estimated Value -23.6
    Confidence Interval (2-Sided) 98.75%
    -39.0 to -8.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    18. Secondary Outcome
    Title Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Least Squares Mean (Standard Error) [percent change]
    1.7
    (2.4)
    4.0
    (2.5)
    9.1
    (2.4)
    1.5
    (2.3)
    -1.8
    (2.3)
    7.2
    (2.3)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Rosuvastatin 20 mg, Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg
    Comments Testing according to the hierarchical testing procedure (previous endpoints were statistically significant for rosuvastatin 10 mg baseline stratification). Statistical analysis used a multiple imputation approach followed by a robust regression model.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value =0.0311
    Comments Threshold for significance ≤ 0.0125.
    Method Regression, Robust
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 7.4
    Confidence Interval (2-Sided) 98.75%
    -1.2 to 16.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    19. Secondary Outcome
    Title Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
    Description Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants analyzed: participants of the ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Mean (Standard Error) [percent change]
    -1.8
    (4.5)
    -8.3
    (4.8)
    -11.2
    (4.6)
    -9.9
    (4.1)
    -11.1
    (4.3)
    -8.7
    (4.5)
    20. Secondary Outcome
    Title Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants analyzed: participants of the ITT population with one baseline and at least one post-baseline Apo A-1 value on- or off-treatment.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 44 44 44 51 48 49
    Least Squares Mean (Standard Error) [percent change]
    5.4
    (1.9)
    5.0
    (1.9)
    6.7
    (1.9)
    2.9
    (1.9)
    -0.9
    (1.9)
    6.7
    (2.0)
    21. Secondary Outcome
    Title Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis
    Description Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    Lipoprotein (a) ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Mean (Standard Error) [percent change]
    -0.7
    (3.5)
    -3.9
    (3.6)
    -20.7
    (3.5)
    3.5
    (4.2)
    7.9
    (4.1)
    -16.0
    (4.2)
    22. Secondary Outcome
    Title Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    HDL-C ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Least Squares Mean (Standard Error) [percent change]
    0.7
    (2.1)
    0.2
    (2.2)
    5.9
    (2.1)
    0.6
    (2.5)
    3.1
    (2.5)
    8.0
    (2.5)
    23. Secondary Outcome
    Title Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
    Description Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    Fasting triglycerides ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 48 47 48 52 50 53
    Mean (Standard Error) [percent change]
    8.1
    (4.1)
    -8.2
    (4.2)
    -14
    (4.1)
    -2.7
    (4.0)
    -12.4
    (4.0)
    -10.1
    (4.0)
    24. Secondary Outcome
    Title Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
    Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.
    Time Frame From Baseline to Week 12

    Outcome Measure Data

    Analysis Population Description
    Apo A-1 ITT population.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    Measure Participants 44 44 44 51 48 49
    Least Squares Mean (Standard Error) [percent change]
    4.0
    (1.6)
    2.6
    (1.6)
    4.3
    (1.6)
    0.9
    (1.8)
    1.8
    (1.8)
    9.1
    (1.8)

    Adverse Events

    Time Frame From Baseline to Week 32
    Adverse Event Reporting Description Treatment emergent adverse events that developed during on-treatment period (the time period from the first double-blind injection of study drug up to the day of last injection + 70 days) are reported.
    Arm/Group Title Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Arm/Group Description Participants who were receiving rosuvastatin 10 mg at baseline, received rosuvastatin 20 mg once daily (QD), placebo for alirocumab every 2 weeks (Q2W), and placebo for ezetimibe QD added to stable lipid-modifying therapy (LMT) for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 10 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 10 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 10 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history. Participants who were receiving rosuvastatin 20 mg at baseline, received rosuvastatin 40 mg QD, placebo for alirocumab Q2W, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received ezetimibe 10 mg QD, rosuvastatin 20 mg QD, and placebo for alirocumab Q2W added to stable LMT for 24 weeks. Participants who were receiving rosuvastatin 20 mg at baseline, received alirocumab 75 mg Q2W, rosuvastatin 20 mg QD, and placebo for ezetimibe QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
    All Cause Mortality
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/48 (8.3%) 5/48 (10.4%) 2/49 (4.1%) 4/53 (7.5%) 3/53 (5.7%) 4/54 (7.4%)
    Blood and lymphatic system disorders
    Iron deficiency anaemia 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 1/53 (1.9%) 1 0/53 (0%) 0 0/54 (0%) 0
    Thrombotic thrombocytopenic purpura 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 1/53 (1.9%) 1 0/53 (0%) 0 0/54 (0%) 0
    Cardiac disorders
    Acute myocardial infarction 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 1/53 (1.9%) 1 0/54 (0%) 0
    Angina unstable 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 1/54 (1.9%) 1
    Arrhythmia 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 1/54 (1.9%) 1
    Atrioventricular block second degree 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 1/53 (1.9%) 1 0/53 (0%) 0 0/54 (0%) 0
    Cardiac failure congestive 1/48 (2.1%) 1 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Gastrointestinal disorders
    Upper gastrointestinal haemorrhage 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 1/53 (1.9%) 1 0/54 (0%) 0
    General disorders
    Non-Cardiac chest pain 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 1/53 (1.9%) 1 0/53 (0%) 0 0/54 (0%) 0
    Infections and infestations
    Spinal cord infection 0/48 (0%) 0 1/48 (2.1%) 1 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Urosepsis 0/48 (0%) 0 0/48 (0%) 0 1/49 (2%) 1 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Viral infection 0/48 (0%) 0 0/48 (0%) 0 1/49 (2%) 1 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Injury, poisoning and procedural complications
    Accidental overdose 0/48 (0%) 0 0/48 (0%) 0 1/49 (2%) 1 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Subdural haematoma 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 1/53 (1.9%) 1 0/54 (0%) 0
    Toxicity to various agents 0/48 (0%) 0 0/48 (0%) 0 1/49 (2%) 1 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Metabolism and nutrition disorders
    Obesity 1/48 (2.1%) 1 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-Small cell lung cancer metastatic 0/48 (0%) 0 1/48 (2.1%) 1 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Prostate cancer 1/48 (2.1%) 1 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Renal cell carcinoma 1/48 (2.1%) 1 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Nervous system disorders
    Haemorrhagic stroke 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 1/53 (1.9%) 1 0/54 (0%) 0
    Paraesthesia 0/48 (0%) 0 1/48 (2.1%) 1 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Subarachnoid haemorrhage 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 1/53 (1.9%) 1 0/54 (0%) 0
    Syncope 0/48 (0%) 0 1/48 (2.1%) 1 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 1/54 (1.9%) 1
    Psychiatric disorders
    Psychotic disorder 0/48 (0%) 0 0/48 (0%) 0 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 1/54 (1.9%) 1
    Renal and urinary disorders
    Haematuria 0/48 (0%) 0 1/48 (2.1%) 1 0/49 (0%) 0 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Other (Not Including Serious) Adverse Events
    Rosuvastatin 20 mg Ezetimibe 10 mg + Rosuvastatin 10 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg Rosuvastatin 40 mg Ezetimibe 10 mg + Rosuvastatin 20 mg Alirocumab 75 mg/up to 150 mg + Rosuvastatin 20 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 11/48 (22.9%) 11/48 (22.9%) 11/49 (22.4%) 20/53 (37.7%) 12/53 (22.6%) 15/54 (27.8%)
    Gastrointestinal disorders
    Nausea 1/48 (2.1%) 1 1/48 (2.1%) 3 3/49 (6.1%) 3 1/53 (1.9%) 1 1/53 (1.9%) 1 0/54 (0%) 0
    Diarrhoea 0/48 (0%) 0 2/48 (4.2%) 2 0/49 (0%) 0 3/53 (5.7%) 3 0/53 (0%) 0 2/54 (3.7%) 2
    General disorders
    Injection site reaction 2/48 (4.2%) 3 0/48 (0%) 0 1/49 (2%) 1 0/53 (0%) 0 0/53 (0%) 0 3/54 (5.6%) 5
    Infections and infestations
    Nasopharyngitis 1/48 (2.1%) 1 2/48 (4.2%) 2 2/49 (4.1%) 2 6/53 (11.3%) 6 3/53 (5.7%) 3 2/54 (3.7%) 2
    Upper respiratory tract infection 3/48 (6.3%) 3 0/48 (0%) 0 2/49 (4.1%) 2 6/53 (11.3%) 7 4/53 (7.5%) 4 4/54 (7.4%) 4
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/48 (2.1%) 1 0/48 (0%) 0 4/49 (8.2%) 4 2/53 (3.8%) 2 1/53 (1.9%) 1 0/54 (0%) 0
    Myalgia 1/48 (2.1%) 2 3/48 (6.3%) 3 0/49 (0%) 0 1/53 (1.9%) 1 1/53 (1.9%) 1 4/54 (7.4%) 5
    Osteoarthritis 1/48 (2.1%) 1 3/48 (6.3%) 3 1/49 (2%) 1 0/53 (0%) 0 0/53 (0%) 0 0/54 (0%) 0
    Pain in extremity 3/48 (6.3%) 3 1/48 (2.1%) 1 2/49 (4.1%) 2 5/53 (9.4%) 5 2/53 (3.8%) 2 0/54 (0%) 0
    Nervous system disorders
    Dizziness 3/48 (6.3%) 4 1/48 (2.1%) 1 1/49 (2%) 1 2/53 (3.8%) 2 1/53 (1.9%) 1 2/54 (3.7%) 2
    Headache 0/48 (0%) 0 1/48 (2.1%) 1 0/49 (0%) 0 3/53 (5.7%) 4 0/53 (0%) 0 0/54 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    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.

    Results Point of Contact

    Name/Title Clinical Trial Management
    Organization Regeneron Pharmaceuticals
    Phone
    Email clinicaltrials@regeneron.com
    Responsible Party:
    Regeneron Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01730053
    Other Study ID Numbers:
    • R727-CL-1118
    First Posted:
    Nov 21, 2012
    Last Update Posted:
    Apr 7, 2020
    Last Verified:
    Mar 1, 2020