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    Clinical Trial Results:
    A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MK-0616 in Adults With Hypercholesterolemia

    Summary
    EudraCT number
    		 2021-005221-24
    Trial protocol
    		 DE   NO  
    Global end of trial date
    28 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Dec 2023
    First version publication date
    01 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    0616-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05261126
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 jRCT2031210701: jRCT
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Nov 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy and safety of MK-0616, an oral PCSK9 inhibitor, in lowering low-density lipoprotein cholesterol (LDL-C) in participants with hypercholesterolemia. The primary hypothesis is that at least one of the four doses of MK-0616 tested in this study is superior to placebo on percent change from baseline in LDL-C at Week 8.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Mar 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Mexico: 119
    Country: Number of subjects enrolled
    Norway: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 138
    Worldwide total number of subjects
    381
    EEA total number of subjects
    40
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    223
    From 65 to 84 years
    158
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of 668 participants screened for inclusion, 381 were randomized 1:1:1:1:1 to receive MK-0616 6 mg, 12 mg, 18 mg, 30 mg, or placebo. Of the 381 randomized participants, one participant did not receive at least one dose of study intervention.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MK-0616 6 mg
    Arm description
    		 Participants received 6 mg of MK-0616 orally once daily (QD) for 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-0616
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    6 mg MK-0616 was administered orally in capsule form for up to 8 weeks.

    Arm title
    		 MK-0616 12 mg
    Arm description
    		 Participants received 12 mg of MK-0616 orally QD for 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-0616
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    12 mg MK-0616 was administered orally in capsule form for up to 8 weeks.

    Arm title
    		 MK-0616 18 mg
    Arm description
    		 Participants received 18 mg of MK-0616 orally QD for 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-0616
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    18 mg MK-0616 was administered orally in capsule form for up to 8 weeks.

    Arm title
    		 MK-0616 30 mg
    Arm description
    		 Participants received 30 mg of MK-0616 orally QD for 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-0616
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg MK-0616 was administered orally in capsule form for up to 8 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Participants received MK-0616-matching placebo orally QD for 8 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to MK-0616
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    MK-0616 matching placebo was administered orally in capsule form for up to 8 weeks.

    Number of subjects in period 1
    		MK-0616 6 mg MK-0616 12 mg MK-0616 18 mg MK-0616 30 mg Placebo
    Started
    77
    76
    76
    76
    76
    Treated
    77
    76
    76
    76
    75
    Completed
    75
    76
    74
    74
    74
    Not completed
    2
    0
    2
    2
    2
         Physician decision
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    1
    -
    1
    1
    -
         Screen Failure
    -
    -
    -
    -
    1
         Death
    -
    -
    1
    -
    -
         Not Recorded
    -
    -
    -
    1
    -
         Lost to follow-up
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MK-0616 6 mg
    Reporting group description
    		 Participants received 6 mg of MK-0616 orally once daily (QD) for 8 weeks

    Reporting group title
    MK-0616 12 mg
    Reporting group description
    		 Participants received 12 mg of MK-0616 orally QD for 8 weeks

    Reporting group title
    MK-0616 18 mg
    Reporting group description
    		 Participants received 18 mg of MK-0616 orally QD for 8 weeks

    Reporting group title
    MK-0616 30 mg
    Reporting group description
    		 Participants received 30 mg of MK-0616 orally QD for 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received MK-0616-matching placebo orally QD for 8 weeks

    Reporting group values
    		 MK-0616 6 mg MK-0616 12 mg MK-0616 18 mg MK-0616 30 mg Placebo Total
    Number of subjects
    		 77 76 76 76 76 381
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 39 47 42 44 51 223
        From 65-84 years
    		 38 29 34 32 25 158
        85 years and over
    		 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.7 ( 10.3 ) 62.0 ( 9.4 ) 62.0 ( 9.2 ) 60.9 ( 10.2 ) 60.6 ( 9.3 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 38 35 39 38 38 188
        Male
    		 39 41 37 38 38 193
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 4 5 5 2 5 21
        Asian
    		 18 13 11 13 8 63
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 4 5 2 9 4 24
        White
    		 49 48 55 44 54 250
        More than one race
    		 2 5 3 8 5 23
        Unknown or Not Reported
    		 0 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 26 29 31 31 37 154
        Not Hispanic or Latino
    		 51 46 45 45 38 225
        Unknown or Not Reported
    		 0 1 0 0 1 2
    Randomization Strata: Background Statin Dose
    Participants were stratified by the following background statin dose: no statin therapy, low-intensity to moderate-intensity statin therapy, or high-intensity statin therapy.
    Units: Subjects
        No Statin Therapy
    		 30 29 31 30 30 150
        Low- to Moderate-intensity Statin Therapy
    		 27 27 26 26 26 132
        High-intensity Statin Therapy
    		 20 20 19 20 20 99
    Randomization Strata: Renal Function
    Estimated glomerular filtration rate (eGFR) was calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine. Participants were stratified by the following renal function at baseline: eGFR ≥60 vs <60 ml/min/1.73 m^2.
    Units: Subjects
        eGFR ≥60 ml/min/1.73 m^2
    		 71 72 72 71 71 357
        eGFR <60 ml/min/1.73 m^2
    		 6 4 4 5 5 24
    Baseline Low-density Lipoprotein Cholesterol (LDL-C)
    Blood samples were taken at baseline to determine baseline LDL-C levels.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 116.5 ( 37.0 ) 117.3 ( 36.4 ) 123.7 ( 35.1 ) 119.4 ( 36.7 ) 120.7 ( 28.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    MK-0616 6 mg
    Reporting group description
    		 Participants received 6 mg of MK-0616 orally once daily (QD) for 8 weeks

    Reporting group title
    MK-0616 12 mg
    Reporting group description
    		 Participants received 12 mg of MK-0616 orally QD for 8 weeks

    Reporting group title
    MK-0616 18 mg
    Reporting group description
    		 Participants received 18 mg of MK-0616 orally QD for 8 weeks

    Reporting group title
    MK-0616 30 mg
    Reporting group description
    		 Participants received 30 mg of MK-0616 orally QD for 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received MK-0616-matching placebo orally QD for 8 weeks

    Primary: Percent Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8

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    End point title
    		 Percent Change from Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Week 8
    End point description
    Blood samples were collected at baseline and after 8 weeks of treatment to assess mean percent change in LDL-C. Based on a constrained longitudinal analysis (cLDA) model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time. The percent change from baseline in LDL-C at week 8 was reported. All randomized participants who received at least one dose of study intervention, had at least one observation for the analysis endpoint, and had baseline data were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline and up to Week 8
    End point values
    		 MK-0616 6 mg MK-0616 12 mg MK-0616 18 mg MK-0616 30 mg Placebo
    Number of subjects analysed
    75
    75
    74
    73
    72
    Units: Percentage Change
        least squares mean (confidence interval 95%)
    -40.0 (-45.2 to -34.8)
    -54.5 (-59.8 to -49.2)
    -57.9 (-63.2 to -52.6)
    -59.7 (-65.0 to -54.5)
    1.2 (-4.1 to 6.5)
    Statistical analysis title
    		 Percent Change from Baseline in LDL-C
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 6 mg v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -41.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -47.8
         upper limit
    		 -34.7
    Statistical analysis title
    		 Percent Change from Baseline in LDL-C
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 12 mg v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -55.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.3
         upper limit
    		 -49.1
    Statistical analysis title
    		 Percent Change from Baseline in LDL-C
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 18 mg v Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -59.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -65.7
         upper limit
    		 -52.5
    Statistical analysis title
    		 Percent Change from Baseline in LDL-C
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 30 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -60.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -67.6
         upper limit
    		 -54.3

    Primary: Percentage of Participants Who Experienced One or More Adverse Events (AEs)

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    End point title
    		 Percentage of Participants Who Experienced One or More Adverse Events (AEs)
    End point description
    An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced at least one AE was reported. All randomized participants who received at least one dose of study intervention were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 17 Weeks
    End point values
    		 MK-0616 6 mg MK-0616 12 mg MK-0616 18 mg MK-0616 30 mg Placebo
    Number of subjects analysed
    77
    76
    76
    76
    75
    Units: Percentage of Participants
        number (not applicable)
    44.2
    39.5
    43.4
    42.1
    44.0
    Statistical analysis title
    		 Difference in Percentage of Participants with AEs
    Statistical analysis description
    Difference in percentage (MK-0616 6 mg minus Placebo) based on Miettinen & Nurminen method.
    Comparison groups
    MK-0616 6 mg v Placebo
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.5
         upper limit
    		 15.8
    Statistical analysis title
    		 Difference in Percentage of Participants with AEs
    Statistical analysis description
    Difference in percentage (MK-0616 12 mg minus Placebo) based on Miettinen & Nurminen method.
    Comparison groups
    MK-0616 12 mg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20
         upper limit
    		 11.2
    Statistical analysis title
    		 Difference in Percentage of Participants with AEs
    Statistical analysis description
    Difference in percentage (MK-0616 18 mg minus Placebo) based on Miettinen & Nurminen method.
    Comparison groups
    MK-0616 18 mg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.3
         upper limit
    		 15.1
    Statistical analysis title
    		 Difference in Percentage of Participants with AEs
    Statistical analysis description
    Difference in percentage (MK-0616 30 mg minus Placebo) based on Miettinen & Nurminen method.
    Comparison groups
    MK-0616 30 mg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.5
         upper limit
    		 13.8

    Primary: Percentage of Participants Who Discontinued Study Intervention Due to AEs

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    End point title
    		 Percentage of Participants Who Discontinued Study Intervention Due to AEs [1]
    End point description
    An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who discontinued study intervention due to AEs was reported. All randomized participants who received at least one dose of study intervention were analyzed.
    End point type
    Primary
    End point timeframe
    Up to approximately 9 Weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed due to a small sample size.
    End point values
    		 MK-0616 6 mg MK-0616 12 mg MK-0616 18 mg MK-0616 30 mg Placebo
    Number of subjects analysed
    77
    76
    76
    76
    75
    Units: Percentage of Participants
        number (not applicable)
    2.6
    0.0
    2.6
    2.6
    1.3
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Apolipoprotein B (ApoB) at Week 8

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    End point title
    		 Percent Change from Baseline in Apolipoprotein B (ApoB) at Week 8
    End point description
    Blood samples were collected at baseline and after 8 weeks of treatment to assess mean percent change in ApoB. The least square mean and 95% CI were obtained from fitting a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time. The percent change from baseline in ApoB at week 8 was reported. All randomized participants who received at least one dose of study intervention, had at least one observation for the analysis endpoint, and had baseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 8
    End point values
    		 MK-0616 6 mg MK-0616 12 mg MK-0616 18 mg MK-0616 30 mg Placebo
    Number of subjects analysed
    76
    75
    74
    74
    72
    Units: Percentage Change
        least squares mean (confidence interval 95%)
    -32.8 (-37.6 to -27.9)
    -45.8 (-50.7 to -40.9)
    -48.7 (-53.6 to -43.8)
    -51.8 (-56.7 to -47.0)
    0.0 (-4.9 to 4.9)
    Statistical analysis title
    		 Percent Change from Baseline in ApoB
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 6 mg v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -32.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.6
         upper limit
    		 -26.9
    Statistical analysis title
    		 Percent Change from Baseline in ApoB
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 12 mg v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -45.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.7
         upper limit
    		 -39.9
    Statistical analysis title
    		 Percent Change from Baseline in ApoB
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 18 mg v Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -48.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.6
         upper limit
    		 -42.8
    Statistical analysis title
    		 Percent Change from Baseline in ApoB
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 30 mg v Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Square Means
    Point estimate
    -51.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.7
         upper limit
    		 -45.9

    Secondary: Percent Change from Baseline in Non-High-density Lipoprotein Cholesterol (non-HDL-C) at Week 8

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    End point title
    		 Percent Change from Baseline in Non-High-density Lipoprotein Cholesterol (non-HDL-C) at Week 8
    End point description
    Blood samples were collected at baseline and after 8 weeks of treatment to assess mean percent change in non-HDL-C. The least square mean and 95% CI were obtained from fitting a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time. The percent change from baseline in non-HDL-C at week 8 was reported. All randomized participants who received at least one dose of study intervention, had at least one observation for the analysis endpoint, and had baseline data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Week 8
    End point values
    		 MK-0616 6 mg MK-0616 12 mg MK-0616 18 mg MK-0616 30 mg Placebo
    Number of subjects analysed
    74
    76
    74
    73
    72
    Units: Percentage Change
        least squares mean (confidence interval 95%)
    -34.4 (-39.6 to -29.2)
    -49.0 (-54.3 to -43.7)
    -51.8 (-57.1 to -46.4)
    -54.3 (-59.6 to -49.1)
    1.5 (-3.9 to 6.8)
    Statistical analysis title
    		 Percent Change from Baseline in Non-HDL-C
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 6 mg v Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -35.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.4
         upper limit
    		 -29.4
    Statistical analysis title
    		 Percent Change from Baseline in Non-HDL-C
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 12 mg v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -50.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57
         upper limit
    		 -44
    Statistical analysis title
    		 Percent Change from Baseline in Non-HDL-C
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 18 mg v Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -53.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -59.7
         upper limit
    		 -46.7
    Statistical analysis title
    		 Percent Change from Baseline in Non-HDL-C
    Statistical analysis description
    One-sided p-value and difference in least squares means based on a cLDA model including terms for treatment, time, baseline statin intensity, baseline renal function, and the interaction of treatment by time.
    Comparison groups
    MK-0616 30 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -55.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.3
         upper limit
    		 -49.3

    Secondary: Percentage of Participants with LDL-C Value at Goal at Week 8

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    End point title
    		 Percentage of Participants with LDL-C Value at Goal at Week 8
    End point description
    LDL-C goal was defined as: LDL-C <70 mg/dL (<1.81 mmol/L) in participants with clinical atherosclerotic cardiovascular disease (ASCVD), LDL-C <100 mg/dL (<2.59 mmol/L) in participants with an ASCVD risk-equivalent and/or a 10-year risk of having an ASCVD event that is ≥7.5%, OR LDL-C <130 mg/dL (<3.37mmol/L) in participants with a 10-year risk of having an ASCVD event that is ≥5.0% and <7.5%. The percentage of participants with LDL-C value at goal at week 8 were reported. All randomized participants who received at least one dose of study intervention and had at least one observation for the analysis endpoint were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 MK-0616 6 mg MK-0616 12 mg MK-0616 18 mg MK-0616 30 mg Placebo
    Number of subjects analysed
    77
    76
    76
    76
    75
    Units: Percentage of Participants
        number (not applicable)
    80.5
    85.5
    90.8
    90.8
    9.3
    Statistical analysis title
    		 Participants with LDL-C Value at Goal
    Statistical analysis description
    One-sided p-value and difference in percentage (MK-0616 6 mg minus Placebo) based on Miettinen & Nurminen method, with sample size weighting, stratified by background statin intensity.
    Comparison groups
    MK-0616 6 mg v Placebo
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in Percentage
    Point estimate
    69.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 56.2
         upper limit
    		 79
    Statistical analysis title
    		 Participants with LDL-C Value at Goal
    Statistical analysis description
    One-sided p-value and difference in percentage (MK-0616 12 mg minus Placebo) based on Miettinen & Nurminen method, with sample size weighting, stratified by background statin intensity.
    Comparison groups
    MK-0616 12 mg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in Percentage
    Point estimate
    75.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 62.9
         upper limit
    		 84
    Statistical analysis title
    		 Participants with LDL-C Value at Goal
    Statistical analysis description
    One-sided p-value and difference in percentage (MK-0616 18 mg minus Placebo) based on Miettinen & Nurminen method, with sample size weighting, stratified by background statin intensity.
    Comparison groups
    MK-0616 18 mg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in Percentage
    Point estimate
    79.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 67.1
         upper limit
    		 87.1
    Statistical analysis title
    		 Participants with LDL-C Value at Goal
    Statistical analysis description
    One-sided p-value and difference in percentage (MK-0616 30 mg minus Placebo) based on Miettinen & Nurminen method, with sample size weighting, stratified by background statin intensity.
    Comparison groups
    MK-0616 30 mg v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in Percentage
    Point estimate
    79.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 67.9
         upper limit
    		 87.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 17 weeks
    Adverse event reporting additional description
    The population analyzed for the All-Cause Mortality was all randomized participants. The population analyzed for AEs was all randomized participants who received at least one dose of study treatment, corresponding to the study treatment they actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    MK-0616 12 mg
    Reporting group description
    		 Participants received 12 mg of MK-0616 orally QD for 8 weeks

    Reporting group title
    MK-0616 6 mg
    Reporting group description
    		 Participants received 6 mg of MK-0616 orally QD for 8 weeks

    Reporting group title
    MK-0616 30 mg
    Reporting group description
    		 Participants received 30 mg of MK-0616 orally QD for 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received MK-0616-matching placebo orally QD for 8 weeks

    Reporting group title
    MK-0616 18 mg
    Reporting group description
    		 Participants received 18 mg of MK-0616 orally QD for 8 weeks

    Serious adverse events
    		 MK-0616 12 mg MK-0616 6 mg MK-0616 30 mg Placebo MK-0616 18 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
    0 / 75 (0.00%)
    2 / 76 (2.63%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Multiple injuries
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Post-traumatic stress disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 77 (0.00%)
    1 / 76 (1.32%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
    0 / 75 (0.00%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MK-0616 12 mg MK-0616 6 mg MK-0616 30 mg Placebo MK-0616 18 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 76 (17.11%)
    11 / 77 (14.29%)
    8 / 76 (10.53%)
    15 / 75 (20.00%)
    15 / 76 (19.74%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 77 (0.00%)
    0 / 76 (0.00%)
    5 / 75 (6.67%)
    1 / 76 (1.32%)
         occurrences all number
    3
    0
    0
    5
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 76 (1.32%)
    5 / 77 (6.49%)
    1 / 76 (1.32%)
    1 / 75 (1.33%)
    3 / 76 (3.95%)
         occurrences all number
    1
    5
    2
    1
    3
    Dyspepsia
         subjects affected / exposed
    5 / 76 (6.58%)
    1 / 77 (1.30%)
    0 / 76 (0.00%)
    1 / 75 (1.33%)
    3 / 76 (3.95%)
         occurrences all number
    5
    1
    0
    1
    3
    Nausea
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 77 (1.30%)
    2 / 76 (2.63%)
    0 / 75 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    1
    1
    2
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 77 (0.00%)
    2 / 76 (2.63%)
    1 / 75 (1.33%)
    1 / 76 (1.32%)
         occurrences all number
    5
    0
    2
    1
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 76 (1.32%)
    6 / 77 (7.79%)
    4 / 76 (5.26%)
    7 / 75 (9.33%)
    5 / 76 (6.58%)
         occurrences all number
    1
    6
    4
    7
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2022
    Amendment 4: The purpose of the amendment was to update the Sponsor's entity name and address change.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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