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    Clinical Trial Results:
    A Randomized, Open-Label, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab Versus Usual Care in Patients with Type 2 Diabetes and Mixed Dyslipidemia at High Cardiovascular Risk with Non-HDL-C Not Adequately Controlled with Maximally Tolerated Statin Therapy

    Summary
    EudraCT number
    		 2015-001934-19
    Trial protocol
    		 FI   DE   GB   SE   IT  
    Global end of trial date
    15 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 May 2018
    First version publication date
    27 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS14354
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02642159
    WHO universal trial number (UTN)
    		 U1111-1172-5262
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.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
    09 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of alirocumab in comparison with usual care in the reduction of non-high-density lipoprotein cholesterol (non-HDL-C) after 24 weeks of treatment in subjects with type 2 diabetes (T2DM) and mixed dyslipidemia at high cardiovascular risk with non-HDL-C not adequately controlled with maximally tolerated statin therapy.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 All subjects received stable antihyperglycemic drugs (including insulin), stable dose of statin without other lipid modifying therapy (LMT) as clinically indicated (except ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid allowed for usual care arm) throughout the duration of study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2016
    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
    Australia: 17
    Country: Number of subjects enrolled
    Brazil: 21
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Italy: 32
    Country: Number of subjects enrolled
    Lebanon: 5
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    United Arab Emirates: 2
    Country: Number of subjects enrolled
    United States: 233
    Country: Number of subjects enrolled
    Norway: 8
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Finland: 15
    Country: Number of subjects enrolled
    Germany: 33
    Worldwide total number of subjects
    413
    EEA total number of subjects
    105
    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)
    216
    From 65 to 84 years
    194
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 119 centers in 15 countries. A total of 864 subjects were screened between March 2016 and September 2016, 451 of whom were screen failures. Screen failures were mainly due to inclusion criteria not met.

    Pre-assignment
    Screening details
    		 Randomization was stratified by investigator’s choice of usual care therapy, which was pre-specified prior to randomization. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 2:1 ratio (alirocumab: usual care) after confirmation of selection criteria. 413 subjects were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W
    Arm description
    		 Alirocumab 75 mg subcutaneous (SC) injection every 2 weeks (Q2W) added to antihyperglycemic drugs (including insulin), stable maximally tolerated dose of statin therapy without other LMT for 24 weeks. Alirocumab dose uptitrated to 150 mg Q2W from Week 12 when non-HDLC levels >=100 mg/dL (2.59 mmol/L) at Week 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alirocumab
    Investigational medicinal product code
    SAR236553, REGN727
    Other name
    Praluent
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self- injection or by another designated person using the auto-injector.

    Arm title
    		 Usual Care
    Arm description
    		 Subjects on usual care continued on antihyperglycemic drugs (including insulin), stable maximally tolerated dose of statin therapy without additional LMT or with either ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid as per Investigator's judgment for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ezetimibe
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ezetimibe was administered as per Investigator’s judgment for 24 weeks.

    Investigational medicinal product name
    Fenofibrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Fenofibrate was administered as per Investigator’s judgment for 24 weeks.

    Investigational medicinal product name
    Nicotinic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nicotinic acid was administered as per Investigator’s judgment for 24 weeks.

    Investigational medicinal product name
    Omega-3 fatty acids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Omega-3 fatty acids were administered as per Investigator’s judgment for 24 weeks.

    Number of subjects in period 1
    		Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Started
    276
    137
    Treated (Safety Population)
    275
    137
    ITT Population
    273
    136
    ITT: Intent to Prescribe Fenofibrate
    47 [1]
    24 [2]
    Completed
    245
    129
    Not completed
    31
    8
         Other than specified above
    10
    3
         Adverse Event
    10
    4
         Randomized but not treated
    1
    -
         Withdrawal by Subject
    9
    1
         Poor compliance to study protocol
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestone represents only those randomised subjects who were included in ITT: Intent to Prescribe Fenofibrate statum. Fenofibrate was only ‘intended to prescribe’ in the Alirocumab arm but not actually administered.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestone represents only those randomised subjects who were included in ITT: Intent to Prescribe Fenofibrate statum.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W
    Reporting group description
    		 Alirocumab 75 mg subcutaneous (SC) injection every 2 weeks (Q2W) added to antihyperglycemic drugs (including insulin), stable maximally tolerated dose of statin therapy without other LMT for 24 weeks. Alirocumab dose uptitrated to 150 mg Q2W from Week 12 when non-HDLC levels >=100 mg/dL (2.59 mmol/L) at Week 8.

    Reporting group title
    Usual Care
    Reporting group description
    		 Subjects on usual care continued on antihyperglycemic drugs (including insulin), stable maximally tolerated dose of statin therapy without additional LMT or with either ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid as per Investigator's judgment for 24 weeks.

    Reporting group values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care Total
    Number of subjects
    		 276 137 413
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.8 ( 9.3 ) 64.1 ( 8.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 129 68 197
        Male
    		 147 69 216
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 35 14 49
        Not Hispanic or Latino
    		 240 123 363
        Unknown or Not Reported
    		 1 0 1
    Race
    Units: Subjects
        White/Caucasian
    		 247 123 370
        Black
    		 16 6 22
        Asian/Oriental
    		 3 7 10
        American Indian or Alaska Native
    		 4 0 4
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Other
    		 6 1 7
    Intent to Prescribe Treatment
    Randomization was stratified by the Investigator’s selection of usual care therapy prior to randomization. LMTs were only ‘intended to prescribe’ in the Alirocumab arm but not actually administered.
    Units: Subjects
        Fenofibrate
    		 48 24 72
        No additional LMT
    		 79 39 118
        Ezetimibe
    		 104 52 156
        Omega-3 fatty acids
    		 43 21 64
        Nicotinic acid
    		 2 1 3
    Non-HDL-C in mg/dL
    non-HDL-C = Total cholesterol (Total-C) minus high-density lipoprotein cholesterol (HDL-C)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 155.1 ( 46.2 ) 161.5 ( 48.8 ) -
    Non-HDL-C in mmol/L
    non-HDL-C = Total-C minus HDL-C
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.0 ( 1.2 ) 4.2 ( 1.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W
    Reporting group description
    		 Alirocumab 75 mg subcutaneous (SC) injection every 2 weeks (Q2W) added to antihyperglycemic drugs (including insulin), stable maximally tolerated dose of statin therapy without other LMT for 24 weeks. Alirocumab dose uptitrated to 150 mg Q2W from Week 12 when non-HDLC levels >=100 mg/dL (2.59 mmol/L) at Week 8.

    Reporting group title
    Usual Care
    Reporting group description
    		 Subjects on usual care continued on antihyperglycemic drugs (including insulin), stable maximally tolerated dose of statin therapy without additional LMT or with either ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid as per Investigator's judgment for 24 weeks.

    Subject analysis set title
    Usual Care: Intent to Prescribe Fenofibrate
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects on usual care continued on antihyperglycemic drugs (including insulin), stable maximally tolerated dose of statin therapy with fenofibrate as per Investigator's judgment for 24 weeks.

    Primary: Percent Change From Baseline in Non-HDL-C at Week 24: Overall Intent-to-treat (ITT) Analysis

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 24: Overall Intent-to-treat (ITT) Analysis
    End point description
    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 8 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis). ITT population: all randomized subjects with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Percent change
        least squares mean (standard error)
    -37.3 ( 3.0 )
    -4.7 ( 3.3 )
    Statistical analysis title
    		 Overall ITT: Statistical Comparison
    Statistical analysis description
    Alirocumab group was compared to usual care group using an appropriate contrast statement.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -32.5
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -38.1
         upper limit
    		 -27
    Notes
    [1] - Threshold for significance <=0.025.

    Primary: Percent Change From Baseline in Non-HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [2]
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 24
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    47
    24
    Units: Percent change
        least squares mean (standard error)
    -41.7 ( 3.4 )
    -8.5 ( 4.8 )
    Statistical analysis title
    		 ITT- Intent to Prescribe : Statistical Comparison
    Statistical analysis description
    Alirocumab group was compared to usual care group for the intent to prescribe fenofibrate using an appropriate contrast statement.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -33.3
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -46.6
         upper limit
    		 -19.9
    Notes
    [3] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Measured Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24: Overall ITT Analysis

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    End point title
    		 Percent Change From Baseline in Measured Low-Density Lipoprotein Cholesterol (LDL-C) at Week 24: Overall ITT Analysis
    End point description
    Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline LDL-C value on-or off-treatment (LDL-C ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Percent change
        least squares mean (standard error)
    -43.3 ( 3.6 )
    -0.3 ( 4.0 )
    Statistical analysis title
    		 Overall ITT: Statistical Comparison
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses for overall ITT analysis. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -43
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -49.7
         upper limit
    		 -36.3
    Notes
    [4] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Measured LDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in Measured LDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [5]
    End point description
    Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. LDL-C ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    47
    24
    Units: Percent change
        least squares mean (standard error)
    -47.0 ( 4.2 )
    8.7 ( 5.8 )
    Statistical analysis title
    		 ITT- Intent to Prescribe : Statistical Comparison
    Statistical analysis description
    A separate hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses for ITT-intent to prescribe fenofibrate stratum. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -55.7
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -71.8
         upper limit
    		 -39.6
    Notes
    [6] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Non-HDL-C at Week 12: Overall ITT Analysis

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 12: Overall ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Percent change
        least squares mean (standard error)
    -35.5 ( 2.9 )
    -9.4 ( 3.2 )
    Statistical analysis title
    		 Overall ITT: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -26.1
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -31.5
         upper limit
    		 -20.7
    Notes
    [7] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Non-HDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in Non-HDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum [8]
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    47
    24
    Units: Percent change
        least squares mean (standard error)
    -34.7 ( 3.2 )
    -7.3 ( 4.5 )
    Statistical analysis title
    		 ITT- Intent to Prescribe : Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT-intent to prescribe fenofibrate stratum was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -27.4
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -40
         upper limit
    		 -14.8
    Notes
    [9] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Measured LDL-C at Week 12: Overall ITT Analysis

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    End point title
    		 Percent Change From Baseline in Measured LDL-C at Week 12: Overall ITT Analysis
    End point description
    Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. LDL-C ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Percent change
        least squares mean (standard error)
    -41.7 ( 3.3 )
    -7.0 ( 3.6 )
    Statistical analysis title
    		 Overall ITT: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -34.7
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -40.8
         upper limit
    		 -28.6
    Notes
    [10] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Measured LDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in Measured LDL-C at Week 12: ITT- Intent to Prescribe Fenofibrate Stratum [11]
    End point description
    Measured LDL-C values via beta quantification method. Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. LDL-C ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    47
    24
    Units: Percent change
        least squares mean (standard error)
    -44.3 ( 3.6 )
    5.4 ( 5.1 )
    Statistical analysis title
    		 ITT- Intent to Prescribe : Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT-intent to prescribe fenofibrate stratum was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -49.7
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -63.7
         upper limit
    		 -35.8
    Notes
    [12] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24: Overall ITT Analysis

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24: Overall ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline Apo-B value on-or off-treatment (Apo-B ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Percent change
        least squares mean (standard error)
    -33.8 ( 2.7 )
    -1.6 ( 3.0 )
    Statistical analysis title
    		 Overall ITT: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -32.3
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -37.3
         upper limit
    		 -27.2
    Notes
    [13] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Apo-B at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in Apo-B at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [14]
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. Apo-B ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    47
    24
    Units: Percent change
        least squares mean (standard error)
    -38.9 ( 3.1 )
    -3.8 ( 4.4 )
    Statistical analysis title
    		 ITT- Intent to Prescribe: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT- intent to prescribe fenofibrate stratum was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -35.2
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -47.4
         upper limit
    		 -22.9
    Notes
    [15] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 : Overall ITT Analysis

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 : Overall ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline Total-C value on- or off-treatment (Total-C ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Percent change
        least squares mean (standard error)
    -27.4 ( 2.3 )
    -2.8 ( 2.5 )
    Statistical analysis title
    		 Overall ITT: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -24.6
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -28.8
         upper limit
    		 -20.3
    Notes
    [16] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Total-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in Total-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [17]
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. Total-C ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    47
    24
    Units: Percent change
        least squares mean (standard error)
    -30.9 ( 2.6 )
    -5.7 ( 3.7 )
    Statistical analysis title
    		 ITT- Intent to Prescribe: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT- intent to prescribe fenofibrate stratum was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -25.3
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -35.4
         upper limit
    		 -15.1
    Notes
    [18] - Threshold for significance <=0.025.

    Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 24 : Overall ITT Analysis

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) at Week 24 : Overall ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment were included in the imputation model. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Percent change
        arithmetic mean (standard error)
    -23.7 ( 1.9 )
    3.7 ( 2.6 )
    Statistical analysis title
    		 Overall ITT: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [19]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -27.4
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -34.6
         upper limit
    		 -20.1
    Notes
    [19] - Threshold for significance <=0.025. Multiple imputation approach followed by robust regression model.

    Secondary: Percent Change From Baseline in Lipoprotein(a) at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [20]
    End point description
    Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    47
    24
    Units: Percent change
        arithmetic mean (standard error)
    -18.9 ( 4.4 )
    3.9 ( 6.6 )
    Statistical analysis title
    		 ITT- Intent to Prescribe: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT- intent to prescribe fenofibrate stratum was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [21]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -22.8
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -40.6
         upper limit
    		 -5
    Notes
    [21] - Threshold for significance <=0.025. Multiple imputation approach followed by robust regression model.

    Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 24: Overall ITT Analysis

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    End point title
    		 Percent Change From Baseline in Fasting Triglycerides at Week 24: Overall ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Percent change
        arithmetic mean (standard error)
    -13.0 ( 2.0 )
    -8.8 ( 2.8 )
    Statistical analysis title
    		 Overall ITT: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of overall ITT analysis was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2191 [22]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -4.2
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -11.8
         upper limit
    		 3.4
    Notes
    [22] - Threshold for significance <=0.025. Multiple imputation approach followed by robust regression.

    Secondary: Percent Change From Baseline in Fasting Triglycerides at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in Fasting Triglycerides at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [23]
    End point description
    Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    47
    24
    Units: Percent change
        arithmetic mean (standard error)
    -15.4 ( 4.7 )
    -24.4 ( 6.6 )
    Statistical analysis title
    		 ITT- Intent to Prescribe: Statistical Comparison
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint of ITT- intent to prescribe fenofibrate stratum was statistically significant).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W v Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2651 [24]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    9
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -9.1
         upper limit
    		 27.1
    Notes
    [24] - Threshold for significance <=0.025. Multiple imputation approach followed by robust regression.

    Secondary: Percent Change From Baseline in HDL-C at Week 24 : Overall ITT Analysis

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 24 : Overall ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline HDL-C value on- or off-treatment (HDL-C ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Percent change
        least squares mean (standard error)
    14.5 ( 2.5 )
    8.2 ( 2.7 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [25]
    End point description
    Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. HDL-C ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    47
    24
    Units: Percent change
        least squares mean (standard error)
    13.5 ( 2.9 )
    12.3 ( 4.1 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in LDL-C Particle Number at Week 24: Overall ITT Analysis

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    End point title
    		 Percent Change From Baseline in LDL-C Particle Number at Week 24: Overall ITT Analysis
    End point description
    LDL-C particle number was calculated from lipid subfractions by nuclear magnetic resonance (NMR) spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline LDL-C particle number on- or off-treatment (LDL-C particle number ITT population).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    270
    135
    Units: Percent change
        least squares mean (standard error)
    -41.6 ( 3.0 )
    -3.9 ( 3.4 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in LDL-C Particle Number at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum

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    End point title
    		 Percent Change From Baseline in LDL-C Particle Number at Week 24: ITT- Intent to Prescribe Fenofibrate Stratum [26]
    End point description
    LDL-C particle number was calculated from lipid subfractions by NMR spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 8 to Week 24 regardless of status on- or off-treatment in the intent to prescribe fenofibrate stratum. The usual care here corresponds to fenofibrate. LDL-C particle number ITT population. Here, ‘Number of subjects analyzed’ = subjects from intent to prescribe fenofibrate stratum who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care: Intent to Prescribe Fenofibrate
    Number of subjects analysed
    46
    24
    Units: Percent change
        least squares mean (standard error)
    -45.4 ( 3.5 )
    -2.9 ( 5.0 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis

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    End point title
    		 Absolute Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 and 24 : Overall ITT Analysis
    End point description
    Absolute change = HbA1c value at specified week minus HbA1c value at baseline. ITT population. Here, 'n' signifies number of subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: mmol/mol
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 265, 133)
    0.59 ( 6.82 )
    0.43 ( 5.70 )
        Change at Week 24 (n= 251, 128)
    2.84 ( 8.04 )
    2.40 ( 8.19 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis

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    End point title
    		 Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 and 24 : Overall ITT Analysis
    End point description
    Absolute change = FPG value at specified week minus FPG value at baseline. ITT population. Here, 'n’ signifies number of subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: mmol/L
    arithmetic mean (standard deviation)
        Change at Week 12 (n=262, 133)
    0.45 ( 2.43 )
    0.21 ( 1.86 )
        Change at Week 24 (n=251, 128)
    0.68 ( 2.54 )
    0.03 ( 2.54 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis

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    End point title
    		 Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Week 12 and 24 : Overall ITT Analysis
    End point description
    Glucose lowering treatment was calculated for non-insulin treatments as one for each unique treatment received and for insulin treatment as one in total for all subjects who have taken one or more treatments. Absolute change = number of glucose-lowering treatments at specified week minus baseline value. ITT population. Here, ‘n’ signifies number of subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Number of subjects analysed
    273
    136
    Units: Glucose lowering treatments
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 271, 136)
    0.04 ( 0.30 )
    0.04 ( 0.19 )
        Change at Week 24 (n=267, 135)
    0.07 ( 0.37 )
    0.04 ( 0.23 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 32) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths are TEAEs that are AEs that developed/worsened and death that occurred during the ‘treatment-emergent period’ (the time from the first dose of study drug up to the last dose of study drug +70 days).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W
    Reporting group description
    		 Alirocumab 75 mg SC injection Q2W added to antihyperglycemic drugs (including insulin), stable maximally tolerated dose of statin therapy without other LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when non- HDL-C levels >=100 mg/dL (2.59 mmol/L) at Week 8.

    Reporting group title
    Usual Care
    Reporting group description
    		 Subjects on usual care continued on antihyperglycemic drugs (including insulin), stable maximally tolerated dose of statin therapy without additional LMT or with either ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid as per Investigator's judgment for 24 weeks.

    Serious adverse events
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 275 (9.45%)
    12 / 137 (8.76%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder Neoplasm
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    2 / 275 (0.73%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal Prolapse
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar I Disorder
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lower Limb Fracture
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 275 (0.36%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    3 / 275 (1.09%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial Paralysis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    2 / 275 (0.73%)
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Osteoarthritis
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diabetic Foot Infection
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 275 (0.73%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 275 (0.36%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 275 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Usual Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 275 (13.45%)
    27 / 137 (19.71%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 275 (5.09%)
    9 / 137 (6.57%)
         occurrences all number
    18
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 275 (2.18%)
    8 / 137 (5.84%)
         occurrences all number
    6
    9
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 275 (1.82%)
    7 / 137 (5.11%)
         occurrences all number
    5
    7
    Urinary Tract Infection
         subjects affected / exposed
    15 / 275 (5.45%)
    5 / 137 (3.65%)
         occurrences all number
    15
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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