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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in Insulin Treated Patients With Type 1 or Type 2 Diabetes and With Hypercholesterolemia at High Cardiovascular Risk not Adequately Controlled on Maximally Tolerated LDL-C Lowering Therapy

    Summary
    EudraCT number
    		 2015-000799-92
    Trial protocol
    		 GB   ES   DE   NL   AT   FR   BE   IT  
    Global end of trial date
    03 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Apr 2018
    First version publication date
    15 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS14355
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02585778
    WHO universal trial number (UTN)
    		 U1111-1172-4772
    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
    28 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 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 placebo in the reduction of calculated low-density lipoprotein cholesterol (LDL-C) after 24 weeks of treatment in subjects with diabetes treated with insulin and with hypercholesterolemia at high cardiovascular risk not adequately controlled on maximally tolerated LDL-C lowering therapy. - To evaluate the safety and tolerability of alirocumab in subjects with diabetes treated with insulin.
    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 maximum tolerated dose of statin with or without other lipid-modifying therapy (LMT), insulin alone or with other antihyperglycemic drugs as clinically indicated throughout the duration of study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 2015
    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
    Austria: 12
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 95
    Country: Number of subjects enrolled
    Italy: 72
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Spain: 69
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    United States: 192
    Worldwide total number of subjects
    517
    EEA total number of subjects
    318
    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)
    277
    From 65 to 84 years
    238
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 103 sites in 10 countries. Of these, 97 active sites randomized at least 1 subject. Overall 796 subjects were screened between October 2015 and August 2016, of whom 279 were screen failures. Screen failures were mainly due to exclusion criteria met or inclusion criteria not met.

    Pre-assignment
    Screening details
    		 Randomization was stratified by diabetes type (Type 1 diabetes mellitus [T1DM] versus Type 2 diabetes mellitus [T2DM]). Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 2:1 ratio (Alirocumab:Placebo). A total of 517 subjects were randomized. Baseline and efficacy data were analyzed per stratum.

    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
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W
    Arm description
    		 Alirocumab 75 mg subcutaneous (SC) injection every 2 weeks (Q2W) added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) 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
    		 Placebo Q2W
    Arm description
    		 Placebo (for alirocumab) SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (for alirocumab)
    Investigational medicinal product code
    Other name
    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.

    Number of subjects in period 1
    		Alirocumab 75 mg Q2W/Up to 150 mg Q2W Placebo Q2W
    Started
    345
    172
    Treated (Safety Population)
    344
    170
    ITT Population
    336
    167
    mITT Population
    333
    164
    T1DM Subjects
    51 [1]
    25 [2]
    T2DM Subjects
    294 [3]
    147 [4]
    Completed
    312
    157
    Not completed
    33
    15
         Other than specified above
    6
    2
         Adverse Event
    17
    4
         Randomized but not treated
    1
    2
         Death
    -
    1
         Subject did not wish to continue
    9
    4
         Poor compliance to study protocol
    -
    2
    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: T1DM subjects and T2DM subjects are strata of randomized arms. Total subjects of these 2 strata are greater than the number of subjects that completed, minus those who left.
    [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: T1DM subjects and T2DM subjects are strata of randomized arms. Total subjects of these 2 strata are greater than the number of subjects that completed, minus those who left.
    [3] - 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: T1DM subjects and T2DM subjects are strata of randomized arms. Total subjects of these 2 strata are greater than the number of subjects that completed, minus those who left.
    [4] - 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: T1DM subjects and T2DM subjects are strata of randomized arms. Total subjects of these 2 strata are greater than the number of subjects that completed, minus those who left.

    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 stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Placebo (for alirocumab) SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks.

    Reporting group values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Placebo Q2W Total
    Number of subjects
    		 345 172 517
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.6 ( 9.6 ) 63.2 ( 9.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 155 77 232
        Male
    		 190 95 285
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 14 8 22
        Not Hispanic or Latino
    		 330 163 493
        Unknown or Not Reported
    		 1 1 2
    Race
    Units: Subjects
        White/Caucasian
    		 309 159 468
        Black
    		 28 7 35
        Asian/Oriental
    		 7 3 10
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or other Pacific Islander
    		 0 0 0
        Other
    		 1 3 4
    Calculated LDL-C in mg/dL
    Calculated LDL-C in mg/dL from Friedewald formula (LDL cholesterol = Total cholesterol - high density lipoprotein [HDL] cholesterol-[Triglyceride/5])
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 113.1 ( 40.7 ) 109.6 ( 38.0 ) -
    Calculated LDL-C in mmol/L
    Calculated LDL-C in mmol/L from Friedewald formula (LDL cholesterol = Total cholesterol - HDL cholesterol - [Triglyceride/2.2]).
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.930 ( 1.053 ) 2.840 ( 0.984 ) -
    Subject analysis sets

    Subject analysis set title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Alirocumab 75 mg SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Subject analysis set title
    Placebo Q2W: T1DM Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo (for alirocumab) SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks.

    Subject analysis set title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Alirocumab 75 mg SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Subject analysis set title
    Placebo Q2W: T2DM Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo (for alirocumab) SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks.

    Subject analysis sets values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects
    51
    25
    294
    147
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.9 ( 10.1 )
    58.5 ( 7.8 )
    63.9 ( 8.9 )
    64.0 ( 9.4 )
    Gender categorical
    Units: Subjects
        Female
    22
    8
    133
    69
        Male
    29
    17
    161
    78
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1
    0
    13
    8
        Not Hispanic or Latino
    50
    25
    280
    138
        Unknown or Not Reported
    0
    0
    1
    1
    Race
    Units: Subjects
        White/Caucasian
    50
    24
    259
    135
        Black
    1
    0
    27
    7
        Asian/Oriental
    0
    0
    7
    3
        American Indian or Alaska Native
    0
    0
    0
    0
        Native Hawaiian or other Pacific Islander
    0
    0
    0
    0
        Other
    0
    1
    1
    2
    Calculated LDL-C in mg/dL
    Calculated LDL-C in mg/dL from Friedewald formula (LDL cholesterol = Total cholesterol - high density lipoprotein [HDL] cholesterol-[Triglyceride/5])
    Units: mg/dL
        arithmetic mean (standard deviation)
    126.4 ( 58.2 )
    110.2 ( 31.2 )
    110.8 ( 36.5 )
    109.6 ( 39.1 )
    Calculated LDL-C in mmol/L
    Calculated LDL-C in mmol/L from Friedewald formula (LDL cholesterol = Total cholesterol - HDL cholesterol - [Triglyceride/2.2]).
    Units: mmol/L
        arithmetic mean (standard deviation)
    3.273 ( 1.506 )
    2.853 ( 0.807 )
    2.871 ( 0.944 )
    2.838 ( 1.013 )

    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 stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Placebo (for alirocumab) SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks.

    Subject analysis set title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Alirocumab 75 mg SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Subject analysis set title
    Placebo Q2W: T1DM Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo (for alirocumab) SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks.

    Subject analysis set title
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Alirocumab 75 mg SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Subject analysis set title
    Placebo Q2W: T2DM Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Placebo (for alirocumab) SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT, insulin alone or with other antihyperglycemic drugs for 24 weeks.

    Primary: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 24 - 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 4 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 calculated LDL-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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: percent change
        least squares mean (standard error)
    -51.8 ( 3.7 )
    -3.9 ( 5.3 )
    -48.2 ( 1.6 )
    0.8 ( 2.2 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Alirocumab group was compared to placebo group using an appropriate contrast statement.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -47.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -60.7
         upper limit
    		 -35
    Notes
    [1] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Alirocumab group was compared to placebo group using an appropriate contrast statement.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    429
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.4
         upper limit
    		 -43.6
    Notes
    [2] - Threshold for significance at 0.05 level.

    Primary: Percentage of Subjects Who Experienced Treatment-Emergent Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects Who Experienced Treatment-Emergent Adverse Events (AEs) [3]
    End point description
    Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘treatment-emergent period’ (the time from the first dose of study drug up to the last dose of study drug +70 days). Safety population: all randomized subjects who received at least one dose or part of a dose of a study drug (treated).
    End point type
    Primary
    End point timeframe
    From Baseline up to 10 weeks after last study drug administration (maximum of 32 weeks)
    Notes
    [3] - 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: Safety analyses were descriptive in nature.
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Placebo Q2W
    Number of subjects analysed
    344
    170
    Units: percentage of subjects
    number (not applicable)
        Any AE
    64.5
    64.1
        Any Serious AE
    9.0
    9.4
        Any AE leading to death
    0
    0.6
        Any AE leading to treatment discontinuation
    4.9
    2.4
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
    End point description
    Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection). Modified ITT population (mITT): all randomized and treated subjects with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: percent change
        least squares mean (standard error)
    -53.8 ( 3.7 )
    -3.2 ( 5.3 )
    -50.9 ( 1.6 )
    0.7 ( 2.2 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level. Hierarchical testing procedure was followed for T1DM and T2DM subjects separately.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -50.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.4
         upper limit
    		 -37.9
    Notes
    [4] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -51.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56.9
         upper limit
    		 -46.4
    Notes
    [5] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Measured LDL-C at Week 24 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Measured LDL-C at Week 24 - 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 4 to Week 24 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline measured LDL-C value on- or off-treatment (Measured 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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    47
    22
    277
    139
    Units: percent change
        least squares mean (standard error)
    -49.4 ( 3.7 )
    -1.1 ( 5.4 )
    -43.3 ( 1.6 )
    2.4 ( 2.2 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -48.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.2
         upper limit
    		 -35.5
    Notes
    [6] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -45.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -50.9
         upper limit
    		 -40.4
    Notes
    [7] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
    End point description
    Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment at Week 12 (ITT population at Week 12).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    284
    140
    Units: percent change
        least squares mean (standard error)
    -49.4 ( 3.5 )
    -4.5 ( 5.0 )
    -48.8 ( 1.4 )
    1.4 ( 2.1 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -44.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56.9
         upper limit
    		 -32.8
    Notes
    [8] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subject
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -50.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.2
         upper limit
    		 -45.3
    Notes
    [9] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in Measured LDL-C at Week 12 - 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 4 to Week 24 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline measured LDL-C value on- or off-treatment at Week 12 (Measured LDL-C ITT population at Week 12).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    45
    22
    275
    136
    Units: percent change
        least squares mean (standard error)
    -46.7 ( 3.6 )
    -4.0 ( 5.1 )
    -44.8 ( 1.4 )
    -0.8 ( 2.0 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -42.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.9
         upper limit
    		 -30.5
    Notes
    [10] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -44.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49
         upper limit
    		 -39.2
    Notes
    [11] - Threshold for significance at 0.05 level.

    Secondary: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis

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    End point title
    		 Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - 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 4 to Week 24 regardless of status on- or off-treatment. Subjects of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment (non-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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: percent change
        least squares mean (standard error)
    -45.9 ( 3.3 )
    -3.2 ( 4.8 )
    -37.9 ( 1.4 )
    0.7 ( 2.0 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -42.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.2
         upper limit
    		 -31.3
    Notes
    [12] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    429
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -38.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.4
         upper limit
    		 -33.9
    Notes
    [13] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - 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 4 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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    47
    22
    279
    140
    Units: percent change
        least squares mean (standard error)
    -39.4 ( 3.0 )
    -0.4 ( 4.3 )
    -33.4 ( 1.3 )
    3.3 ( 1.7 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.4
         upper limit
    		 -28.7
    Notes
    [14] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -36.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.9
         upper limit
    		 -32.5
    Notes
    [15] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - 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 4 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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: percent change
        least squares mean (standard error)
    -29.9 ( 2.5 )
    -0.7 ( 3.6 )
    -26.8 ( 1.0 )
    0.8 ( 1.5 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -29.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.8
         upper limit
    		 -20.7
    Notes
    [16] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    429
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -27.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.2
         upper limit
    		 -24.1
    Notes
    [17] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis

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    End point title
    		 Percentage of Subjects Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
    End point description
    Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline data from Week 4 to Week 24 (i.e. up to 21 days after last injection). mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: percentage of subjects
        number (not applicable)
    70.2
    5.1
    76.4
    7.4
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum). Multiple imputation approach followed by logistic regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [18]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    117
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.1
         upper limit
    		 1041.8
    Notes
    [18] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum). Multiple imputation approach followed by logistic regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [19]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    84.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 36.5
         upper limit
    		 196.1
    Notes
    [19] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects Reaching Calculated LDL-C <50 mg/dL (1.3 mmol/L) at Week 24 - On-Treatment Analysis

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    End point title
    		 Percentage of Subjects Reaching Calculated LDL-C <50 mg/dL (1.3 mmol/L) at Week 24 - On-Treatment Analysis
    End point description
    Adjusted percentages at Week 24 from last observation carried forward (LOCF) approach (for T1DM subjects) and multiple imputation approach model (for T2DM subjects) including available post-baseline data from Week 4 to Week 24 (i.e. up to 21 days after last injection). The maximum likelihood estimate did not exist as response rate was zero in a treatment group of T1DM subjects. mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: percentage of subjects
        number (not applicable)
    55.1
    0
    50.7
    2.7
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Multiple imputation approach followed by logistic regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [20]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    52.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.6
         upper limit
    		 168.3
    Notes
    [20] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects Reaching Calculated Non-HDL-C <100 mg/dL at Week 24 - On-Treatment Analysis

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    End point title
    		 Percentage of Subjects Reaching Calculated Non-HDL-C <100 mg/dL at Week 24 - On-Treatment Analysis
    End point description
    Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline data from Week 4 to Week 24 (i.e. up to 21 days after last injection). Subjects of the mITT population with one baseline and at least one post-baseline Non-HDL-C value on-treatment (Non-HDL-C mITT population).
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: percentage of subjects
        number (not applicable)
    79.0
    22.9
    70.9
    13.8
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum). Multiple imputation approach followed by logistic regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [21]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    33.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8
         upper limit
    		 137.4
    Notes
    [21] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum). Multiple imputation approach followed by logistic regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [22]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    27.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.2
         upper limit
    		 51.5
    Notes
    [22] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects Reaching Calculated Non-HDL-C <80 mg/dL at Week 24 - On-Treatment Analysis

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    End point title
    		 Percentage of Subjects Reaching Calculated Non-HDL-C <80 mg/dL at Week 24 - On-Treatment Analysis
    End point description
    Adjusted percentages at Week 24 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection). Non-HDL-C mITT population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: percentage of subjects
        number (not applicable)
    59.6
    5.3
    52.3
    1.7
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum). Multiple imputation approach followed by logistic regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [23]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    55.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.5
         upper limit
    		 473.7
    Notes
    [23] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum). Multiple imputation approach followed by logistic regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [24]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    103.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 24.6
         upper limit
    		 433.1
    Notes
    [24] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach for handling of missing data followed by robust regression model. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were included in the imputation model. ITT 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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: percent change
        arithmetic mean (standard error)
    -23.0 ( 3.8 )
    -4.3 ( 5.3 )
    -19.0 ( 1.6 )
    -0.5 ( 2.2 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum). Multiple imputation approach followed by robust regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0039 [25]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -18.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.4
         upper limit
    		 -6
    Notes
    [25] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum). Multiple imputation approach followed by robust regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    429
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [26]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -18.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.7
         upper limit
    		 -13.2
    Notes
    [26] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in HDL-C at Week 24 - 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 4 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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: percent change
        least squares mean (standard error)
    11.2 ( 2.4 )
    7.3 ( 3.5 )
    8.1 ( 1.0 )
    3.7 ( 1.4 )
    Statistical analysis title
    		 Alirocumab:T1DM Subjects vs. Placebo:T1DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects v Placebo Q2W: T1DM Subjects
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3434 [27]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.2
         upper limit
    		 12
    Notes
    [27] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum).
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    429
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [28]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 7.7
    Notes
    [28] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
    End point description
    Adjusted means and standard errors at Week 24 from multiple imputation approach for handling of missing data followed by robust regression model including all available post-baseline data from Week 4 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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: percent change
        arithmetic mean (standard error)
    -13.6 ( 4.7 )
    1.9 ( 6.7 )
    -5.7 ( 2.0 )
    0.0 ( 2.7 )
    Statistical analysis title
    		 Alirocumab:T2DM Subjects vs. Placebo:T2DM Subjects
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant in relevant diabetes stratum). Multiple imputation approach followed by robust regression model.
    Comparison groups
    Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects v Placebo Q2W: T2DM Subjects
    Number of subjects included in analysis
    429
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0902 [29]
    Method
    		 Regression, Robust
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -5.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.3
         upper limit
    		 0.9
    Notes
    [29] - Threshold for significance at 0.05 level.

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

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    End point title
    		 Percent Change From Baseline in LDL-C Particle Number at Week 24 - 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 4 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 value 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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    45
    22
    272
    134
    Units: percent change
        least squares mean (standard error)
    -44.4 ( 3.2 )
    -4.4 ( 4.6 )
    -38.3 ( 1.3 )
    1.9 ( 1.9 )
    No statistical analyses for this end point

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

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    End point title
    		 Percent Change From Baseline in LDL-C Particle Size at Week 24 - ITT Analysis
    End point description
    LDL-C particle size was calculated from lipid subfractions by NMR spectroscopy. Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline data from Week 4 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 size value on- or off-treatment (LDL-C particle size 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: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    44
    22
    267
    134
    Units: percent change
        least squares mean (standard error)
    -2.3 ( 0.3 )
    0.8 ( 0.5 )
    -2.8 ( 0.1 )
    -0.3 ( 0.2 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Weeks 12 and 24 - ITT Analysis

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    End point title
    		 Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Weeks 12 and 24 - ITT Analysis
    End point description
    Absolute change = HbA1c value at specified weeks minus HbA1c value at baseline. ITT population. Here, 'n' = subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: percentage of hemoglobin
    arithmetic mean (standard deviation)
        Change at Week 12 (n=48, 22, 281, 138)
    0.00 ( 0.46 )
    -0.22 ( 0.39 )
    -0.04 ( 0.57 )
    0.00 ( 0.58 )
        Change at Week 24 (n=47, 22, 261, 135)
    -0.03 ( 0.60 )
    -0.23 ( 0.36 )
    0.18 ( 0.74 )
    0.06 ( 0.66 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in HbA1c at Weeks 12 and 24 - On-Treatment Analysis

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    End point title
    		 Absolute Change From Baseline in HbA1c at Weeks 12 and 24 - On-Treatment Analysis
    End point description
    Absolute change = HbA1c value at specified weeks minus HbA1c value at baseline. mITT population. Here, 'n' = subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: percentage of hemoglobin
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 48, 22, 275, 136)
    0.00 ( 0.46 )
    -0.22 ( 0.39 )
    -0.04 ( 0.57 )
    0.00 ( 0.59 )
        Change at Week 24 (n= 43, 20, 243, 129)
    -0.05 ( 0.61 )
    -0.27 ( 0.34 )
    0.18 ( 0.74 )
    0.06 ( 0.67 )
    No statistical analyses for this end point

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

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    End point title
    		 Absolute Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 12 and 24 - ITT Analysis
    End point description
    Absolute change = FPG value at specified weeks minus FPG value at baseline. ITT population. Here, 'n' = subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: mmol/L
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 46, 20, 278, 138)
    0.23 ( 4.44 )
    0.45 ( 4.73 )
    0.25 ( 2.73 )
    0.13 ( 2.73 )
        Change at Week 24 (n= 46, 22, 257, 135)
    0.52 ( 5.20 )
    0.81 ( 4.21 )
    0.52 ( 3.43 )
    0.55 ( 2.62 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in FPG at Weeks 12 and 24 - On-Treatment Analysis

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    End point title
    		 Absolute Change From Baseline in FPG at Weeks 12 and 24 - On-Treatment Analysis
    End point description
    Absolute change = FPG value at specified weeks minus FPG value at baseline. mITT population. Here, 'n' = subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: mmol/L
    arithmetic mean (standard deviation)
        Change at Week 12 (n=46, 20, 272, 136)
    0.23 ( 4.44 )
    0.45 ( 4.73 )
    0.22 ( 2.70 )
    0.15 ( 2.74 )
        Change at Week 24 (n= 42, 20, 240, 129)
    0.38 ( 5.24 )
    0.71 ( 4.19 )
    0.52 ( 3.47 )
    0.48 ( 2.53 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Total Daily Insulin Dose at Weeks 12 and 24 - ITT Analysis

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    End point title
    		 Absolute Change From Baseline in Total Daily Insulin Dose at Weeks 12 and 24 - ITT Analysis
    End point description
    Absolute change = total daily insulin dose at specified weeks minus baseline value. ITT population . Here, 'n' = subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: units (U)
    arithmetic mean (standard deviation)
        Change at Week 12 (n=47, 21, 279, 136)
    -10.0 ( 48.7 )
    -1.3 ( 9.6 )
    0.2 ( 7.9 )
    1.4 ( 11.4 )
        Change at Week 24 (n= 48, 23, 258, 130)
    -2.2 ( 11.3 )
    -0.8 ( 9.8 )
    2.2 ( 14.8 )
    1.6 ( 11.4 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Total Daily Insulin Dose at Weeks 12 and 24 - On-Treatment Analysis

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    End point title
    		 Absolute Change From Baseline in Total Daily Insulin Dose at Weeks 12 and 24 - On-Treatment Analysis
    End point description
    Absolute change = total daily insulin dose at specified weeks minus baseline value. mITT population. Here, 'n' = subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: units (U)
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 47, 21, 278, 135)
    -10.0 ( 48.7 )
    -1.3 ( 9.6 )
    0.2 ( 7.9 )
    1.4 ( 11.4 )
        Change at Week 24 (n=48, 23, 257, 129)
    -2.2 ( 11.3 )
    -0.8 ( 9.8 )
    1.7 ( 11.7 )
    1.6 ( 11.5 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Insulin Daily Dose/Kg at Weeks 12 and 24 - ITT Analysis

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    End point title
    		 Absolute Change From Baseline in Insulin Daily Dose/Kg at Weeks 12 and 24 - ITT Analysis
    End point description
    Absolute change = daily insulin dose/kg at specified weeks minus baseline value. ITT population . Here, 'n' = subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: U/kg
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 47, 21, 279, 136)
    -0.1 ( 0.5 )
    0.0 ( 0.1 )
    0.0 ( 0.1 )
    0.0 ( 0.1 )
        Change at Week 24 (n= 48, 23, 258, 130)
    0.0 ( 0.1 )
    0.0 ( 0.1 )
    0.0 ( 0.2 )
    0.0 ( 0.1 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Insulin Daily Dose/Kg at Weeks 12 and 24 - On-Treatment Analysis

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    End point title
    		 Absolute Change From Baseline in Insulin Daily Dose/Kg at Weeks 12 and 24 - On-Treatment Analysis
    End point description
    Absolute change = daily insulin dose/kg at specified weeks minus baseline value. mITT population. Here, 'n' = subjects with available data at the specified time points for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: U/kg
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 47, 21, 278, 135)
    -0.1 ( 0.5 )
    0.0 ( 0.1 )
    0.0 ( 0.1 )
    0.0 ( 0.1 )
        Change at Week 24 (n= 48, 23, 257, 129)
    0.0 ( 0.1 )
    0.0 ( 0.1 )
    0.0 ( 0.1 )
    0.0 ( 0.1 )
    No statistical analyses for this end point

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

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    End point title
    		 Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Weeks 12 and 24 - 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 weeks minus baseline value. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    25
    287
    142
    Units: glucose lowering treatments
    arithmetic mean (standard deviation)
        Change at week 12
    0 ( 0 )
    0 ( 0 )
    0 ( 0.1 )
    0 ( 0.2 )
        Change at Week 24
    0 ( 0 )
    0 ( 0 )
    0 ( 0.3 )
    0 ( 0.2 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Weeks 12 and 24 - On-Treatment Analysis

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    End point title
    		 Absolute Change From Baseline in Number of Glucose-Lowering Treatments at Weeks 12 and 24 - On-Treatment 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 weeks minus baseline value. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12 and 24
    End point values
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T1DM Subjects Placebo Q2W: T1DM Subjects Alirocumab 75 mg Q2W/Up to 150 mg Q2W: T2DM Subjects Placebo Q2W: T2DM Subjects
    Number of subjects analysed
    49
    24
    284
    140
    Units: glucose lowering treatments
    arithmetic mean (standard deviation)
        Change at Week 12
    0 ( 0 )
    0 ( 00 )
    0 ( 0.1 )
    0 ( 0.2 )
        Change at Week 24
    0 ( 0 )
    0 ( 0 )
    0 ( 0.3 )
    0 ( 0.2 )
    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 final visit (Week 32) in the study regardless of seriousness or relationship to study drugs.
    Adverse event reporting additional description
    Reported AEs and deaths are TEAEs that is 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
    19.1
    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 stable, maximally tolerated dose of statin therapy with or without other LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.

    Reporting group title
    Placebo Q2W
    Reporting group description
    		 Placebo (for alirocumab) SC injection Q2W added to stable, maximally tolerated dose of statin therapy with or without other LMT for 24 weeks.

    Serious adverse events
    		 Alirocumab 75 mg Q2W/Up to 150 mg Q2W Placebo Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 344 (9.01%)
    16 / 170 (9.41%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma Pancreas
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's Disease
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Cancer Metastatic
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (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
    Influenza Like Illness
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural Hypotension
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 344 (0.29%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic Valve Stenosis
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Occlusion
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Cardiomyopathy
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid Arteriosclerosis
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudoradicular Syndrome
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radicular Syndrome
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (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
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous Haemorrhage
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Haemorrhage
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (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
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mixed Connective Tissue Disease
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral Foraminal Stenosis
         subjects affected / exposed
    2 / 344 (0.58%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter Gastroenteritis
         subjects affected / exposed
    0 / 344 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Foot Infection
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (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 / 344 (0.29%)
    0 / 170 (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
    1 / 344 (0.29%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 344 (0.29%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 344 (0.58%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         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 Placebo Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 344 (4.94%)
    9 / 170 (5.29%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    17 / 344 (4.94%)
    9 / 170 (5.29%)
         occurrences all number
    18
    9

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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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