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    Clinical Trial Results:
    Effect and safety of liraglutide 3.0 mg in subjects with overweight or obesity and type 2 diabetes mellitus treated with basal insulin

    Summary
    EudraCT number
    2015-005619-33
    Trial protocol
    DE   IT  
    Global end of trial date
    25 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Oct 2019
    First version publication date
    04 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN8022-4272
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02963922
    WHO universal trial number (UTN)
    U1111-1177-4903
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.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
    04 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm superiority of liraglutide 3.0 mg vs. placebo, as an adjunct to a reduced-calorie diet and increased physical activity, on weight loss effectiveness in subjects with overweight or obesity and T2DM treated with a basal insulin and up to 2 OAD medications (metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, glinide or sulphonylurea).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, ICH GCP and FDA 21 CFR 312.120. In addition, the 21 Code of Federal Regulations, parts 312, 50, and 56 were followed.
    Background therapy
    The following products were regarded as non-investigational medicinal products (non-IMPs) in this trial: Oral antidiabetic drugs (OADs) and insulin. OADs: Subjects were allowed to take the following OADs throughout the treatment period: Any approved and marketed metformin, glitazone, SGLT-2 inhibitor, alpha glucosidase inhibitor, glinide or sulphonylurea product or combination products.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    06 Feb 2017
    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
    Canada: 44
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Mexico: 44
    Country: Number of subjects enrolled
    Turkey: 51
    Country: Number of subjects enrolled
    United States: 152
    Worldwide total number of subjects
    396
    EEA total number of subjects
    83
    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)
    293
    From 65 to 84 years
    103
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 53 sites in Canada (7), Germany (7), Israel (6), Italy (4), Mexico (2), Turkey (7) and United States (20).

    Pre-assignment
    Screening details
    Subjects were randomised in a 1:1 manner to receive either liraglutide or placebo as an adjunct to a reduced-calorie diet and increased physical activity as part of a comprehensive lifestyle intervention program.

    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
    Blinding implementation details
    Liraglutide and placebo were visually identical in order to ensure double-blinding in the trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Liraglutide 3.0 mg
    Arm description
    Subjects received liraglutide subcutaneous injections for 56 weeks. The starting dose was 0.6 milligrams (mg) for the first week. The dose was then escalated in weekly increments of 0.6 mg until the maintenance dose of 3.0 mg was reached after 4 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Saxenda®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide was administered once daily by subcutaneous injection irrespective of the timing of meals for 56 weeks. Subjects received 0.6 mg liraglutide during the first week. The dose was escalated in weekly increments of 0.6 mg until the maintenance dose of 3.0 mg was reached after 4 weeks.

    Arm title
    Placebo
    Arm description
    Subjects received matching placebo once daily by subcutaneous injection for 56 weeks. Dose escalation for placebo matched that of liraglutide.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo was administered once daily by subcutaneous injection irrespective of the timing of meals for 56 weeks. Dose escalation for placebo matched that of liraglutide.

    Number of subjects in period 1
    Liraglutide 3.0 mg Placebo
    Started
    198
    198
    Completed
    166
    168
    Not completed
    32
    30
         Adverse event, non-fatal
    15
    6
         Protocol deviation
    6
    6
         Unclassified
    8
    14
         Lost to follow-up
    2
    3
         Lack of efficacy
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Liraglutide 3.0 mg
    Reporting group description
    Subjects received liraglutide subcutaneous injections for 56 weeks. The starting dose was 0.6 milligrams (mg) for the first week. The dose was then escalated in weekly increments of 0.6 mg until the maintenance dose of 3.0 mg was reached after 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received matching placebo once daily by subcutaneous injection for 56 weeks. Dose escalation for placebo matched that of liraglutide.

    Reporting group values
    Liraglutide 3.0 mg Placebo Total
    Number of subjects
    198 198 396
    Age Categorical
    Units: Subjects
        Adults (18- <65 years)
    151 142 293
        From 65- <75 years
    42 48 90
        75- <85 years
    5 8 13
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    55.9 ± 11.3 57.6 ± 10.4 -
    Gender Categorical
    Units: Subjects
        Female
    108 99 207
        Male
    90 99 189
    Body weight
    Units: Kilograms (kg)
        arithmetic mean (standard deviation)
    100.6 ± 20.8 98.9 ± 19.9 -

    End points

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    End points reporting groups
    Reporting group title
    Liraglutide 3.0 mg
    Reporting group description
    Subjects received liraglutide subcutaneous injections for 56 weeks. The starting dose was 0.6 milligrams (mg) for the first week. The dose was then escalated in weekly increments of 0.6 mg until the maintenance dose of 3.0 mg was reached after 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received matching placebo once daily by subcutaneous injection for 56 weeks. Dose escalation for placebo matched that of liraglutide.

    Primary: Change in body weight (%)

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    End point title
    Change in body weight (%)
    End point description
    Change in body weight from baseline (week 0) to week 56 was evaluated based on full analysis set (FAS) in-trial data and on-drug data. FAS includes all randomised subjects. In-trial observation period: the uninterrupted time interval from the date of randomisation until and including the date of the follow-up visit or date of last contact. On-drug observation period: includes all time intervals in which subjects are considered to be on treatment from the date of first trial product administration to 7 days (or 14 days for adverse events [AEs]) after the final trial product administration, excluding potential off-treatment time intervals triggered by at least 7 consecutive missed doses (or 14 consecutive missed doses for AEs). 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Primary
    End point timeframe
    From baseline to week 56
    End point values
    Liraglutide 3.0 mg Placebo
    Number of subjects analysed
    198
    198
    Units: Percentage of body weight
    arithmetic mean (standard deviation)
        In-trial observation period (n=191,193)
    -6.0 ± 6.0
    -1.5 ± 5.4
        On-drug observation period (n=163,168)
    -6.5 ± 5.8
    -1.7 ± 5.2
    Statistical analysis title
    Liraglutide 3.0 mg vs Placebo
    Statistical analysis description
    Analysis of in-trial data with missing observations imputed from placebo arm based on jump to reference multiple (x100) imputation approach. Week 56 responses were analysed using an analysis of covariance model with treatment, body mass index (BMI) groups and sex as factors and baseline body weight as covariate. The treatment policy estimand evaluated treatment effect (liraglutide 3.0 mg vs placebo) at week 56 for all randomised subjects regardless of premature discontinuation of trial product.
    Comparison groups
    Placebo v Liraglutide 3.0 mg
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Treatment difference
    Point estimate
    -4.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.48
         upper limit
    -3.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.59
    Statistical analysis title
    Liraglutide 3.0 mg vs Placebo
    Statistical analysis description
    Analysis of on-drug before first drug discontinuation date using a mixed model for repeated measurements with treatment, BMI groups and sex as factors and baseline body weight as covariate, all nested within visit. The hypothetical estimand evaluated the treatment effect (liraglutide 3.0 mg vs placebo) for all randomised subjects assuming that all subjects remained on trial product (on-treatment principle).
    Comparison groups
    Liraglutide 3.0 mg v Placebo
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed model for repeated measurements
    Parameter type
    Treatment difference
    Point estimate
    -5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.3
         upper limit
    -3.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61

    Primary: Proportion of subjects losing at least 5% of baseline body weight

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    End point title
    Proportion of subjects losing at least 5% of baseline body weight
    End point description
    The estimated percentage of subjects losing at least 5% of baseline (week 0) body weight at week 56 was presented based on FAS in-trial data and on-drug data. In-trial observation period: the uninterrupted time interval from the date of randomisation until and including the date of the follow-up visit or date of last contact. On-drug observation period: includes all time intervals in which participants are considered to be on treatment from the date of first trial product administration to 7 days (or 14 days for adverse events [AEs]) after the final trial product administration, excluding potential off-treatment time intervals triggered by at least 7 consecutive missed doses (or 14 consecutive missed doses for AEs). 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Primary
    End point timeframe
    Week 56
    End point values
    Liraglutide 3.0 mg Placebo
    Number of subjects analysed
    198
    198
    Units: Percentage of subjects
    number (not applicable)
        In-trial observation period (n=191,193)
    51.80
    23.98
        On-drug observation period (n=195,197)
    56.92
    21.83
    Statistical analysis title
    Liraglutide 3.0 mg vs Placebo
    Statistical analysis description
    Analysis of in-trial data with missing observations imputed from the placebo arm based on a jump to reference multiple (x100) imputation approach. Week 56 responses were analysed using a logistic regression model with treatment, BMI groups and sex as factors and baseline body weight as covariate.
    Comparison groups
    Liraglutide 3.0 mg v Placebo
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.19
         upper limit
    5.31
    Statistical analysis title
    Liraglutide 3.0 mg vs Placebo
    Statistical analysis description
    Analysis of on-drug before first drug discontinuation date using a mixed model for repeated measurements with treatment, BMI groups and sex as factors and baseline body weight as covariate, all nested within visit. The MMRM was used to classify responders and analysed with a logistic regression with treatment as the only factor.
    Comparison groups
    Liraglutide 3.0 mg v Placebo
    Number of subjects included in analysis
    396
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed model for repeated measurements
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.04
         upper limit
    7.36

    Secondary: Proportion of subjects losing more than 10% of baseline body weight

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    End point title
    Proportion of subjects losing more than 10% of baseline body weight
    End point description
    The estimated percentage of subjects losing more than 10% of baseline (week 0) body weight at week 56 was presented based on FAS in-trial data and on-drug data. In-trial observation period: the uninterrupted time interval from the date of randomisation until and including the date of the follow-up visit or date of last contact. On-drug observation period: includes all time intervals in which participants are considered to be on treatment from the date of first trial product administration to 7 days (or 14 days for adverse events [AEs]) after the final trial product administration, excluding potential off-treatment time intervals triggered by at least 7 consecutive missed doses (or 14 consecutive missed doses for AEs). 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Secondary
    End point timeframe
    Week 56
    End point values
    Liraglutide 3.0 mg Placebo
    Number of subjects analysed
    198
    198
    Units: Percentage of subjects
    number (not applicable)
        In-trial observation period (n=191,193)
    22.77
    6.55
        On-drug observation period (n=195,197)
    22.56
    5.58
    No statistical analyses for this end point

    Secondary: Change in waist circumference

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    End point title
    Change in waist circumference
    End point description
    Change in waist circumference from baseline (week 0) to week 56 was presented based on FAS in-trial data and on-drug data. In-trial observation period: the uninterrupted time interval from the date of randomisation until and including the date of the follow-up visit or date of last contact. On-drug observation period: includes all time intervals in which subjects are considered to be on treatment from the date of first trial product administration to 7 days (or 14 days for AEs) after the final trial product administration, excluding potential off-treatment time intervals triggered by at least 7 consecutive missed doses (or 14 consecutive missed doses for AEs). 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Liraglutide 3.0 mg Placebo
    Number of subjects analysed
    198
    198
    Units: Centimeters (cm)
    arithmetic mean (standard deviation)
        In-trial observation period (n=189,193)
    -5.40 ± 6.06
    -2.60 ± 5.72
        On-drug observation period (n=163,168)
    -5.71 ± 6.05
    -2.78 ± 5.63
    No statistical analyses for this end point

    Secondary: Change in HbA1c

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    End point title
    Change in HbA1c
    End point description
    Change in glycosylated haemoglobin (HbA1c) from baseline (week 0) to week 56 was presented based on FAS in-trial data and on-drug data. In-trial observation period: the uninterrupted time interval from the date of randomisation until and including the date of the follow-up visit or date of last contact. On-drug observation period: includes all time intervals in which subjects are considered to be on treatment from the date of first trial product administration to 7 days (or 14 days for AEs) after the final trial product administration, excluding potential off-treatment time intervals triggered by at least 7 consecutive missed doses (or 14 consecutive missed doses for AEs). 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Liraglutide 3.0 mg Placebo
    Number of subjects analysed
    198
    198
    Units: Percentage of HbA1c
    arithmetic mean (standard deviation)
        In-trial observation period (n=187,188)
    -1.1 ± 1.2
    -0.5 ± 1.2
        On-drug observation period (n=160,164)
    -1.2 ± 1.1
    -0.7 ± 1.0
    No statistical analyses for this end point

    Secondary: Change in fasting plasma glucose

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    End point title
    Change in fasting plasma glucose
    End point description
    Change from baseline (week 0) in fasting plasma glucose (FPG) was presented based on FAS in-trial data and on-drug data. In-trial observation period: the uninterrupted time interval from the date of randomisation until and including the date of the follow-up visit or date of last contact. On-drug observation period: includes all time intervals in which subjects are considered to be on treatment from the date of first trial product administration to 7 days (or 14 days for AEs) after the final trial product administration, excluding potential off-treatment time intervals triggered by at least 7 consecutive missed doses (or 14 consecutive missed doses for AEs). 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Liraglutide 3.0 mg Placebo
    Number of subjects analysed
    198
    198
    Units: Millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        In-trial observation period (n=187,188)
    -0.91 ± 3.13
    -0.68 ± 3.04
        On-drug observation period (n=162,165)
    -1.05 ± 3.08
    -0.96 ± 2.68
    No statistical analyses for this end point

    Secondary: Change in Short Form-36 (SF-36) v2.0 acute, physical functioning score

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    End point title
    Change in Short Form-36 (SF-36) v2.0 acute, physical functioning score
    End point description
    SF-36 is a 36-item patient-reported survey of patient health that measures the subject's overall health-related quality of life (HRQoL). SF-36v2™ questionnaire measured the HRQoL on 8 domains on individual scale ranges. The scores 0-100 (where higher scores indicated a better HRQoL) from the SF-36 were converted to norm-based scores to enable a direct interpretation in relation to the distribution of the scores in the 2009 U.S. general population. A norm-based score of 50 corresponds to the mean score and 10 corresponds to the standard deviation of the 2009 U.S. general population. Change from baseline (week 0) in SF-36 physical functioning score was presented based on FAS in-trial data and on-drug data. A positive change score indicates an improvement since baseline. 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Liraglutide 3.0 mg Placebo
    Number of subjects analysed
    198
    198
    Units: Score on a scale
    arithmetic mean (standard deviation)
        In-trial observation period (n=186,187)
    2.5 ± 7.9
    2.6 ± 7.3
        On-drug observation period (n=161,167)
    2.9 ± 7.8
    2.5 ± 7.1
    No statistical analyses for this end point

    Secondary: Change in Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT), physical function domain (5-items) score

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    End point title
    Change in Impact of Weight on Quality of Life-Lite for Clinical Trial Version (IWQoL-Lite for CT), physical function domain (5-items) score
    End point description
    IWQoL-Lite for CT is a modified version of an instrument designed to assess weight-related quality of life. The scores ranged between 0-100 where higher scores indicated a better quality of life. A positive change score indicates an improvement since baseline. The endpoint was presented based on FAS in-trial data and on-drug data. In-trial observation period: the uninterrupted time interval from the date of randomisation until and including the date of the follow-up visit or date of last contact. On-drug observation period: includes all time intervals in which subjects are considered to be on treatment from the date of first trial product administration to 7 days (or 14 days for AEs) after the final trial product administration, excluding potential off-treatment time intervals triggered by at least 7 consecutive missed doses (or 14 consecutive missed doses for AEs). 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Liraglutide 3.0 mg Placebo
    Number of subjects analysed
    198
    198
    Units: Score on a scale
    arithmetic mean (standard deviation)
        In-trial observation period (n=186,187)
    7.3 ± 22.5
    6.8 ± 21.5
        On-drug observation period (n=161,167)
    8.2 ± 20.9
    6.5 ± 21.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of first dose of trial product (week 0) to end of treatment (week 56) + post treatment follow-up of 30 days.
    Adverse event reporting additional description
    Evaluation of safety was based on SAS comprised of all randomised subjects who received at least one dose of trial product. AEs with onset during the on-treatment period were considered treatment-emergent. ‘Number of deaths causally related to treatment’ is the data considered to present under ‘total number of deaths resulting from adverse events’.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Liraglutide 3.0 mg
    Reporting group description
    Subjects received liraglutide subcutaneous injections for 56 weeks. The starting dose was 0.6 milligrams (mg) for the first week. The dose was then escalated in weekly increments of 0.6 mg until the maintenance dose of 3.0 mg was reached after 4 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received matching placebo once daily by subcutaneous injection for 56 weeks. Dose escalation for placebo matched that of liraglutide.

    Serious adverse events
    Liraglutide 3.0 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 195 (8.21%)
    19 / 197 (9.64%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Lipoma excision
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (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
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metaphyseal corner fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postpericardiotomy syndrome
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention postoperative
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 195 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         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 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Relapsing-remitting multiple sclerosis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (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 disorder
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (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
    2 / 195 (1.03%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 197 (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
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Liraglutide 3.0 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    162 / 195 (83.08%)
    141 / 197 (71.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 195 (2.05%)
    12 / 197 (6.09%)
         occurrences all number
    4
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 195 (6.67%)
    7 / 197 (3.55%)
         occurrences all number
    18
    7
    Headache
         subjects affected / exposed
    29 / 195 (14.87%)
    29 / 197 (14.72%)
         occurrences all number
    36
    47
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 195 (7.18%)
    10 / 197 (5.08%)
         occurrences all number
    18
    11
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    11 / 195 (5.64%)
    8 / 197 (4.06%)
         occurrences all number
    17
    11
    Abdominal pain upper
         subjects affected / exposed
    12 / 195 (6.15%)
    8 / 197 (4.06%)
         occurrences all number
    17
    9
    Constipation
         subjects affected / exposed
    28 / 195 (14.36%)
    17 / 197 (8.63%)
         occurrences all number
    36
    21
    Diarrhoea
         subjects affected / exposed
    45 / 195 (23.08%)
    30 / 197 (15.23%)
         occurrences all number
    77
    54
    Dyspepsia
         subjects affected / exposed
    12 / 195 (6.15%)
    5 / 197 (2.54%)
         occurrences all number
    13
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    10 / 195 (5.13%)
    2 / 197 (1.02%)
         occurrences all number
    12
    2
    Nausea
         subjects affected / exposed
    58 / 195 (29.74%)
    23 / 197 (11.68%)
         occurrences all number
    105
    27
    Vomiting
         subjects affected / exposed
    32 / 195 (16.41%)
    12 / 197 (6.09%)
         occurrences all number
    53
    13
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    7 / 195 (3.59%)
    10 / 197 (5.08%)
         occurrences all number
    7
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 195 (6.15%)
    24 / 197 (12.18%)
         occurrences all number
    14
    37
    Back pain
         subjects affected / exposed
    13 / 195 (6.67%)
    12 / 197 (6.09%)
         occurrences all number
    13
    17
    Osteoarthritis
         subjects affected / exposed
    6 / 195 (3.08%)
    12 / 197 (6.09%)
         occurrences all number
    9
    13
    Pain in extremity
         subjects affected / exposed
    16 / 195 (8.21%)
    19 / 197 (9.64%)
         occurrences all number
    17
    21
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    15 / 195 (7.69%)
    5 / 197 (2.54%)
         occurrences all number
    15
    5
    Influenza
         subjects affected / exposed
    12 / 195 (6.15%)
    22 / 197 (11.17%)
         occurrences all number
    14
    26
    Nasopharyngitis
         subjects affected / exposed
    42 / 195 (21.54%)
    36 / 197 (18.27%)
         occurrences all number
    48
    49
    Sinusitis
         subjects affected / exposed
    9 / 195 (4.62%)
    10 / 197 (5.08%)
         occurrences all number
    11
    11
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 195 (12.31%)
    29 / 197 (14.72%)
         occurrences all number
    32
    37
    Urinary tract infection
         subjects affected / exposed
    7 / 195 (3.59%)
    19 / 197 (9.64%)
         occurrences all number
    12
    22
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 195 (9.74%)
    5 / 197 (2.54%)
         occurrences all number
    24
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jan 2017
    Key changes: 1. Addition of bicarbonate as a part of the biochemistry laboratory assessment 2. Updated the wording in reporting of insulin dose and transcription of insulin dose to eCRF 3. Updated the time period of an eye examination performed prior to randomisation.
    18 Apr 2017
    Key changes: 1. Clarification of the criteria to allow two additional oral antidiabetic drug (OAD) classes- alpha glucosidase inhibitors and glinides 2. Clarification of the criteria to continue on their standard insulin treatment.
    09 Apr 2018
    Key changes: 1. Included the Short-form 36 (SF-36) 2.0 questionnaire as a confirmatory secondary endpoint 2. Systolic blood pressure has been added as a supportive secondary endpoint.

    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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