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    Clinical Trial Results:
    Efficacy in controlling glycaemia with Victoza® (liraglutide) as add-on to metformin vs. OADs as add-on to metformin after up to 104 weeks of treatment in subjects with type 2 diabetes inadequately controlled with metformin monotherapy and treated in a primary care setting. A 104-week randomised, phase 4, two-arm, open-label, active-controlled, multicentre, multinational, parallel-group trial.

    Summary
    EudraCT number
    		 2015-002417-29
    Trial protocol
    		 LV  
    Global end of trial date
    12 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Aug 2020
    First version publication date
    19 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN2211-4232
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02730377
    WHO universal trial number (UTN)
    		 U1111-1170-7035
    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, +1 866 8677178, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, +1 866 8677178, 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
    24 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy in controlling glycaemia with Victoza® (liraglutide) as add-on to metformin vs. oral antidiabetic drugs (OADs) as add-on to metformin after up to 104 weeks of treatment in subjects with type 2 diabetes (T2D) treated in primary care, inadequately controlled with metformin monotherapy.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice including archiving of essential document.
    Background therapy
    		 Subjects were to continue their pre-trial metformin treatment maintained at the pre-trial dose and frequency during the entire trial treatment period unless there was a safety concern.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    28 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Latvia: 30
    Country: Number of subjects enrolled
    Canada: 102
    Country: Number of subjects enrolled
    Colombia: 30
    Country: Number of subjects enrolled
    India: 207
    Country: Number of subjects enrolled
    Lebanon: 20
    Country: Number of subjects enrolled
    Russian Federation: 85
    Country: Number of subjects enrolled
    Serbia: 60
    Country: Number of subjects enrolled
    Turkey: 33
    Country: Number of subjects enrolled
    United States: 1424
    Worldwide total number of subjects
    1991
    EEA total number of subjects
    30
    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)
    1490
    From 65 to 84 years
    495
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 219 sites in Canada (11), Colombia (3), India (16), Latvia (2), Lebanon (4), Russian Federation (5), Serbia (6), Turkey (4) and the United States (168).

    Pre-assignment
    Screening details
    		 Subjects were randomised in a 1:1 manner to receive either liraglutide or an oral antidiabetic drug (OAD) both as add-on to background therapy with metformin.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Liraglutide 1.8 mg
    Arm description
    		 Subjects were to receive a subcutaneous injection of liraglutide once daily. Subjects received 0.6 milligrams (mg) liraglutide during the first week. The dose was escalated in weekly increments of 0.6 mg until the dose of 1.8 mg was reached. The treatment period was 104 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Victoza
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received s.c. injection of 0.6 mg liraglutide during the first week. The dose was escalated in weekly increments of 0.6 mg until the dose of 1.8 mg was reached. A maintenance dose of 1.2 mg was accepted if the subject’s HbA1c was < 7.0% (53 millimoles per mole [mmol/mol]), however, escalation to 1.8 mg was to be attempted if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Arm title
    		 Oral antidiabetic drug
    Arm description
    		 Subjects were to receive one selected OAD. The following OADs were allowed: alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinides, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, sulfonylureas or thiazolidinediones. The treatment period was 104 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received sitagliptin 100 mg tablets once daily. The dose was escalated to the maximum approved or maximum tolerated dose according to approved local label at the discretion of the investigator. A maintenance dose below the maximum approved or maximum tolerated dose was acceptable if the subject’s HbA1c was <7.0% (53 mmol/mol). However, escalation to the maximum approved or maximum tolerated dose was to be attempted, at the discretion of the investigator, if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Investigational medicinal product name
    Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 5 mg of linagliptin in total during the treatment period. The dose was escalated to the maximum approved or maximum tolerated dose according to approved local label at the discretion of the investigator. A maintenance dose below the maximum approved or maximum tolerated dose was acceptable if the subject’s HbA1c was <7.0% (53 mmol/mol). However, escalation to the maximum approved or maximum tolerated dose was to be attempted, at the discretion of the investigator, if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Investigational medicinal product name
    Saxagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 5 mg of saxagliptin per day orally. The dose was escalated to the maximum approved or maximum tolerated dose according to approved local label at the discretion of the investigator. A maintenance dose below the maximum approved or maximum tolerated dose was acceptable if the subject’s HbA1c was <7.0% (53 mmol/mol). However, escalation to the maximum approved or maximum tolerated dose was to be attempted, at the discretion of the investigator, if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Investigational medicinal product name
    Vildagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 100 mg of vildagliptin per day orally. The dose was escalated to the maximum approved or maximum tolerated dose according to approved local label at the discretion of the investigator. A maintenance dose below the maximum approved or maximum tolerated dose was acceptable if the subject’s HbA1c was <7.0% (53 mmol/mol). However, escalation to the maximum approved or maximum tolerated dose was to be attempted, at the discretion of the investigator, if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg of dapagliflozin per day orally. The dose was escalated to the maximum approved or maximum tolerated dose according to approved local label at the discretion of the investigator. A maintenance dose below the maximum approved or maximum tolerated dose was acceptable if the subject’s HbA1c was <7.0% (53 mmol/mol). However, escalation to the maximum approved or maximum tolerated dose was to be attempted, at the discretion of the investigator, if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 25 mg of empagliflozin per day orally. The dose was escalated to the maximum approved or maximum tolerated dose according to approved local label at the discretion of the investigator. A maintenance dose below the maximum approved or maximum tolerated dose was acceptable if the subject’s HbA1c was <7.0% (53 mmol/mol). However, escalation to the maximum approved or maximum tolerated dose was to be attempted, at the discretion of the investigator, if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Investigational medicinal product name
    Gliclazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 120 mg of gliclazide per day orally. The dose was escalated to the maximum approved or maximum tolerated dose according to approved local label at the discretion of the investigator. A maintenance dose below the maximum approved or maximum tolerated dose was acceptable if the subject’s HbA1c was <7.0% (53 mmol/mol). However, escalation to the maximum approved or maximum tolerated dose was to be attempted, at the discretion of the investigator, if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 6 mg of glimepiride per day orally. The dose was escalated to the maximum approved or maximum tolerated dose according to approved local label at the discretion of the investigator. A maintenance dose below the maximum approved or maximum tolerated dose was acceptable if the subject’s HbA1c was <7.0% (53 mmol/mol). However, escalation to the maximum approved or maximum tolerated dose was to be attempted, at the discretion of the investigator, if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Investigational medicinal product name
    Pioglitazone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 45 mg of pioglitazone per day orally. The dose was escalated to the maximum approved or maximum tolerated dose according to approved local label at the discretion of the investigator. A maintenance dose below the maximum approved or maximum tolerated dose was acceptable if the subject’s HbA1c was <7.0% (53 mmol/mol). However, escalation to the maximum approved or maximum tolerated dose was to be attempted, at the discretion of the investigator, if the subjects’ HbA1c was ≥ 7% (53 mmol/mol).

    Number of subjects in period 1
    		Liraglutide 1.8 mg Oral antidiabetic drug
    Started
    996
    995
    Treated
    980
    984
    Full analysis set (FAS)
    996
    995
    Safety analysis set (SAS)
    980
    984
    Completed
    446
    362
    Not completed
    550
    633
         Adverse event, serious fatal
    1
    8
         Consent withdrawn by subject
    45
    42
         Adverse event, non-fatal
    79
    41
         Pregnancy
    -
    1
         Inadequate glycaemic control
    368
    473
         Unspecified
    5
    4
         Lost to follow-up
    25
    21
         Lack of efficacy
    4
    13
         Protocol deviation
    23
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Subjects were to receive a subcutaneous injection of liraglutide once daily. Subjects received 0.6 milligrams (mg) liraglutide during the first week. The dose was escalated in weekly increments of 0.6 mg until the dose of 1.8 mg was reached. The treatment period was 104 weeks.

    Reporting group title
    Oral antidiabetic drug
    Reporting group description
    		 Subjects were to receive one selected OAD. The following OADs were allowed: alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinides, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, sulfonylureas or thiazolidinediones. The treatment period was 104 weeks.

    Reporting group values
    		 Liraglutide 1.8 mg Oral antidiabetic drug Total
    Number of subjects
    		 996 995 1991
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.6 ( 11.0 ) 57.1 ( 10.7 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 476 471 947
        Male
    		 520 524 1044

    End points

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    End points reporting groups
    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Subjects were to receive a subcutaneous injection of liraglutide once daily. Subjects received 0.6 milligrams (mg) liraglutide during the first week. The dose was escalated in weekly increments of 0.6 mg until the dose of 1.8 mg was reached. The treatment period was 104 weeks.

    Reporting group title
    Oral antidiabetic drug
    Reporting group description
    		 Subjects were to receive one selected OAD. The following OADs were allowed: alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinides, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, sulfonylureas or thiazolidinediones. The treatment period was 104 weeks.

    Primary: Time to inadequate glycaemic control defined as HbA1c > 7.0% (53 mmol/mol) at two scheduled consecutive visits

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    End point title
    		 Time to inadequate glycaemic control defined as HbA1c > 7.0% (53 mmol/mol) at two scheduled consecutive visits
    End point description
    Inadequate glycaemic control was defined as glycosylated haemoglobin (HbA1c) of 7.0% (53 mmol/mol) or greater at two consecutive visits after the first 26 weeks of treatment and up to 104 weeks. 25%, median (50%) and 75% percentiles for the cumulative distribution function, are obtained from the Kaplan-Meier survival function. HbA1c was recorded at weeks 38, 52, 65, 78, 91 and 104. Results are based on the full analysis set (FAS) which included all randomised subjects. Number of subjects analysed = subjects with available data.
    End point type
    Primary
    End point timeframe
    After the first 26 weeks of treatment and up to 104 weeks
    End point values
    		 Liraglutide 1.8 mg Oral antidiabetic drug
    Number of subjects analysed
    416
    547
    Units: Weeks
        median (inter-quartile range (Q1-Q3))
    108.9 (37.7 to 99999)
    64.9 (35.4 to 107.4)
    Statistical analysis title
    		 Liraglutide 1.8 mg vs Oral antidiabetic drug
    Statistical analysis description
    Test for no treatment difference is based on using a generalised log-rank test for interval censored failure time data.
    Comparison groups
    Liraglutide 1.8 mg v Oral antidiabetic drug
    Number of subjects included in analysis
    963
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Confidence interval

    Secondary: Number of subjects who achieve (Yes/No): HbA1c ≤6.5% (48 mmol/mol)

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    End point title
    		 Number of subjects who achieve (Yes/No): HbA1c ≤6.5% (48 mmol/mol)
    End point description
    Subjects who achieved HbA1c ≤6.5% (yes/no) is presented. Results are based on the full analysis set (FAS) which included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    At 104 weeks or at premature treatment discontinuation
    End point values
    		 Liraglutide 1.8 mg Oral antidiabetic drug
    Number of subjects analysed
    996
    995
    Units: subjects
        Yes
    255
    162
        No
    741
    833
    No statistical analyses for this end point

    Secondary: Number of subjects who achieve (Yes/No): HbA1c ≤7.0% (53 mmol/mol) without weight gain

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    End point title
    		 Number of subjects who achieve (Yes/No): HbA1c ≤7.0% (53 mmol/mol) without weight gain
    End point description
    Subjects who achieved HbA1c ≤7.0% without weight gain (yes/no) is presented. Results are based on the full analysis set (FAS) which included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    At 104 weeks or at premature treatment discontinuation
    End point values
    		 Liraglutide 1.8 mg Oral antidiabetic drug
    Number of subjects analysed
    996
    995
    Units: subjects
        Yes
    329
    234
        No
    667
    761
    No statistical analyses for this end point

    Secondary: Change from baseline in fasting plasma glucose (FPG)

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    End point title
    		 Change from baseline in fasting plasma glucose (FPG)
    End point description
    Change from baseline (week 0) in FPG at week 104 or at premature treatment discontinuation is presented. Results are based on the full analysis set (FAS) which included all randomised subjects. In the below table, n refer to number of subjects analysed per treatment arm.
    End point type
    Secondary
    End point timeframe
    At 104 weeks or at premature treatment discontinuation
    End point values
    		 Liraglutide 1.8 mg Oral antidiabetic drug
    Number of subjects analysed
    996
    995
    Units: Millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Week 104 (n=418, 346)
    -2.2 ( 2.65 )
    -1.2 ( 2.46 )
        Premature treatment discontinuation (n=103, 78)
    -0.6 ( 2.91 )
    -0.6 ( 3.76 )
    No statistical analyses for this end point

    Secondary: Change from baseline in body weight

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    End point title
    		 Change from baseline in body weight
    End point description
    Change from baseline (week 0) in body weight at week 104 or at premature treatment discontinuation is presented. Results are based on the full analysis set (FAS) which included all randomised subjects. In the below table, n refer to number of subjects analysed per treatment arm.
    End point type
    Secondary
    End point timeframe
    At 104 weeks or at premature treatment discontinuation
    End point values
    		 Liraglutide 1.8 mg Oral antidiabetic drug
    Number of subjects analysed
    996
    995
    Units: Kilogram (Kg)
    arithmetic mean (standard deviation)
        Change at week 104 (n=427, 349)
    -3.8 ( 6.38 )
    -3.5 ( 6.19 )
        Premature treatment discontinuation (n=116, 86)
    -2.9 ( 3.74 )
    -2.2 ( 4.93 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Weeks 0-105
    Adverse event reporting additional description
    All presented AEs are TEAEs. A TEAE was defined as an event that had onset date on or after the first day of exposure to trial product and no later than 7 days after the last day of trial product administration. Results are based on the SAS which included all participants exposed to at least one dose of trial product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Oral antidiabetic drug
    Reporting group description
    		 Subjects were to receive one selected OAD. The following OADs were allowed: alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, meglitinides, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, sulfonylureas or thiazolidinediones. The treatment period was 104 weeks.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Subjects were to receive a subcutaneous injection of liraglutide once daily. Subjects received 0.6 milligrams (mg) liraglutide during the first week. The dose was escalated in weekly increments of 0.6 mg until the dose of 1.8 mg was reached. The treatment period was 104 weeks.

    Serious adverse events
    		 Oral antidiabetic drug Liraglutide 1.8 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    81 / 984 (8.23%)
    92 / 980 (9.39%)
         number of deaths (all causes)
    8
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Astrocytoma
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer metastatic
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (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 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural mesothelioma malignant
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (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 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer stage III
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Triple negative breast cancer
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 984 (0.20%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         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
    2 / 984 (0.20%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Coronary artery bypass
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrectomy
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric bypass
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic surgery
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal laminectomy
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 984 (0.10%)
    4 / 980 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         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
    Endometriosis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Conversion disorder
         subjects affected / exposed
    0 / 984 (0.00%)
    2 / 980 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusional disorder, unspecified type
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Troponin increased
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial bypass occlusion
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 984 (0.20%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 984 (0.20%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    6 / 984 (0.61%)
    5 / 980 (0.51%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 984 (0.10%)
    4 / 980 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 984 (0.20%)
    3 / 980 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 984 (0.41%)
    3 / 980 (0.31%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         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
    2 / 984 (0.20%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 984 (0.20%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 984 (0.10%)
    4 / 980 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 984 (0.00%)
    2 / 980 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord haematoma
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 984 (0.20%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exophthalmos
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erosive duodenitis
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 984 (0.20%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    2 / 984 (0.20%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 984 (0.20%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatosplenomegaly
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal hypertension
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 984 (0.20%)
    6 / 980 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 984 (0.00%)
    2 / 980 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 984 (0.20%)
    2 / 980 (0.20%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Empty sella syndrome
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc displacement
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 984 (0.00%)
    2 / 980 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 984 (0.00%)
    2 / 980 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 984 (0.10%)
    3 / 980 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         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 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fournier's gangrene
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (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 / 984 (0.10%)
    0 / 980 (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
    5 / 984 (0.51%)
    4 / 980 (0.41%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 984 (0.30%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 984 (0.10%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 984 (0.10%)
    0 / 980 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 984 (0.00%)
    1 / 980 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 984 (0.10%)
    2 / 980 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Oral antidiabetic drug Liraglutide 1.8 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 984 (1.52%)
    65 / 980 (6.63%)
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    15 / 984 (1.52%)
    65 / 980 (6.63%)
         occurrences all number
    21
    82

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jul 2016
    It included updates to drug accountability, inclusion criterion number 4, statistical section and other clarifications and minor updates. Inclusion criteria-4: Stable daily dose of metformin as monotherapy ≥1500 mg or maximum tolerated dose for ≥60 days prior to the screening visit.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/6617804
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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