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    Clinical Trial Results:
    A 104 week clinical trial comparing long term glycaemic control of insulin degludec/liraglutide (IDegLira) versus insulin glargine therapy in subjects with type 2 diabetes mellitus

    Summary
    EudraCT number
    		 2014-005639-15
    Trial protocol
    		 GB   HU   SK   CZ   NO   PL   IT  
    Global end of trial date
    03 Oct 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9068-4228
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02501161
    WHO universal trial number (UTN)
    		 U1111-1165-3914
    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 8668677178, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, +1 8668677178, 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
    13 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare long-term glycaemic control of IDegLira vs. IGlar in insulin naïve subjects with type 2 diabetes mellitus (T2DM) inadequately controlled with oral anti-diabetic drug OAD(s).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice, including archiving of essential documents and FDA 21 CFR 312.120.
    Background therapy
    		 All subjects were continued on pre-trial OAD(s) except dipeptidyl peptidase-4 inhibitors (DPP-4i) and glinides, which were discontinued at randomisation. Pre-trial OADs allowed were: biguanides, sulphonylurea, glinides, pioglitazone, and DPP4-inhibitors, though glinides and DPP4-inhibitors were not allowed as monotherapy or in combination. When trial product (IDegLira or IGlar) was added to sulphonylurea therapy, a reduction in the dose of sulphonylurea was to be considered based on glycaemic response.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    08 Jan 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
    Argentina: 78
    Country: Number of subjects enrolled
    Czech Republic: 30
    Country: Number of subjects enrolled
    United Kingdom: 70
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    India: 92
    Country: Number of subjects enrolled
    Israel: 50
    Country: Number of subjects enrolled
    Italy: 60
    Country: Number of subjects enrolled
    Mexico: 104
    Country: Number of subjects enrolled
    Norway: 32
    Country: Number of subjects enrolled
    Poland: 35
    Country: Number of subjects enrolled
    Russian Federation: 81
    Country: Number of subjects enrolled
    Slovakia: 42
    Country: Number of subjects enrolled
    Turkey: 63
    Country: Number of subjects enrolled
    United States: 152
    Country: Number of subjects enrolled
    South Africa: 89
    Worldwide total number of subjects
    1012
    EEA total number of subjects
    303
    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)
    780
    From 65 to 84 years
    232
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 130 sites in Argentina (4), Czech Republic (4), Hungary (5), India (11), Israel (8), Italy (7), Mexico (4), Norway (7), Poland (3), Russian Federation (8), Slovakia (5), South Africa (10), Turkey (8), United Kingdom (9) and United States (37).

    Pre-assignment
    Screening details
    		 Trial design: Subjects were randomised in a 1:1 manner to receive either IDegLira or IGlar as an adjunct to oral anti-diabetic drugs (OADs).

    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
    		 Insulin degludec/liraglutide
    Arm description
    		 Subjects received subcutaneous (s.c.) injection of Insulin degludec/liraglutide (IDegLira) once daily in dose escalation manner up to 104 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin degludec liraglutide
    Investigational medicinal product code
    Other name
    Xultophy®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received s.c. injection of IDegLira once daily up to 104 weeks. Subjects received 10 dose steps (10 units IDeg/0.36 milligrams [mg] liraglutide) initially. The dose was then escalated twice weekly until the fasting plasma glucose (FPG) target between 4.0−5.0 millimoles per liter (mmol/L) (72−90 milligrams per deciliter [mg/dL]) was reached. The maximum dose was 50 dose steps (50 units IDeg/1.8 mg liraglutide).

    Arm title
    		 Insulin glargine
    Arm description
    		 Subjects received s.c. injection of Insulin glargine (IGlar) once daily up to 104 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Lantus®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received s.c. injection of IGlar once daily up to 104 weeks. Subjects received 10 units of IGlar initially. The dose was then escalated twice weekly until the FPG target between 4.0−5.0 mmol/L (72−90 mg/dL) was reached.

    Number of subjects in period 1
    		Insulin degludec/liraglutide Insulin glargine
    Started
    506
    506
    Exposed
    506
    504
    Completed
    484
    481
    Not completed
    22
    25
         Consent withdrawn by subject
    10
    15
         Adverse event, non-fatal
    2
    6
         Unspecified
    3
    -
         Lost to follow-up
    7
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin degludec/liraglutide
    Reporting group description
    		 Subjects received subcutaneous (s.c.) injection of Insulin degludec/liraglutide (IDegLira) once daily in dose escalation manner up to 104 weeks.

    Reporting group title
    Insulin glargine
    Reporting group description
    		 Subjects received s.c. injection of Insulin glargine (IGlar) once daily up to 104 weeks.

    Reporting group values
    		 Insulin degludec/liraglutide Insulin glargine Total
    Number of subjects
    		 506 506 1012
    Age categorical
    Units: Subjects
        18<= to <40 years
    		 30 29 59
        40<= to <65 years
    		 363 358 721
        65<= to <75 years
    		 102 107 209
        75<= years
    		 11 12 23
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.8 ± 10.0 56.4 ± 10.1 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 226 231 457
        Male
    		 280 275 555

    End points

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    End points reporting groups
    Reporting group title
    Insulin degludec/liraglutide
    Reporting group description
    		 Subjects received subcutaneous (s.c.) injection of Insulin degludec/liraglutide (IDegLira) once daily in dose escalation manner up to 104 weeks.

    Reporting group title
    Insulin glargine
    Reporting group description
    		 Subjects received s.c. injection of Insulin glargine (IGlar) once daily up to 104 weeks.

    Primary: Time from randomisation to inadequate glycaemic control and need for treatment intensification, defined as a glycosylated haemoglobin (HbA1c) of ≥7.0% at 2 consecutive visits from week 26, including week 26 if HbA1c was ≥7% at week 12

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    End point title
    		 Time from randomisation to inadequate glycaemic control and need for treatment intensification, defined as a glycosylated haemoglobin (HbA1c) of ≥7.0% at 2 consecutive visits from week 26, including week 26 if HbA1c was ≥7% at week 12
    End point description
    Inadequate glycaemic control and need for treatment intensification was defined as HbA1c of 7.0% or greater at 2 consecutive visits from week 26, including week 26 if HbA1c≥7% at week 12. Time was analysed using stratified log-rank test where treatment, baseline HbA1c group and previous OAD treatment were included as strata in the model. The variable “baseline HbA1c group” was a dichotomised baseline HbA1c variable with 2 categories: HbA1c<8.5% or HbA1c≥8.5% and “previous OAD treatment” was a categorical variable with 2 categories: SU±OAD(s) (SU users) or OAD(s) (Non-SU users). 25%, median (50%) and 75% percentiles for the cumulative distribution function were obtained from Kaplan-Meier survival function. Results are based on full analysis set (FAS) consisted of all randomised subjects. Number of subjects analyzed = number of subjects with available data. 99999 indicates the estimated data was not available as the proportion was not reached within study period.
    End point type
    Primary
    End point timeframe
    Up to 104 weeks
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    506
    506
    Units: Weeks
    median (inter-quartile range (Q1-Q3))
        Baseline HbA1c <8.5% + Non-SU users
    99999 (104.0 to 99999)
    104.3 (38.1 to 99999)
        Baseline HbA1c <8.5% + SU users
    106.7 (89.9 to 99999)
    90.3 (26.4 to 105.1)
        Baseline HbA1c >=8.5% + Non-SU users
    99999 (39.7 to 99999)
    64.6 (26.1 to 105.1)
        Baseline HbA1c >=8.5% + SU users
    104.0 (26.4 to 99999)
    26.6 (26.1 to 91.1)
    Statistical analysis title
    		 Insulin degludec/liraglutide vs Insulin glargine
    Statistical analysis description
    Test for no treatment difference was based on using a stratified log-rank test where treatment, baseline HbA1c group and pre-trial OAD treatment group were included as strata in the model.
    Comparison groups
    Insulin degludec/liraglutide v Insulin glargine
    Number of subjects included in analysis
    1012
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Stratified log-rank test
    Confidence interval

    Secondary: Time from randomisation to an HbA1c > 6.5% at 2 consecutive visits

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    End point title
    		 Time from randomisation to an HbA1c > 6.5% at 2 consecutive visits
    End point description
    Time to HbA1c>6.5% at 2 consecutive visits is defined as time from randomization to HbA1c>6.5% at 2 consecutive visits from week 26 including week 26 if HbA1c>6.5% at week 12. Time was analysed using stratified log-rank test where treatment, baseline HbA1c group and previous OAD treatment were included as strata in the model. The variable “baseline HbA1c group” was a dichotomised baseline HbA1c variable with 2 categories: HbA1c<8.5% or HbA1c≥8.5% and the variable “previous OAD treatment” was a categorical variable with 2 categories: SU±OAD(s) (SU users) or OAD(s) (Non-SU users). 25%, median (50%) and 75% percentiles for the cumulative distribution function were obtained from the Kaplan-Meier survival function. Results are based on FAS consisted of all randomised subjects. Number of subjects analyzed = number of subjects with available data. 99999 indicates the estimated data was not available as the proportion was not reached within study period.
    End point type
    Secondary
    End point timeframe
    From week 26
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    506
    506
    Units: Weeks
    median (inter-quartile range (Q1-Q3))
        Baseline HbA1c <8.5% + Non-SU users
    99999 (52.1 to 99999)
    64.1 (26.1 to 104.3)
        Baseline HbA1c <8.5% + SU users
    90.1 (27.0 to 99999)
    26.6 (26.1 to 89.9)
        Baseline HbA1c >=8.5% + Non-SU users
    64.1 (26.1 to 99999)
    26.6 (26.1 to 90.1)
        Baseline HbA1c >=8.5% + SU users
    52.1 (26.1 to 104.1)
    26.1 (26.1 to 38.1)
    No statistical analyses for this end point

    Secondary: Change from baseline in HbA1c

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    End point title
    		 Change from baseline in HbA1c
    End point description
    Change in HbA1c from baseline (week 0) to week 26 is presented. Results are based on the FAS which consisted of all randomised subjects. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    481
    466
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    -1.99 ± 1.14
    -1.69 ± 1.10
    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 in body weight from baseline (week 0) to week 26 is presented. Results are based on the FAS which consisted of all randomised subjects. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    481
    466
    Units: Kilogram (kg)
    arithmetic mean (standard deviation)
        Week 26
    0.5 ± 3.3
    2.2 ± 3.6
    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 in FPG from baseline (week 0) at week 26 is presented. Results are based on the FAS which consisted of all randomised subjects. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    475
    461
    Units: Millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Week 26
    -3.97 ± 3.06
    -3.79 ± 3.18
    No statistical analyses for this end point

    Secondary: Change from baseline in 9-point Self-measured plasma glucose (SMPG) profile (individual points in the profile)

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    End point title
    		 Change from baseline in 9-point Self-measured plasma glucose (SMPG) profile (individual points in the profile)
    End point description
    Subjects measured plasma glucose values using the blood glucose meter at 9 time points: before breakfast, 90 min after start of breakfast, before lunch, 90 minutes after start of lunch, before dinner, 90 min after start of dinner, bedtime, at 4:00 am and before breakfast the following day. SMPG-9-point profile (individual points in the profile) at week 26 is presented. Results are based on the FAS which consisted of all randomised subjects. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    506
    506
    Units: mmol/L
    arithmetic mean (standard deviation)
        Before breakfast (n=437,413)
    5.59 ± 1.57
    5.58 ± 1.58
        90 minutes after breakfast (n=425,409)
    8.34 ± 2.62
    8.76 ± 2.68
        Before lunch (n=435,407)
    6.03 ± 2.00
    6.43 ± 2.24
        90 minutes after lunch (n=433,407)
    8.02 ± 2.32
    8.79 ± 2.64
        Before dinner (n=434,408)
    6.67 ± 2.26
    6.91 ± 2.35
        90 minutes after dinner (n=428,406)
    8.31 ± 2.47
    9.10 ± 2.70
        Bedtime (n=423,398)
    7.48 ± 2.42
    8.13 ± 2.68
        At 4:00 a.m. (n=419,398)
    5.72 ± 1.55
    5.91 ± 1.99
        Before breakfast the following day (n=433,403)
    5.53 ± 1.37
    5.56 ± 1.56
    No statistical analyses for this end point

    Secondary: Insulin dose

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    End point title
    		 Insulin dose
    End point description
    Insulin dose after 26 weeks of treatment is presented. Results are based on the safety analysis set (SAS) included all participants receiving at least 1 dose of the investigational product (IDegLira) or comparator (IGlar). Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    476
    449
    Units: Units
    arithmetic mean (standard deviation)
        Week 26
    34.6 ± 13.4
    48.6 ± 28.2
    No statistical analyses for this end point

    Secondary: Responder (yes/no): HbA1c < 7.0%

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    End point title
    		 Responder (yes/no): HbA1c < 7.0%
    End point description
    Percentage of subjects who achieved HbA1c < 7.0% at week 26 and week 104 is presented. Results are based on the FAS which consisted of all randomised subjects. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 26 and 104 weeks of treatment
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    506
    506
    Units: Percentage of subjects
    number (not applicable)
        Week 26: Yes
    78.7
    55.7
        Week 26: No
    21.3
    44.3
        Week 104: Yes
    55.5
    28.5
        Week 104: No
    44.5
    71.5
    No statistical analyses for this end point

    Secondary: Responder (yes/no): HbA1c ≤ 6.5%

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    End point title
    		 Responder (yes/no): HbA1c ≤ 6.5%
    End point description
    Percentage of subjects who achieved HbA1c ≤ 6.5% at week 26 and week 104 is presented. Results are based on the FAS which consisted of all randomised subjects. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 26 and 104 weeks of treatment
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    506
    506
    Units: Percentage of subjects
    number (not applicable)
        Week 26: Yes
    63.6
    35.4
        Week 26: No
    36.4
    64.6
        Week 104: Yes
    43.3
    21.7
        Week 104: No
    56.7
    78.3
    No statistical analyses for this end point

    Secondary: Number of treatment-emergent severe or blood glucose confirmed symptomatic hypoglycaemic episodes

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    End point title
    		 Number of treatment-emergent severe or blood glucose confirmed symptomatic hypoglycaemic episodes
    End point description
    Severe or BG confirmed symptomatic hypoglycaemia is defined as an episode that is severe according to the ADA classification or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Hypoglycaemic episodes were defined as treatment-emergent if the onset of the episode occurred on or after the first day of trial product administration, and no later than 7 calendar days after the last day on trial product. Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 26 and 104 weeks of treatment is presented. Results are based on the SAS included all participants receiving at least 1 dose of the investigational product (IDegLira) or comparator (IGlar). Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    During 26 and 104 weeks of treatment
    End point values
    		 Insulin degludec/liraglutide Insulin glargine
    Number of subjects analysed
    506
    504
    Units: Episodes
        During 26 weeks of treatment
    143
    261
        During 104 weeks of treatment
    319
    642
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Weeks 0-104 (treatment period) + 7 days follow-up-1 + 30 days follow-up-2
    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 subjects receiving at least one dose of trial product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Insulin degludec/liraglutide
    Reporting group description
    		 Subjects received s.c. injection of IDegLira once daily up to 104 weeks. The maximum dose was 50 dose steps (50 units IDeg/1.8 mg liraglutide).

    Reporting group title
    Insulin glargine
    Reporting group description
    		 Subjects received s.c. injection of IGlar once daily up to 104 weeks.

    Serious adverse events
    		 Insulin degludec/liraglutide Insulin glargine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    60 / 506 (11.86%)
    43 / 504 (8.53%)
         number of deaths (all causes)
    2
    5
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 506 (0.00%)
    2 / 504 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign hepatic neoplasm
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (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 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         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
    3 / 506 (0.59%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasoconstriction
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         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 arterial stent insertion
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Percutaneous coronary intervention
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tympanoplasty
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 506 (0.20%)
    2 / 504 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 506 (0.20%)
    2 / 504 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung perforation
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (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
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (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
    3 / 506 (0.59%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve injury
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial reocclusion
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory fume inhalation disorder
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 506 (0.20%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stab wound
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (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
    3 / 506 (0.59%)
    2 / 504 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    4 / 506 (0.79%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 506 (0.00%)
    2 / 504 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 506 (0.00%)
    2 / 504 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiac failure
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 506 (0.20%)
    2 / 504 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 506 (0.00%)
    2 / 504 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 506 (0.40%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (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
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular degeneration
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroduodenitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    3 / 506 (0.59%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 506 (0.40%)
    3 / 504 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (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
    Haematuria
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (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
    Arthralgia
         subjects affected / exposed
    1 / 506 (0.20%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    4 / 506 (0.79%)
    3 / 504 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (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
    Bronchitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryocystitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 506 (0.59%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 506 (0.20%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 506 (0.00%)
    2 / 504 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 506 (0.00%)
    1 / 504 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 504 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Insulin degludec/liraglutide Insulin glargine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    206 / 506 (40.71%)
    156 / 504 (30.95%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    58 / 506 (11.46%)
    45 / 504 (8.93%)
         occurrences all number
    98
    89
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    39 / 506 (7.71%)
    12 / 504 (2.38%)
         occurrences all number
    52
    14
    Nausea
         subjects affected / exposed
    31 / 506 (6.13%)
    8 / 504 (1.59%)
         occurrences all number
    39
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 506 (4.74%)
    29 / 504 (5.75%)
         occurrences all number
    27
    36
    Back pain
         subjects affected / exposed
    25 / 506 (4.94%)
    27 / 504 (5.36%)
         occurrences all number
    30
    40
    Infections and infestations
    Influenza
         subjects affected / exposed
    36 / 506 (7.11%)
    28 / 504 (5.56%)
         occurrences all number
    46
    38
    Nasopharyngitis
         subjects affected / exposed
    57 / 506 (11.26%)
    44 / 504 (8.73%)
         occurrences all number
    71
    53
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 506 (5.53%)
    36 / 504 (7.14%)
         occurrences all number
    30
    44

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jul 2016
    1) Clarification of inclusion criteria, concerning OAD treatments allowed in the trial. 2) Low FPG should be reported as Clinical Laboratory Adverse Event not AE. 3) New process of drug accountability. 4)Visit specific diary covering visit 13- 14
    01 Feb 2017
    1) Minimum mandatory safety text updated. 2) Clarifications concerning distribution of human insulin results, storage of abnormal haematology samples and MACE definition. 3) ‘(x)’ removed from pregnancy test in flowchart.

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

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