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    Clinical Trial Results:
    Efficacy and safety of semaglutide once weekly versus insulin glargine once daily as add on to metformin with or without sulphonylurea in insulin-naïve subjects with type 2 diabetes

    Summary
    EudraCT number
    2013-004392-12
    Trial protocol
    SI   SK   DE   GB   NL   RO   HR  
    Global end of trial date
    03 Sep 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Sep 2016
    First version publication date
    18 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9535-3625
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02128932
    WHO universal trial number (UTN)
    U1111-1146-0211
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of once-weekly dosing of two dose levels of semaglutide versus insulin glargine once-daily on glycaemic control after 30 weeks of treatment in insulin-naïve subjects with type 2 diabetes.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice.
    Background therapy
    The following compounds were considered as background medication and were administered at the described doses: Metformin: doses ≥1500 mg or maximum tolerated dose. Treatment with extended/slow release was allowed Sulphonylurea (SU): doses ≥half of maximum dose allowed according to national label.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    04 Aug 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 41
    Country: Number of subjects enrolled
    Croatia: 25
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 81
    Country: Number of subjects enrolled
    India: 83
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 30
    Country: Number of subjects enrolled
    Mexico: 44
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Romania: 44
    Country: Number of subjects enrolled
    Slovakia: 45
    Country: Number of subjects enrolled
    Slovenia: 38
    Country: Number of subjects enrolled
    South Africa: 40
    Country: Number of subjects enrolled
    United Kingdom: 89
    Country: Number of subjects enrolled
    United States: 495
    Worldwide total number of subjects
    1082
    EEA total number of subjects
    349
    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)
    840
    From 65 to 84 years
    242
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 196 sites in 14 countries Argentina: 3 sites; Croatia: 3 sites; France: 5 sites; Germany: 11 sites; India: 12 sites; Macedonia: 3 sites; Mexico: 3 sites; Netherlands: 3 sites; Romania: 5 sites; Slovakia: 5 sites; Slovenia: 3 sites; South Africa: 4 sites; United Kingdom: 13 sites; United States :123 sites.

    Pre-assignment
    Screening details
    Insulin-naïve subjects diagnosed with type 2 diabetes and on stable diabetes treatment with metformin or metformin and SU (metformin ≥1500 mg or maximum tolerated dose and SU ≥ half of maximum allowed dose according to national label) for at least 90 days before screening. Stable is defined as unchanged medication and unchanged dose.

    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
    Open label, active-controlled, parallel design, multinational, three-armed trial

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Semaglutide 0.5 mg/week
    Arm description
    Subjects on semaglutide followed a fixed dose-escalation. The maintenance dose of 0.5 mg was to be reached after 4 doses (4 weeks) of 0.25 mg semaglutide. Doses could not be changed during the trial after the maintenance dose had been reached. There were 49 premature dis continuations in this arm.
    Arm type
    Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One test pen was to be supplied per subject at the screening visit in order to ensure the subject`s willingness and ability to self-inject. The test pen contained semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector and was to be administered once. The PDS290 pen-injector for semaglutide is a prefilled pen integrated with a 1.5 mL cartridge containing semaglutide 1.34 mg/mL and is designed to be used with NovoFine®, NovoFine® Plus and NovoTwist® disposable needles Once weekly (same day of the week) administered by s.c. injection in thigh, abdomen or upper arm, at any time of the day

    Arm title
    Semaglutide 1.0 mg/week
    Arm description
    Subjects randomised to semaglutide followed a fixed dose-escalation regimen, The maintenance dose of 1.0 mg was to be reached after 4 doses (4 weeks) of 0.25 mg, followed by 4 doses (4 weeks) of 0.5 mg semaglutide. Doses could not be changed during the trial after the maintenance dose had been reached. There were 55 premature dis continuations in this arm.
    Arm type
    Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One test pen was to be supplied per subject at the screening visit in order to ensure the subject`s willingness and ability to self-inject. The test pen contained semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-injector and was to be administered once. The PDS290 pen-injector for semaglutide is a prefilled pen integrated with a 1.5 mL cartridge containing semaglutide 1.34 mg/mL and is designed to be used with NovoFine®, NovoFine® Plus and NovoTwist® disposable needles Once weekly (same day of the week) administered by s.c. injection in thigh, abdomen or upper arm, at any time of the day.

    Arm title
    Insulin glargine
    Arm description
    Subjects on insulin glargine were to start on 10 IU subcutaneous(s.c.) injected once daily (OD). The insulin dose adjustment had to aim to reach a pre-breakfast FPG of 4.0 to <5.5 mmol/L (71- <100 mg/dL). There were 26 premature dis continuations in this arm.
    Arm type
    Active comparator

    Investigational medicinal product name
    Lantus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Once daily solution for injection in a 3 mL pre-filled SoloStar® pen to be administered in the thigh, abdomen or upper arm , at any time of the day

    Number of subjects in period 1
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine
    Started
    362
    360
    360
    Completed
    335
    341
    342
    Not completed
    27
    19
    18
         Not completed
    27
    19
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide 0.5 mg/week
    Reporting group description
    Subjects on semaglutide followed a fixed dose-escalation. The maintenance dose of 0.5 mg was to be reached after 4 doses (4 weeks) of 0.25 mg semaglutide. Doses could not be changed during the trial after the maintenance dose had been reached. There were 49 premature dis continuations in this arm.

    Reporting group title
    Semaglutide 1.0 mg/week
    Reporting group description
    Subjects randomised to semaglutide followed a fixed dose-escalation regimen, The maintenance dose of 1.0 mg was to be reached after 4 doses (4 weeks) of 0.25 mg, followed by 4 doses (4 weeks) of 0.5 mg semaglutide. Doses could not be changed during the trial after the maintenance dose had been reached. There were 55 premature dis continuations in this arm.

    Reporting group title
    Insulin glargine
    Reporting group description
    Subjects on insulin glargine were to start on 10 IU subcutaneous(s.c.) injected once daily (OD). The insulin dose adjustment had to aim to reach a pre-breakfast FPG of 4.0 to <5.5 mmol/L (71- <100 mg/dL). There were 26 premature dis continuations in this arm.

    Reporting group values
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine Total
    Number of subjects
    362 360 360 1082
    Age Categorical
    Full analysis set (FAS): included all randomised subjects who had received at least one dose of randomised semaglutide (s.c.) or insulin glargine. Subjects in the FAS contributed to the evaluation based on the treatment assigned at randomisation.
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    278 281 281 840
        From 65-84 years
    84 79 79 242
        85 years and over
    0 0 0 0
    Age Continuous
    Full analysis set (FAS): included all randomised subjects who had received at least one dose of randomised semaglutide (s.c.) or insulin glargine. Subjects in the FAS contributed to the evaluation based on the treatment assigned at randomisation.
    Units: years
        arithmetic mean (standard deviation)
    56.5 ± 10.3 56.7 ± 10.4 56.2 ± 10.6 -
    Gender Categorical
    Full analysis set (FAS): included all randomised subjects who had received at least one dose of randomised semaglutide (s.c.) or insulin glargine. Subjects in the FAS contributed to the evaluation based on the treatment assigned at randomisation.
    Units: Subjects
        Female
    165 178 165 508
        Male
    197 182 195 574
    HbA1c
    Full analysis set (FAS): included all randomised subjects who had received at least one dose of randomised semaglutide (s.c.) or insulin glargine. Subjects in the FAS contributed to the evaluation based on the treatment assigned at randomisation.
    Units: percentage
        arithmetic mean (standard deviation)
    8.13 ± 0.85 8.25 ± 0.94 8.13 ± 0.88 -
    Fasting Plasma Glucose
    Full analysis set (FAS): included all randomised subjects who had received at least one dose of randomised semaglutide (s.c.) or insulin glargine. Subjects in the FAS contributed to the evaluation based on the treatment assigned at randomisation.
    Units: mg/dL
        arithmetic mean (standard deviation)
    172.4 ± 50.52 179.2 ± 53.74 174.2 ± 49.06 -
    Body weight
    Full analysis set (FAS): included all randomised subjects who had received at least one dose of randomised semaglutide (s.c.) or insulin glargine. Subjects in the FAS contributed to the evaluation based on the treatment assigned at randomisation.
    Units: kg
        arithmetic mean (standard deviation)
    93.73 ± 21.39 94 ± 22.48 92.61 ± 21.52 -
    Diastolic blood pressure
    Full analysis set (FAS): included all randomised subjects who had received at least one dose of randomised semaglutide (s.c.) or insulin glargine. Subjects in the FAS contributed to the evaluation based on the treatment assigned at randomisation.
    Units: mmHg
        arithmetic mean (standard deviation)
    79.67 ± 8.04 80.32 ± 8.32 79.78 ± 9.2 -
    Systolic Blood Pressure
    Full analysis set (FAS): included all randomised subjects who had received at least one dose of randomised semaglutide (s.c.) or insulin glargine. Subjects in the FAS contributed to the evaluation based on the treatment assigned at randomisation.
    Units: mmHg
        arithmetic mean (standard deviation)
    131.57 ± 14.06 132.21 ± 16.05 132.38 ± 15.77 -

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 0.5 mg/week
    Reporting group description
    Subjects on semaglutide followed a fixed dose-escalation. The maintenance dose of 0.5 mg was to be reached after 4 doses (4 weeks) of 0.25 mg semaglutide. Doses could not be changed during the trial after the maintenance dose had been reached. There were 49 premature dis continuations in this arm.

    Reporting group title
    Semaglutide 1.0 mg/week
    Reporting group description
    Subjects randomised to semaglutide followed a fixed dose-escalation regimen, The maintenance dose of 1.0 mg was to be reached after 4 doses (4 weeks) of 0.25 mg, followed by 4 doses (4 weeks) of 0.5 mg semaglutide. Doses could not be changed during the trial after the maintenance dose had been reached. There were 55 premature dis continuations in this arm.

    Reporting group title
    Insulin glargine
    Reporting group description
    Subjects on insulin glargine were to start on 10 IU subcutaneous(s.c.) injected once daily (OD). The insulin dose adjustment had to aim to reach a pre-breakfast FPG of 4.0 to <5.5 mmol/L (71- <100 mg/dL). There were 26 premature dis continuations in this arm.

    Primary: Change in HbA1c

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    End point title
    Change in HbA1c
    End point description
    Change in HbA1c from baseline to week 30. These analyses were done using the FAS. The full analysis set (FAS) included all randomised subjects who had received at least one dose ofrandomised semaglutide 0.5 mg, semaglutide 1.0 mg or insulin glargine.
    End point type
    Primary
    End point timeframe
    From baseline to week 30
    End point values
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine
    Number of subjects analysed
    362
    360
    360
    Units: percentage
        least squares mean (standard error)
    -1.21 ± 0.05
    -1.64 ± 0.05
    -0.83 ± 0.05
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The post baseline responses were analysed using a mixed model for repeated measurements with treatment and country as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg/week v Insulin glargine
    Number of subjects included in analysis
    722
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.52
         upper limit
    -0.24
    Notes
    [1] - Non-inferiority was concluded if the upper limit of the two-sided 95% confidence interval for the estimated treatment difference between semaglutide 1.0 mg or semaglutide 0.5 mg and insulin glargine was below the pre-specified non-inferiority margin (0.3 %).
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The post baseline responses were analysed using a mixed model for repeated measurements with treatment and country as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg/week v Insulin glargine
    Number of subjects included in analysis
    720
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.96
         upper limit
    -0.67
    Notes
    [2] - Non-inferiority was concluded if the upper limit of the two-sided 95% confidence interval for the estimated treatment difference between semaglutide 1.0 mg or semaglutide 0.5 mg and insulin glargine was below the pre-specified non-inferiority margin (0.3 %).

    Secondary: Change in body weight

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    End point title
    Change in body weight
    End point description
    Change in body weight from baseline to week 30. These analyses were done using the FAS. The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 0.5 mg, semaglutide 1.0 mg or insulin glargine.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine
    Number of subjects analysed
    362
    360
    360
    Units: kg
        least squares mean (standard error)
    -3.47 ± 0.24
    -5.17 ± 0.24
    1.15 ± 0.23
    No statistical analyses for this end point

    Secondary: Change in Fasting plasma glucose

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    End point title
    Change in Fasting plasma glucose
    End point description
    Change in Fasting plasma glucose from baseline to week 30. These analyses were done using the FAS. The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 0.5 mg, semaglutide 1.0 mg or insulin glargine
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine
    Number of subjects analysed
    362
    360
    360
    Units: mg/dL
        least squares mean (standard error)
    -36.74 ± 2.14
    -49.21 ± 2.15
    -38.18 ± 2.03
    No statistical analyses for this end point

    Secondary: Change in diastolic blood pressure

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    End point title
    Change in diastolic blood pressure
    End point description
    Change in diastolic blood pressure from baseline to week 30. These analyses were done using the FAS. The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 0.5mg, semaglutide 1.0 mg or insulin glargine.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine
    Number of subjects analysed
    362
    360
    360
    Units: mmHg
        least squares mean (standard error)
    -1.38 ± 0.43
    -0.98 ± 0.44
    -1.44 ± 0.41
    No statistical analyses for this end point

    Secondary: Change in systolic blood pressure

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    End point title
    Change in systolic blood pressure
    End point description
    Change in systolic blood pressure from basleine to week 30. These analyses were done using the FAS. The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 0.5 mg, semaglutide 1.0 mg or insulin glargine.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine
    Number of subjects analysed
    362
    360
    360
    Units: mmHg
        least squares mean (standard error)
    -4.65 ± 0.72
    -5.17 ± 0.73
    -1.68 ± 0.68
    No statistical analyses for this end point

    Secondary: Change in patient reported outcome questionnaires (PROs), SF-36v2™

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    End point title
    Change in patient reported outcome questionnaires (PROs), SF-36v2™
    End point description
    The Short Form (SF)-36v2™ health survey (SF-36v2™ )questionnaire was to be used to assess the subject’s overall HRQoL and could also be used to estimate quality adjusted life years, which is used in cost effectiveness calculations. This questionnaire contains 36 items and measures the individual overall health related quality of life on 8 domains; physical functioning, role functioning, bodily pain, general health, vitality, social functioning, role emotional and mental health. These analyses were done using the FAS. The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 0.5 mg, semaglutide 1.0 mg or insulin glargine.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine
    Number of subjects analysed
    362
    360
    360
    Units: Score on a scale
    least squares mean (standard error)
        Bodily pain
    0.95 ± 0.51
    1.76 ± 0.51
    0.9 ± 0.48
        General Health
    1.95 ± 0.38
    2.78 ± 0.38
    1.63 ± 0.36
        Mental Component summary, MCS
    1.23 ± 0.47
    1.33 ± 0.47
    0.25 ± 0.44
        Mental Health
    1.69 ± 0.46
    1.17 ± 0.47
    0.54 ± 0.44
        Physical Component summary, PCS
    1.18 ± 0.36
    2.09 ± 0.36
    1.18 ± 0.34
        Physical Functioning
    1.64 ± 0.43
    1.49 ± 0.43
    0.69 ± 0.41
        Role -emotional
    0.88 ± 0.54
    1.73 ± 0.54
    0.06 ± 0.51
        Role -physical
    0.9 ± 0.46
    1.97 ± 0.46
    0.78 ± 0.43
        Social functinoning
    1.13 ± 0.48
    1.04 ± 0.48
    0.36 ± 0.45
        Vitality
    1.71 ± 0.46
    2.09 ± 0.46
    0.95 ± 0.44
    No statistical analyses for this end point

    Secondary: Change in patient reported outcome questionnaires. (PROs), DTSQs

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    End point title
    Change in patient reported outcome questionnaires. (PROs), DTSQs
    End point description
    The Diabetes Treatment Satisfaction Questionnaire (DTSQs) questionnaire was to be used to assess a subject’s treatment satisfaction. This questionnaire contains 8 items and measures the treatment for diabetes (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings regarding treatment. These analyses were done using the FAS. The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 0.5 mg, semaglutide 1.0 mg or insulin glargine. The result presented is the 'Treatment Satisfaction' summary score, which is the sum of 6 of the 8 items of the DTSQs questionnaire.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine
    Number of subjects analysed
    362
    360
    360
    Units: Scores on a scale
    least squares mean (standard error)
        Treatment satisfaction
    4.86 ± 0.28
    5.37 ± 0.29
    3.99 ± 0.27
    No statistical analyses for this end point

    Secondary: Subjects who achieve HbA1c ≤6.5% (48 mmol/mol), American Association of Clinical Endocrinologists (AACE)

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    End point title
    Subjects who achieve HbA1c ≤6.5% (48 mmol/mol), American Association of Clinical Endocrinologists (AACE)
    End point description
    Subjects who achieve HbA1c ≤6.5% (48 mmol/mol), American Association of Clinical Endocrinologists (AACE) after 30 weeks of treatment
    End point type
    Secondary
    End point timeframe
    After 30 weeks' treatment
    End point values
    Semaglutide 0.5 mg/week Semaglutide 1.0 mg/week Insulin glargine
    Number of subjects analysed
    362
    360
    360
    Units: Number of subjects
    number (not applicable)
        Yes
    135
    195
    63
        No
    227
    165
    297
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the first trial-related activity after the subject had signed the informed consent until the end of the post-treatment follow-up period. (Week 0-week 30 and 5 week follow-up period)
    Adverse event reporting additional description
    A treatment-emergent adverse event (TEAE) was defined as an AE that had onset date (or increased in severity) during the ‘on-treatment’ observation period. The number of deaths causally related to treatment is the data considered to present under ‘total number of deaths resulting from adverse events’
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Semaglutide 0.5 mg/week
    Reporting group description
    Subjects on semaglutide followed a fixed dose-escalation. The maintenance dose of 0.5 mg was to be reached after 4 doses (4 weeks) of 0.25 mg semaglutide. Doses could not be changed during the trial after the maintenance dose had been reached.

    Reporting group title
    Insulin glargine
    Reporting group description
    Subjects on insulin glargine were to start on 10 IU subcutaneous (S.C.) injected once daily ( OD) The insulin dose adjustment had to aim to reach a pre-breakfast FPG of 4.0 to <5.5 mmol/L (71- <100 mg/dL).

    Reporting group title
    Semaglutide 1.0 mg/week
    Reporting group description
    Subjects randomised to semaglutide followed a fixed dose-escalation regimen, The maintenance dose of 1.0 mg was to be reached after 4 doses (4 weeks) of 0.25 mg, followed by 4 doses (4 weeks) of 0.5 mg semaglutide. Doses could not be changed during the trial after the maintenance dose had been reached.

    Serious adverse events
    Semaglutide 0.5 mg/week Insulin glargine Semaglutide 1.0 mg/week
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 362 (6.08%)
    18 / 360 (5.00%)
    17 / 360 (4.72%)
         number of deaths (all causes)
    4
    2
    0
         number of deaths resulting from adverse events
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Nasopharyngeal cancer
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Carotid endarterectomy
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary arterial stent insertion
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eyelid operation
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Corneal graft rejection
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocephalus
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 360 (0.28%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    2 / 360 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fissure
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chondropathy
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 360 (0.28%)
    2 / 360 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 362 (0.00%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 362 (0.55%)
    1 / 360 (0.28%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 360 (0.00%)
    1 / 360 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 360 (0.00%)
    0 / 360 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Semaglutide 0.5 mg/week Insulin glargine Semaglutide 1.0 mg/week
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    172 / 362 (47.51%)
    107 / 360 (29.72%)
    192 / 360 (53.33%)
    Investigations
    Lipase increased
         subjects affected / exposed
    36 / 362 (9.94%)
    15 / 360 (4.17%)
    30 / 360 (8.33%)
         occurrences all number
    39
    17
    32
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 362 (5.25%)
    20 / 360 (5.56%)
    23 / 360 (6.39%)
         occurrences all number
    40
    26
    33
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    59 / 362 (16.30%)
    16 / 360 (4.44%)
    69 / 360 (19.17%)
         occurrences all number
    67
    18
    118
    Dyspepsia
         subjects affected / exposed
    12 / 362 (3.31%)
    2 / 360 (0.56%)
    24 / 360 (6.67%)
         occurrences all number
    24
    2
    39
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 362 (1.10%)
    3 / 360 (0.83%)
    19 / 360 (5.28%)
         occurrences all number
    4
    4
    20
    Nausea
         subjects affected / exposed
    77 / 362 (21.27%)
    12 / 360 (3.33%)
    80 / 360 (22.22%)
         occurrences all number
    101
    15
    117
    Vomiting
         subjects affected / exposed
    24 / 362 (6.63%)
    10 / 360 (2.78%)
    37 / 360 (10.28%)
         occurrences all number
    28
    12
    119
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    11 / 362 (3.04%)
    7 / 360 (1.94%)
    18 / 360 (5.00%)
         occurrences all number
    11
    10
    20
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    45 / 362 (12.43%)
    44 / 360 (12.22%)
    29 / 360 (8.06%)
         occurrences all number
    58
    51
    37
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 362 (2.76%)
    24 / 360 (6.67%)
    14 / 360 (3.89%)
         occurrences all number
    10
    25
    16
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    25 / 362 (6.91%)
    1 / 360 (0.28%)
    23 / 360 (6.39%)
         occurrences all number
    34
    1
    23

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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