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    Clinical Trial Results:
    The efficacy of insulin degludec/liraglutide as add-on therapy in controlling glycaemia in adults with type 2 diabetes inadequately controlled on sulphonylurea with or without metformin therapy

    Summary
    EudraCT number
    		 2012-000140-97
    Trial protocol
    		 DE   BG  
    Global end of trial date
    23 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    28 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9068-3951
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01618162
    WHO universal trial number (UTN)
    		 U1111-1126-9776
    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
    08 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm superiority of insulin degludec/liraglutide compared to insulin degludec/liraglutide placebo in controlling glycaemia as add-on treatment in insulin naïve subjects with Type 2 Diabetes Mellitus (T2DM) inadequately controlled on sulphonylurea (SU) with or without metformin therapy after 26 weeks of treatment.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, (59th WMA Assembly, Oct 2008), ICH Good Clinical Practice (May 1996) and 21 CFR 312.120.
    Background therapy
    		 Sulphonylurea and metformin were the background medications.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    29 Aug 2012
    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
    Bulgaria: 110
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Canada: 38
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    India: 64
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    United States: 150
    Worldwide total number of subjects
    435
    EEA total number of subjects
    156
    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)
    310
    From 65 to 84 years
    124
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 77 sites in 7 countries randomised subjects: Bulgaria (7), Canada (9), Germany (6), India (6), Israel (7), Turkey (3), United States (39)

    Pre-assignment
    Screening details
    		 The trial included a 2 week screening period to assess subject eligibility

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IDegLira
    Arm description
    		 In this arm, subjects were subcutaneously (s.c.) injected with IDegLira.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IDegLira
    Investigational medicinal product code
    Other name
    Insulin degludec/liraglutide
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IDegLira was to be injected s.c. in the thigh, upper arm (deltoid region) or abdomen once daily preferably at the same time every day. The injection area chosen was to remain unchanged throughout the trial, but rotation within the area was to be recommended. Treatment with IDegLira was initiated at 10 dose steps containing 10 units IDeg and 0.36 mg liraglutide. Adjustment of the IDegLira dose was to be performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days.

    Arm title
    		 Placebo
    Arm description
    		 In this arm, subjects were subcutaneously (s.c.) injected with placebo solution for IDegLira.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The placebo treatment was to be initiated and titrated as described for IDegLira.

    Number of subjects in period 1
    		IDegLira Placebo
    Started
    289
    146
    Exposed
    288
    146
    Completed
    251
    111
    Not completed
    38
    35
         Withdrawal Criteria
    2
    10
         Adverse event, non-fatal
    9
    2
         Unclassified
    14
    13
         Protocol deviation
    13
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IDegLira
    Reporting group description
    		 In this arm, subjects were subcutaneously (s.c.) injected with IDegLira.

    Reporting group title
    Placebo
    Reporting group description
    		 In this arm, subjects were subcutaneously (s.c.) injected with placebo solution for IDegLira.

    Reporting group values
    		 IDegLira Placebo Total
    Number of subjects
    		 289 146 435
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60 ± 9.6 59.4 ± 10.8 -
    Gender categorical
    Units: Subjects
        Female
    		 135 73 208
        Male
    		 154 73 227
    Glycosylated haemoglobin
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    		 7.9 ± 0.6 7.9 ± 0.6 -
    Fasting plasma glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.1 ± 2.2 9.1 ± 2.1 -

    End points

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    End points reporting groups
    Reporting group title
    IDegLira
    Reporting group description
    		 In this arm, subjects were subcutaneously (s.c.) injected with IDegLira.

    Reporting group title
    Placebo
    Reporting group description
    		 In this arm, subjects were subcutaneously (s.c.) injected with placebo solution for IDegLira.

    Primary: Change in glycosylated haemoglobin (HbA1c) from baseline

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    End point title
    		 Change in glycosylated haemoglobin (HbA1c) from baseline
    End point description
    Change in HbA1c from baseline to 26 weeks of treatment
    End point type
    Primary
    End point timeframe
    After 26 weeks of treatment.
    End point values
    		 IDegLira Placebo
    Number of subjects analysed
    289
    146
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    -1.45 ± 0.84
    -0.46 ± 0.83
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    IDegLira v Placebo
    Number of subjects included in analysis
    435
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Estimated treatment difference
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.18
         upper limit
    		 -0.87
    Notes
    [1] - Superiority of IDegLira versus placebo therapy would be concluded if the 95% CI for the treatment differences for change in HbA1c lied entirely below 0%; implying that the two-sided p-value calculated by the ANCOVA model for testing the hypothesis of no difference between treatments was less than 5%.

    Secondary: Responders achieving pre-defined target for HbA1c. i.e., HbA1c <7.0% (53 mmol/mol)

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    End point title
    		 Responders achieving pre-defined target for HbA1c. i.e., HbA1c <7.0% (53 mmol/mol)
    End point description
    Responders achieving pre-defined target for HbA1c
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 IDegLira Placebo
    Number of subjects analysed
    289
    146
    Units: Percentage (%)
        number (not applicable)
    79.2
    28.8
    No statistical analyses for this end point

    Secondary: Responders achieving pre-defined target for HbA1c. i.e., HbA1c ≤6.5% (48 mmol/mol).

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    End point title
    		 Responders achieving pre-defined target for HbA1c. i.e., HbA1c ≤6.5% (48 mmol/mol).
    End point description
    Responders achieving pre-defined target for HbA1c
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 IDegLira Placebo
    Number of subjects analysed
    289
    146
    Units: Percentage (%)
        number (not applicable)
    64
    12.3
    No statistical analyses for this end point

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

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    End point title
    		 Change from baseline in fasting plasma glucose (FPG).
    End point description
    Change from baseline in fasting plasma glucose
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 IDegLira Placebo
    Number of subjects analysed
    286
    144
    Units: mmol/L
        arithmetic mean (standard deviation)
    -2.6 ± 2.61
    -0.31 ± 2.43
    No statistical analyses for this end point

    Secondary: Change from baseline in body weight

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    End point title
    		 Change from baseline in body weight
    End point description
    Change from baseline in body weight
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment.
    End point values
    		 IDegLira Placebo
    Number of subjects analysed
    289
    146
    Units: Kg
        arithmetic mean (standard deviation)
    0.5 ± 3.1
    -1 ± 2.6
    No statistical analyses for this end point

    Secondary: Number of treatment emergent (confirmed) hypoglycaemic episodes

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    End point title
    		 Number of treatment emergent (confirmed) hypoglycaemic episodes
    End point description
    Number of treatment emergent (confirmed) hypoglycaemic episodes
    End point type
    Secondary
    End point timeframe
    During 26 weeks of treatment.
    End point values
    		 IDegLira Placebo
    Number of subjects analysed
    288
    146
    Units: Event rate per 100 PYE
        number (not applicable)
    351.7
    135.2
    No statistical analyses for this end point

    Secondary: Number of treatment emergent adverse events (AEs)

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    End point title
    		 Number of treatment emergent adverse events (AEs)
    End point description
    Number of treatment emergent adverse events (AEs). A treatment-emergent AE (TEAE) was defined as an event that had onset date on or after the first day of exposure to randomised treatment and no later than 7 days after the last day on randomised treatment.
    End point type
    Secondary
    End point timeframe
    During 26 weeks of treatment.
    End point values
    		 IDegLira Placebo
    Number of subjects analysed
    288
    146
    Units: Event rate per 100 PYE
        number (not applicable)
    401.4
    367
    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 treatment period to follow up period (26 weeks + 1 week).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 All 146 subjects receiving at least one dose of placebo were evaluated for AE.

    Reporting group title
    IDegLira
    Reporting group description
    		 All 288 subjects receiving at least one dose of IDegLira were evaluated for AE.

    Serious adverse events
    		 Placebo IDegLira
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 146 (3.42%)
    14 / 288 (4.86%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pleural mesothelioma malignant
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         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 revascularisation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stab wound
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 288 (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
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Normal tension glaucoma
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 288 (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
    Renal failure acute
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis haemophilus
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo IDegLira
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 146 (26.03%)
    83 / 288 (28.82%)
    Investigations
    Lipase increased
         subjects affected / exposed
    6 / 146 (4.11%)
    27 / 288 (9.38%)
         occurrences all number
    8
    29
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 146 (5.48%)
    15 / 288 (5.21%)
         occurrences all number
    11
    18
    Infections and infestations
    Influenza
         subjects affected / exposed
    8 / 146 (5.48%)
    8 / 288 (2.78%)
         occurrences all number
    9
    8
    Nasopharyngitis
         subjects affected / exposed
    12 / 146 (8.22%)
    25 / 288 (8.68%)
         occurrences all number
    15
    29
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    6 / 146 (4.11%)
    19 / 288 (6.60%)
         occurrences all number
    7
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Feb 2013
    Hypoglycaemic and adverse events definitions were updated. Informed consent was updated for blood volume drawn and for increased heart rate as per liraglutide Investigator's brochure. List of participating countries, recruitment timeliens, blood volume to be drawn and list of adverse events of special interest was updated.

    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.
    Not Applicable
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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