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    Clinical Trial Results:
    A trial comparing sequential addition of insulin aspart versus further dose increase with insulin degludec/liraglutide in subjects with type 2 diabetes mellitus, previously treated with insulin degludec/liraglutide and metformin and in need of further intensification

    Summary
    EudraCT number
    		 2013-002878-47
    Trial protocol
    		 ES   GR   HU   SK  
    Global end of trial date
    27 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2016
    First version publication date
    12 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9068-4119
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02100475
    WHO universal trial number (UTN)
    		 U1111-1145-0183
    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 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To explore the efficacy of dose adjustment of insulin degludec/liraglutide to a maximum dose of 80 dose steps as compared to adding insulin aspart to insulin degludec/liraglutide with a maximum dose of 50 dose steps, both arms in combination with metformin, in controlling glycaemia.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Seoul, 2008), ICH Good Clinical Practice and FDA 21 CFR 312.120.
    Background therapy
    		 As a background therapy, subjects continued metformin treatment at pre-trial dose level (dose as taken at visit 28 in NN9068-3952) throughout the trial period. However, reduction in dose of metformin treatment was allowed for safety reasons based on the investigator's judgement.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    03 Apr 2014
    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: 7
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    South Africa: 1
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 1
    Worldwide total number of subjects
    31
    EEA total number of subjects
    10
    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)
    22
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 19 sites in 8 countries as follows: Argentina: 2 sites; Greece: 2 sites, Hungary: 1 site; Russian Federation: 5 sites; Slovakia: 4 sites, South Africa: 1 site; Spain: 1 site, United States: 3 sites.

    Pre-assignment
    Screening details
    		 Subjects with type 2 diabetes mellitus who were inadequately controlled (HbA1c level ≥ 7% [53 mmol/mol]) on treatment with IDegLira after 26 weeks of treatment in the NN9068-3952 trial were screened for this trial. Eligible subjects were randomised in a 1:1 manner to one of the two parallel treatment groups (IDegLira or IDegLira + IAsp).

    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
    		 IDegLira
    Arm description
    		 Insulin degludec/liraglutide (IDegLira) was given subcutaneously (s.c., under the skin) once daily in combination with metformin. Treatment intensification with IDegLira was done by increasing the dose up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    IDegLira
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects started on the same treatment dose of IDegLira as used in the NN9068-3952 trial at visit 28 (end of 26 weeks of treatment). IDegLira was given subcutaneously (s.c., under the skin), once daily. Treatment intensification with IDegLira was done by increasing the dose up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira).

    Arm title
    		 IDegLira + IAsp
    Arm description
    		 IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. IDegLira titrated up to a maximum dose of 50 steps (50 units IDeg/1.8 mg Lira) with the sequential add-on of bolus IAsp. Dose titration of insulin aspart was based on the respective pre-meal(s) and bedtime self-measured plasma glucose (SMPG) measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    IAsp
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IAsp was given subcutaneously (s.c., under the skin), 1, 2 or 3 times per day. The starting dose of IAsp for subjects intensified with IDegLira + IAsp was 4 units of IAsp. Dose titration of insulin aspart was based on the respective pre-meal(s) and bedtime self-measured plasma glucose measured daily. No maximum dose of IAsp was specified. An extra IAsp dose was allowed at the investigator’s discretion.

    Investigational medicinal product name
    IDegLira
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects started on the same treatment dose of IDegLira as used in the NN9068-3952 trial at visit 28 (end of 26 weeks of treatment). IDegLira was given subcutaneously (s.c., under the skin) once daily. IDegLira titrated up to a maximum dose of 50 steps (50 units IDeg/1.8 mg Lira).

    Number of subjects in period 1
    		IDegLira IDegLira + IAsp
    Started
    16
    15
    Completed
    14
    13
    Not completed
    2
    2
         unclassified
    1
    2
         withdrawal criteria
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IDegLira
    Reporting group description
    		 Insulin degludec/liraglutide (IDegLira) was given subcutaneously (s.c., under the skin) once daily in combination with metformin. Treatment intensification with IDegLira was done by increasing the dose up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).

    Reporting group title
    IDegLira + IAsp
    Reporting group description
    		 IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. IDegLira titrated up to a maximum dose of 50 steps (50 units IDeg/1.8 mg Lira) with the sequential add-on of bolus IAsp. Dose titration of insulin aspart was based on the respective pre-meal(s) and bedtime self-measured plasma glucose (SMPG) measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).

    Reporting group values
    		 IDegLira IDegLira + IAsp Total
    Number of subjects
    		 16 15 31
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.3 ± 11.7 57.4 ± 11.2 -
    Gender categorical
    Units: Subjects
        Female
    		 9 8 17
        Male
    		 7 7 14
    HbA1c
    Units: Percentage
        arithmetic mean (standard deviation)
    		 7.6 ± 0.9 7.7 ± 0.7 -

    End points

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    End points reporting groups
    Reporting group title
    IDegLira
    Reporting group description
    		 Insulin degludec/liraglutide (IDegLira) was given subcutaneously (s.c., under the skin) once daily in combination with metformin. Treatment intensification with IDegLira was done by increasing the dose up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).

    Reporting group title
    IDegLira + IAsp
    Reporting group description
    		 IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. IDegLira titrated up to a maximum dose of 50 steps (50 units IDeg/1.8 mg Lira) with the sequential add-on of bolus IAsp. Dose titration of insulin aspart was based on the respective pre-meal(s) and bedtime self-measured plasma glucose (SMPG) measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).

    Primary: Change from baseline in HbA1c

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    End point title
    		 Change from baseline in HbA1c
    End point description
    Change from baseline in HbA1c after 26 weeks of treatment. Full analysis set (FAS) included all randomised subjects (31 subjects). Data were presented based on last observation carried forward (LOCF) method.
    End point type
    Primary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 IDegLira IDegLira + IAsp
    Number of subjects analysed
    16
    15
    Units: percent
        arithmetic mean (standard deviation)
    -0.43 ± 0.94
    -0.14 ± 1.09
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The response and change from baseline in the response after 26 weeks of treatment was analysed using an analysis of covariance (ANCOVA) method with treatment and baseline IDegLira dose strata as fixed factors and baseline response as a covariate. Missing data were imputed using LOCF.
    Comparison groups
    IDegLira v IDegLira + IAsp
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.427
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.05
         upper limit
    		 0.46
    Variability estimate
    Standard error of the mean

    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 after 26 weeks of treatment. FAS included all randomised subjects (31 subjects). Data were presented based on LOCF method.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    		 IDegLira IDegLira + IAsp
    Number of subjects analysed
    16
    15
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    0.9 ± 2.1
    1.5 ± 3.2
    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
    Safety analysis set (SAS) included all subjects receiving at least one dose of the investigational product or comparator (31 subjects). Treatment-emergent Hypoglycaemic episodes: if the onset of the episode occurred on or after the first day of investigational medicinal product administration, and no later than 7 days after the last day on investigational medicinal product. Confirmed hypoglycaemia: Subject unable to treat himself/herself and/or have a recorded plasma glucose < 3.1 mmol/L (56 mg/dL).
    End point type
    Secondary
    End point timeframe
    During 26 weeks of treatment
    End point values
    		 IDegLira IDegLira + IAsp
    Number of subjects analysed
    16
    15
    Units: number of episodes
    34
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first day of exposure to randomised treatment to 7 days after the last day of randomised treatment.
    Adverse event reporting additional description
    SAS included all subjects receiving at least one dose of the investigational product or comparator, (SAS = 31 subjects). A treatment-emergent adverse event (TEAE) was defined as an event that had an onset date on or after the first day of exposure to randomised treatment and no later than seven days after the last day of randomised treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    IDegLira + IAsp
    Reporting group description
    		 IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. IDegLira titrated up to a maximum dose of 50 steps (50 units IDeg/1.8 mg Lira) with the sequential add-on of bolus IAsp. Dose titration of insulin aspart was based on the respective pre-meal(s) and bedtime SMPG measured daily. All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).

    Reporting group title
    IDegLira
    Reporting group description
    		 IDegLira was given subcutaneously (s.c., under the skin) once daily in combination with metformin. Treatment intensification with IDegLira was done by increasing the dose up to a maximum of 80 dose steps (80 units IDeg/2.9 mg Lira). All subjects continued with metformin at pre-trial doses (≥ 1500 mg or the maximum tolerated dose).

    Serious adverse events
    		 IDegLira + IAsp IDegLira
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 16 (6.25%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (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 coronary syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         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 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    		 IDegLira + IAsp IDegLira
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
    11 / 16 (68.75%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Blood calcitonin increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Cardiac murmur
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Lipase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Tooth disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Renal cyst
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Tendonitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0

    More information

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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.
    Due to the small number of subjects in this trial, the data should be interpreted with caution.
    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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