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    Clinical Trial Results:
    Multicentre, randomized, controlled open-label study over 24 weeks comparing metformin/vildagliptin + basal insulin versus metformin/sulphonylurea + basal insulin therapy in type 2 diabetes patients initiating insulin after a dual therapy by metformin/suphonylurea

    Summary
    EudraCT number
    		 2012-005183-94
    Trial protocol
    		 FR  
    Global end of trial date
    23 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2016
    First version publication date
    09 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLAF237AFR07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01871558
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH 4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    23 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the proportion of patients presenting no episode of symptomatic hypoglycaemia during the 24 weeks of randomized treatment in each treatment arm (in association with basal insulin).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jun 2013
    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
    France: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    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)
    21
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Eligible patients were randomized in a 1:1 ratio between the vildagliptin arm (Vildagliptin 50 mg 2 tablets/day) + metformin and SU/or glinide arm + metformin (control treatment).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Metformin/vildagliptin + Basal Insulin
    Arm description
    		 Randomized patient will receive Vildagliptin 50 mg twice daily (b.i.d) + continued therapy with Metformin, + start of Basal Insulin up-titrated as per usual algorithms primarily based on FPG
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vildagliptin
    Investigational medicinal product code
    LAF237
    Other name
    Galvus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg b.i.d

    Arm title
    		 SU+metformin + Basal Insulin
    Arm description
    		 Randomized patient will remain on their previous dual therapy by SU+metformin, which will be kept unchanged, + start of Basal Insulin up-titrated as per usual algorithms primarily based on FPG
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SU+metformin + Basal Insulin

    Number of subjects in period 1
    		Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Started
    21
    21
    Completed
    18
    19
    Not completed
    3
    2
         Consent withdrawn by subject
    2
    -
         Other reason
    -
    1
         antidiabetic drug prematurely stopped
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metformin/vildagliptin + Basal Insulin
    Reporting group description
    		 Randomized patient will receive Vildagliptin 50 mg twice daily (b.i.d) + continued therapy with Metformin, + start of Basal Insulin up-titrated as per usual algorithms primarily based on FPG

    Reporting group title
    SU+metformin + Basal Insulin
    Reporting group description
    		 Randomized patient will remain on their previous dual therapy by SU+metformin, which will be kept unchanged, + start of Basal Insulin up-titrated as per usual algorithms primarily based on FPG

    Reporting group values
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin Total
    Number of subjects
    		 21 21 42
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 12 9 21
        From 65-84 years
    		 9 12 21
        85 years and over
    		 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 60.6 ± 12.52 66.8 ± 7.8 -
    Gender, Male/Female
    Units: participants
        Female
    		 10 8 18
        Male
    		 11 13 24

    End points

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    End points reporting groups
    Reporting group title
    Metformin/vildagliptin + Basal Insulin
    Reporting group description
    		 Randomized patient will receive Vildagliptin 50 mg twice daily (b.i.d) + continued therapy with Metformin, + start of Basal Insulin up-titrated as per usual algorithms primarily based on FPG

    Reporting group title
    SU+metformin + Basal Insulin
    Reporting group description
    		 Randomized patient will remain on their previous dual therapy by SU+metformin, which will be kept unchanged, + start of Basal Insulin up-titrated as per usual algorithms primarily based on FPG

    Primary: Percentage of patients who reported at least one symptomatic hypoglycemic event during the 24 week randomized period in both treatment arms

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    End point title
    		 Percentage of patients who reported at least one symptomatic hypoglycemic event during the 24 week randomized period in both treatment arms
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Number of subjects analysed
    21
    21
    Units: percent of participants
        number (not applicable)
    22.2
    45
    Statistical analysis title
    		 Primary Stats
    Comparison groups
    Metformin/vildagliptin + Basal Insulin v SU+metformin + Basal Insulin
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.139
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Percentage of patients reaching their glycemic target without hypoglycemic events

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    End point title
    		 Percentage of patients reaching their glycemic target without hypoglycemic events
    End point description
    Glycemic target is defined as Glycated hemoglobin(HbA1c) ≤ 7%
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Number of subjects analysed
    19
    19
    Units: percent of participants
        number (not applicable)
    44.4
    47.4
    No statistical analyses for this end point

    Secondary: Change from baseline in HbA1c to week 24 in both treatment arms

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    End point title
    		 Change from baseline in HbA1c to week 24 in both treatment arms
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Number of subjects analysed
    18
    19
    Units: HbA1c percent
    arithmetic mean (standard deviation)
        baseline
    8.2 ± 0.56
    8.2 ± 0.42
        week 24
    7.2 ± 0.71
    7.4 ± 0.89
    No statistical analyses for this end point

    Secondary: Change from baseline in body weight in both treatment arms

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    End point title
    		 Change from baseline in body weight in both treatment arms
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Number of subjects analysed
    21
    21
    Units: kg
        arithmetic mean (standard deviation)
    -0.3 ± 2.51
    1.4 ± 2.61
    No statistical analyses for this end point

    Secondary: Mean daily insulin dose at Week 24

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    End point title
    		 Mean daily insulin dose at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Number of subjects analysed
    18
    19
    Units: (U/d)
        arithmetic mean (standard deviation)
    33 ± 23.08
    19.8 ± 13.83
    No statistical analyses for this end point

    Secondary: Percentage of patients with severe and confirmed hypoglycemic events

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    End point title
    		 Percentage of patients with severe and confirmed hypoglycemic events
    End point description
    Severe hypoglycemic events (and number of events) , defined as events requiring assistance of a third party, and with confirmed hypoglycemic events (and number of events) defined as events with concomitant self monitoring of blood glucose (SMBG) < 70 mg/dL
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Number of subjects analysed
    18
    17
    Units: percent participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: percent of participants that reach therapeutic goal (HbA1c ≤ 7%) at Week 24 without any hypoglycaemic episode (symptomatic or not) and without any weight gain (variation ≥3% compared to baseline)

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    End point title
    		 percent of participants that reach therapeutic goal (HbA1c ≤ 7%) at Week 24 without any hypoglycaemic episode (symptomatic or not) and without any weight gain (variation ≥3% compared to baseline)
    End point description
    HbA1c <= 7% without any hypoglycaemic episode (symptomatic or not) and without any weight gain
    End point type
    Secondary
    End point timeframe
    week 24
    End point values
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Number of subjects analysed
    19
    19
    Units: percent of participants
        number (not applicable)
    27.8
    21.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Metformin/vildagliptin + Basal Insulin
    Reporting group description
    		 Randomized patient will receive Vildagliptin 50 mg twice daily (b.i.d) + continued therapy with Metformin, + start of Basal Insulin up-titrated as per usual algorithms primarily based on FPG

    Reporting group title
    SU+metformin + Basal Insulin
    Reporting group description
    		 Randomized patient will remain on their previous dual therapy by SU+metformin, which will be kept unchanged, + start of Basal Insulin up-titrated as per usual algorithms primarily based on FPG

    Serious adverse events
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Metformin/vildagliptin + Basal Insulin SU+metformin + Basal Insulin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 21 (19.05%)
    10 / 21 (47.62%)
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Parkinson's disease
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Visual impairment
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Infections and infestations
    Tooth abscess
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2013
    The time required for the dual therapy by metformin + SU (or glinides) before enrolling
    13 Jun 2014
    This statistical amendment aimed in turning the ADDONIS study into an exploratory pilot

    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
    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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