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    Clinical Trial Results:
    A double blind, double dummy, randomised, multi-centre study to assess the tolerability and efficacy profile of vildagliptin compared to gliclazide as dual therapy with metformin in Muslim patients with type 2 diabetes fasting during Ramadan

    Summary
    EudraCT number
    		 2011-005499-41
    Trial protocol
    		 DK   ES   GB  
    Global end of trial date
    05 Sep 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    24 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLAF237A2411
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01758380
    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
    05 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate in Muslim patients with T2DM who plan to fast during the Ramadan fasting period: The proportion of patients with at least one HE (Hypoglycaemic event) is lower in the vildagliptin plus metformin arm compared to the gliclazide plus metformin arm during the Ramadan fasting period.
    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. Basal insulin could be used as rescue medication at the discretion of the investigator any time during the study after randomization for those patients who were not achieving a satisfactory therapeutic effect.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jan 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
    Denmark: 1
    Country: Number of subjects enrolled
    Egypt: 86
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Indonesia: 38
    Country: Number of subjects enrolled
    Jordan: 35
    Country: Number of subjects enrolled
    Kuwait: 13
    Country: Number of subjects enrolled
    Lebanon: 85
    Country: Number of subjects enrolled
    Malaysia: 21
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    Saudi Arabia: 13
    Country: Number of subjects enrolled
    Singapore: 31
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Tunisia: 57
    Country: Number of subjects enrolled
    Turkey: 25
    Country: Number of subjects enrolled
    United Arab Emirates: 10
    Country: Number of subjects enrolled
    United Kingdom: 31
    Worldwide total number of subjects
    557
    EEA total number of subjects
    93
    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)
    491
    From 65 to 84 years
    66
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A screening period of up to 4 weeks was used to ensure the entry criteria are met and allowing test results to be received and evaluated.

    Period 1
    Period 1 title
    Double blind randomized (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The identity of the treatments was concealed by the use of study drugs that were identical in packaging, labeling, schedule of administration and appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vildagliptin (50 mg bid) + Metformin
    Arm description
    		 Metformin 1500-2500 mg daily plus vildagliptin 50 mg bid plus gliclazide placebo (in multiples of 80 mg only). The overall treatment duration consisted of a ≥ 8 week pre-Ramadan stabilization period, the 4-week Ramadan period and a post-Ramadan period of ≤ 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin 500 mg tablets 1500-2500 mg daily for the ≥ 8 week pre-Ramadan stabilization period, the 4-week Ramadan period and a post-Ramadan period of ≤ 4 weeks.

    Investigational medicinal product name
    Vildagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vildagliptin 50 mg tablets twice a day (bid) for the ≥ 8 week pre-Ramadan stabilization period, the 4-week Ramadan period and a post-Ramadan period of ≤ 4 weeks.

    Investigational medicinal product name
    Gliclazide placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Gliclazide 80 mg matching placebo capsules administered at an equivalent dose to previous sulfonylurea treatment or adjusted in accordance with international or local guidelines, for the ≥ 8 week pre-Ramadan stabilization period, the 4-week Ramadan period and a post-Ramadan period of ≤ 4 weeks.

    Arm title
    		 Gliclazide (80-320 mg/d) + Metformin
    Arm description
    		 Metformin 1500-2500 mg daily plus gliclazide 80-320 mg/d (in multiples of 80 mg only) plus vildagliptin 50 mg placebo.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin 500 mg tablets 1500-2500 mg daily for the ≥ 8 week pre-Ramadan stabilization period, the 4-week Ramadan period and a post-Ramadan period of ≤ 4 weeks.

    Investigational medicinal product name
    Vildagliptin Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vildagliptin 50 mg matching placebo tablets twice a day (bid) for the ≥ 8 week pre-Ramadan stabilization period, the 4-week Ramadan period and a post-Ramadan period of ≤ 4 weeks.

    Investigational medicinal product name
    Gliclazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Gliclazide 80-320 mg/d (80 mg capsules) administered at an equivalent dose to previous sulfonylurea treatment or adjusted in accordance with international or local guidelines, for the ≥ 8 week pre-Ramadan stabilization period, the 4-week Ramadan period and a post-Ramadan period of ≤ 4 weeks.

    Number of subjects in period 1
    		Vildagliptin (50 mg bid) + Metformin Gliclazide (80-320 mg/d) + Metformin
    Started
    279
    278
    Completed
    239
    239
    Not completed
    40
    39
         Consent withdrawn by subject
    14
    13
         Adverse event, non-fatal
    8
    10
         Unsatisfactory therapeutic effect
    2
    1
         Administrative problems
    9
    7
         Lost to follow-up
    7
    7
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vildagliptin (50 mg bid) + Metformin
    Reporting group description
    		 Metformin 1500-2500 mg daily plus vildagliptin 50 mg bid plus gliclazide placebo (in multiples of 80 mg only). The overall treatment duration consisted of a ≥ 8 week pre-Ramadan stabilization period, the 4-week Ramadan period and a post-Ramadan period of ≤ 4 weeks.

    Reporting group title
    Gliclazide (80-320 mg/d) + Metformin
    Reporting group description
    		 Metformin 1500-2500 mg daily plus gliclazide 80-320 mg/d (in multiples of 80 mg only) plus vildagliptin 50 mg placebo.

    Reporting group values
    		 Vildagliptin (50 mg bid) + Metformin Gliclazide (80-320 mg/d) + Metformin Total
    Number of subjects
    		 279 278 557
    Age categorical
    Units: Subjects
        <65
    		 248 243 491
        ≥65
    		 31 35 66
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.6 ( 9.28 ) 54.3 ( 9.07 ) -
    Gender categorical
    Units: Subjects
        Female
    		 147 150 297
        Male
    		 132 128 260

    End points

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    End points reporting groups
    Reporting group title
    Vildagliptin (50 mg bid) + Metformin
    Reporting group description
    		 Metformin 1500-2500 mg daily plus vildagliptin 50 mg bid plus gliclazide placebo (in multiples of 80 mg only). The overall treatment duration consisted of a ≥ 8 week pre-Ramadan stabilization period, the 4-week Ramadan period and a post-Ramadan period of ≤ 4 weeks.

    Reporting group title
    Gliclazide (80-320 mg/d) + Metformin
    Reporting group description
    		 Metformin 1500-2500 mg daily plus gliclazide 80-320 mg/d (in multiples of 80 mg only) plus vildagliptin 50 mg placebo.

    Subject analysis set title
    Vildagliptin (50 mg bid) + Metformin Per Protocol Set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS consisted of all randomized patients that received at least one dose of study medication and fasted at least 10 days or stopped fasting due to hypoglycemia during the Ramadan fasting period, and had no major protocol deviations and had taken study medication for at least 10 days during Ramadan.

    Subject analysis set title
    Gliclazide (80-320 mg/d) + Metformin Per Protocol Set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS consisted of all randomized patients that received at least one dose of study medication and fasted at least 10 days or stopped fasting due to hypoglycemia during the Ramadan fasting period, and had no major protocol deviations and had taken study medication for at least 10 days during Ramadan.

    Subject analysis set title
    Vildagliptin (50 mg bid) + Metformin Safety Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAF consisted of all randomized patients that received at least one dose of study medication.

    Subject analysis set title
    Gliclazide (80-320 mg/d) + Metformin Safety Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAF consisted of all randomized patients that received at least one dose of study medication.

    Subject analysis set title
    Vildagliptin (50 mg bid) + Metformin Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS consisted of all randomized patients that received at least one dose of study medication.

    Subject analysis set title
    Gliclazide (80-320 mg/d) + Metformin Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS consisted of all randomized patients that received at least one dose of study medication.

    Primary: Percentage of Participants Reporting at Least One Hypoglycemic Event (HE) During the Ramadan Fasting Period While Not on Rescue Medication

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    End point title
    		 Percentage of Participants Reporting at Least One Hypoglycemic Event (HE) During the Ramadan Fasting Period While Not on Rescue Medication
    End point description
    HEs are defined as: a) symptoms suggestive of hypoglycemia, where the patient is able to initiate self-treatment and plasma glucose measurement is < 3.9 mmol/L (grade 1 HEs), b) symptoms suggestive of hypoglycemia, where the patient is able to initiate self-treatment and no plasma glucose measurement is available (suspected grade 1 HEs), c) symptoms suggestive of hypoglycemia, where the patient is unable to initiate self-treatment and plasma glucose measurement is <3.9 mmol/L (grade 2 HEs), d) symptoms suggestive of hypoglycemia, where the patient is unable to initiate self-treatment and no plasma glucose measurement is available (suspected grade 2 HEs), e) Plasma glucose measurement < 3.9 mmol/L without symptoms (asymptomatic HEs).
    End point type
    Primary
    End point timeframe
    1 month
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Per Protocol Set (PPS) Gliclazide (80-320 mg/d) + Metformin Per Protocol Set (PPS)
    Number of subjects analysed
    234
    230
    Units: percentage of participants
        number (confidence interval 95%)
    6 (3.31 to 9.83)
    8.7 (5.39 to 13.11)
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Vildagliptin (50 mg bid) + Metformin Per Protocol Set (PPS) v Gliclazide (80-320 mg/d) + Metformin Per Protocol Set (PPS)
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.173
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.06

    Secondary: Change from Pre-Ramadan to Post-Ramadan HbA1c (Glycosylated Hemoglobin / Hemoglobin A1c)

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    End point title
    		 Change from Pre-Ramadan to Post-Ramadan HbA1c (Glycosylated Hemoglobin / Hemoglobin A1c)
    End point description
    Pre-Ramadan is the measurement obtained at Visit 3 (within 4 weeks before start of Ramadam). Post-Ramadan is defined as the final available post-baseline HbA1c measurement obtained at any visit (scheduled or unscheduled) during or after Ramadan, prior to or at the start of rescue medication use, up to final scheduled visit (Visit 4). The endpoint (for PPS) was defined as the final HbA1c measurement obtained during or after Ramadan, prior to or at the initiation of rescue medication.
    End point type
    Secondary
    End point timeframe
    Visit 3 (anytime from week -4 to day -1 before start of Ramadan) to visit 4 (within 4 weeks post-Ramadan fasting period) (minimum 4.5 weeks to maximum 12 weeks).
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Per Protocol Set (PPS) Gliclazide (80-320 mg/d) + Metformin Per Protocol Set (PPS)
    Number of subjects analysed
    224 [1]
    218 [2]
    Units: HbA1c
        least squares mean (standard error)
    0.05 ( 0.04 )
    -0.03 ( 0.04 )
    Notes
    [1] - Number of participants with observations at both Pre-Ramadan and Post-Ramadan.
    [2] - Number of participants with observations at both Pre-Ramadan and Post-Ramadan.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Endpoint in Glycosylated Hemoglobin (HbA1c)

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    End point title
    		 Change from Baseline to Endpoint in Glycosylated Hemoglobin (HbA1c)
    End point description
    Endpoint is defined as the visit 4 (post-Ramadan) measurement or the last observation obtained during or after Ramadan, prior to or at initiation of rescue medication. Baseline HbA1c was the measurement obtained on the day of randomization (Visit 2), or the closest prior measurement to Visit 2 (including scheduled and unscheduled visits) if the Visit 2 measurement was missing. Post-Ramadan is defined as the final available post baseline HbA1c measurement obtained at any visit (scheduled or unscheduled) during or after Ramadan, prior to or at the start of rescue medication.
    End point type
    Secondary
    End point timeframe
    Baseline to visit 4 (within 4 weeks post-Ramadan fasting period) (minimum 12.5 weeks to maximum 30 weeks)
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Per Protocol Set (PPS) Gliclazide (80-320 mg/d) + Metformin Per Protocol Set (PPS)
    Number of subjects analysed
    227 [3]
    220 [4]
    Units: HbA1c
        least squares mean (standard error)
    -0.01 ( 0.05 )
    -0.13 ( 0.05 )
    Notes
    [3] - Number of participants with observations at both Baseline and Post-Ramadan.
    [4] - Number of participants with observations at both Baseline and Post-Ramadan.
    No statistical analyses for this end point

    Secondary: Percentage of Participants achieving composite endpoint from Pre- to Post-Ramadan prior to the start of rescue medication

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    End point title
    		 Percentage of Participants achieving composite endpoint from Pre- to Post-Ramadan prior to the start of rescue medication
    End point description
    The composite endpoint was defined as change in HbA1c pre- to post-Ramadan not larger than 0.3% and no HEs during the Ramadan fasting period.
    End point type
    Secondary
    End point timeframe
    Visit 3 (anytime from week -4 to day -1 before start of Ramadan) to visit 4 (within 4 weeks post- Ramadan fasting period) (minimum 4.5 weeks to maximum 12 weeks) for HbA1c; and during 1 month (Ramadan) for HEs
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Per Protocol Set (PPS) Gliclazide (80-320 mg/d) + Metformin Per Protocol Set (PPS)
    Number of subjects analysed
    234
    230
    Units: percentage of participants
        number (not applicable)
    79.5
    74.8
    No statistical analyses for this end point

    Secondary: Mean Amplitude of Glycemic Excursions (MAGE) to Measure Glucose Fluctuations During the Day

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    End point title
    		 Mean Amplitude of Glycemic Excursions (MAGE) to Measure Glucose Fluctuations During the Day
    End point description
    MAGE was to be assessed in a selected subgroup of patients. Analysis was not done due lack of enough evaluable data.
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Per Protocol Set (PPS) Gliclazide (80-320 mg/d) + Metformin Per Protocol Set (PPS)
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: no units
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [5] - Not done due to lack of enough evaluable data.
    [6] - Not done due to lack of enough evaluable data.
    No statistical analyses for this end point

    Secondary: Change from Pre-Ramadan to Post-Ramadan Body Weight

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    End point title
    		 Change from Pre-Ramadan to Post-Ramadan Body Weight
    End point description
    Baseline body weight was the measurement obtained on the day of randomization (Visit 2), or the closest prior measurement to Visit 2 (including scheduled and unscheduled visits) if the Visit 2 measurement was missing. Post-Ramadan is defined as the final available post-baseline measurement of body weight obtained at any visit (scheduled or unscheduled) during or after Ramadan, prior to or at the start of rescue medication use, up to final scheduled visit (Visit 4). The endpoint (for PPS) was defined as the final body weight measurement obtained during or after Ramadan, prior to or at the initiation of rescue medication.
    End point type
    Secondary
    End point timeframe
    Visit 3 (anytime from week -4 to day -1 before start of Ramadan) to visit 4 (within 4 weeks post- Ramadan fasting period) (minimum 4.5 weeks to maximum 12 weeks)
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Per Protocol Set (PPS) Gliclazide (80-320 mg/d) + Metformin Per Protocol Set (PPS)
    Number of subjects analysed
    231 [7]
    226 [8]
    Units: kg
        least squares mean (standard error)
    -1.06 ( 0.15 )
    -1.06 ( 0.15 )
    Notes
    [7] - Number of participants with observations at both pre-Ramadan and post- Ramadan.
    [8] - Number of participants with observations at both pre-Ramadan and post- Ramadan.
    No statistical analyses for this end point

    Secondary: Number of Days Fasted During the Ramadan Fasting Period

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    End point title
    		 Number of Days Fasted During the Ramadan Fasting Period
    End point description
    End point type
    Secondary
    End point timeframe
    1 month
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Safety Set (SAF) Gliclazide (80-320 mg/d) + Metformin Safety Set (SAF)
    Number of subjects analysed
    241 [9]
    242 [10]
    Units: days
        arithmetic mean (standard deviation)
    28.3 ( 3.03 )
    28.1 ( 3.83 )
    Notes
    [9] - Safety Set participants with observations on the number of days fasted during Ramadan.
    [10] - Safety Set participants with observations on the number of days fasted during Ramadan.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Having at Least 1 Unscheduled Visit to the Health Care Professional (HCP)

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    End point title
    		 Percentage of Participants Having at Least 1 Unscheduled Visit to the Health Care Professional (HCP)
    End point description
    End point type
    Secondary
    End point timeframe
    Between the pre- Ramadan visit (Visit 3) and the post-Ramadan visit (Visit 4)/end of study
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Full Analysis Set (FAS) Gliclazide (80-320 mg/d) + Metformin Full Analysis Set (FAS)
    Number of subjects analysed
    273
    274
    Units: percentage of participants
        number (not applicable)
    1.5
    3.3
    No statistical analyses for this end point

    Secondary: Overall Treatment Adherence During the Ramadan Fasting Period

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    End point title
    		 Overall Treatment Adherence During the Ramadan Fasting Period
    End point description
    Treatment adherence (%) was defined as: [number of days during Ramadan fasting period * (recommended therapy (metformin, vildagliptin, gliclazide) daily dose during Ramadan period) – (number of missed doses during Ramadan period)] *100/ [number of days during Ramadan fasting period * (recommended therapy daily dose during Ramadan period)]. Overall adherence (%) was defined as metformin adherence + vildagliptin adherence + gliclazide adherence / 3.
    End point type
    Secondary
    End point timeframe
    Number of days from start of Ramadan to the Ramadan end period date (minimum 4.5 weeks to maximum 12 weeks).
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Safety Set (SAF) Gliclazide (80-320 mg/d) + Metformin Safety Set (SAF)
    Number of subjects analysed
    273
    274
    Units: percentage
        arithmetic mean (standard deviation)
    96.7 ( 10.4 )
    95.8 ( 11.59 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Serious or Clinically Significant Adverse Events (AEs)

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    End point title
    		 Percentage of Participants with Serious or Clinically Significant Adverse Events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to visit 4 (within 4 weeks post-Ramadan fasting period) (minimum 12.5 weeks to maximum 30 weeks)
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Safety Set (SAF) Gliclazide (80-320 mg/d) + Metformin Safety Set (SAF)
    Number of subjects analysed
    273
    274
    Units: percentage of participants
    number (not applicable)
        Deaths
    0
    0
        Serious AEs
    2.2
    1.5
        Discontinuation due to AEs
    2.9
    4
        AEs causing dose adjustment or drug interruption
    2.6
    3.6
        AEs of predefined risk
    5.5
    9.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Severe Hypoglycemia or Hypoglycemic Events that Occurred During the Ramadan Fasting Period

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    End point title
    		 Percentage of Participants with Severe Hypoglycemia or Hypoglycemic Events that Occurred During the Ramadan Fasting Period
    End point description
    Severe hypoglycemia and hypoglycemic events are defined as suspected grade 2 (requiring 3rd party assistance).
    End point type
    Secondary
    End point timeframe
    1 month
    End point values
    		 Vildagliptin (50 mg bid) + Metformin Per Protocol Set (PPS) Gliclazide (80-320 mg/d) + Metformin Per Protocol Set (PPS)
    Number of subjects analysed
    234
    230
    Units: percentage of participants
        number (not applicable)
    0
    0
    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
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Vildagliptin (50 mg bid) + Metformin
    Reporting group description
    		 Metformin 1500-2500 mg daily plus vildagliptin 50 mg bid plus gliclazide placebo (in multiples of 80 mg only). The overall treatment duration consisted of a ≥ 8 week pre-Ramadan stabilization period, the 4- week Ramadan period and a post-Ramadan period of ≤ 4 weeks.

    Reporting group title
    Gliclazide (80-320 mg/d) + Metformin
    Reporting group description
    		 Metformin 1500-2500 mg daily plus gliclazide 80-320 mg/d (in multiples of 80 mg only) plus vildagliptin 50 mg placebo.

    Serious adverse events
    		 Vildagliptin (50 mg bid) + Metformin Gliclazide (80-320 mg/d) + Metformin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 273 (2.20%)
    4 / 274 (1.46%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    2 / 273 (0.73%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fissure
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 274 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 274 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 274 (0.36%)
         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: 1%
    Non-serious adverse events
    		 Vildagliptin (50 mg bid) + Metformin Gliclazide (80-320 mg/d) + Metformin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 273 (17.22%)
    56 / 274 (20.44%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    3 / 273 (1.10%)
    3 / 274 (1.09%)
         occurrences all number
    3
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 273 (1.10%)
    2 / 274 (0.73%)
         occurrences all number
    3
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 273 (1.10%)
    1 / 274 (0.36%)
         occurrences all number
    4
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 273 (1.83%)
    4 / 274 (1.46%)
         occurrences all number
    6
    5
    Headache
         subjects affected / exposed
    3 / 273 (1.10%)
    11 / 274 (4.01%)
         occurrences all number
    3
    14
    Lethargy
         subjects affected / exposed
    3 / 273 (1.10%)
    0 / 274 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 273 (0.37%)
    3 / 274 (1.09%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 273 (0.73%)
    3 / 274 (1.09%)
         occurrences all number
    2
    3
    Abdominal pain
         subjects affected / exposed
    0 / 273 (0.00%)
    3 / 274 (1.09%)
         occurrences all number
    0
    4
    Abdominal pain upper
         subjects affected / exposed
    5 / 273 (1.83%)
    2 / 274 (0.73%)
         occurrences all number
    5
    2
    Constipation
         subjects affected / exposed
    5 / 273 (1.83%)
    1 / 274 (0.36%)
         occurrences all number
    6
    1
    Diarrhoea
         subjects affected / exposed
    11 / 273 (4.03%)
    12 / 274 (4.38%)
         occurrences all number
    13
    15
    Flatulence
         subjects affected / exposed
    3 / 273 (1.10%)
    0 / 274 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    7 / 273 (2.56%)
    7 / 274 (2.55%)
         occurrences all number
    9
    8
    Vomiting
         subjects affected / exposed
    3 / 273 (1.10%)
    2 / 274 (0.73%)
         occurrences all number
    3
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 273 (0.37%)
    7 / 274 (2.55%)
         occurrences all number
    1
    10
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 273 (0.37%)
    4 / 274 (1.46%)
         occurrences all number
    1
    4
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 273 (1.47%)
    4 / 274 (1.46%)
         occurrences all number
    4
    4
    Nasopharyngitis
         subjects affected / exposed
    1 / 273 (0.37%)
    3 / 274 (1.09%)
         occurrences all number
    1
    3
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 273 (0.73%)
    4 / 274 (1.46%)
         occurrences all number
    2
    4
    Vitamin D deficiency
         subjects affected / exposed
    3 / 273 (1.10%)
    1 / 274 (0.36%)
         occurrences all number
    3
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2013
    When the study was designed, a very short recruitment period was envisioned. Enrolling patients within a very narrow time window would have ensured that all patients have a very similar overall study duration (i.e., from randomization (Visit 2) to last visit (Visit 4)). This was an important consideration for a reliable efficacy assessment over the entire treatment period. However, during the operational set-up phase of the study it became obvious that a longer time frame would be required to successfully complete recruitment: a large number of patients (>550) had to be enrolled in a very short period of time and due to the fixed start date of Ramadan no extension of the recruitment period would have been possible. Thus, to limit the risk of incomplete enrollment and to facilitate the study operationally, the time window for enrollment was markedly increased compared to the initial predictions, and patients therefore entered the study over a ~4 months period. Consequently, the time period from randomization to last visit varied considerably between patients (from ~13 to ~29 weeks). Given the different individual study durations, there was also a significant risk that the mean treatment duration may no longer be balanced between the treatments arms. In addition, from a clinical perspective, this may likely have an impact on the stability of treatment in the now extended pre-Ramadan period, with a higher probability of dose adjustments. Taken together, all these factors impact the validity/robustness of the non-inferiority (NI) assessment of the HbA1c changes from randomization to the last visit between treatments, which was a co-primary endpoint in the original protocol. Thus it was decided to focus the primary objective on the most important and new aspect of this study, i.e., to test in an interventional, double-blind setting the hypothesis of a lower incidence of hypoglycemia with vildagliptin versus SUs during the key study period of Ramadan.

    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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