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    Clinical Trial Results:
    A randomized, controlled multi-centre trial of 26 weeks of subcutaneous Liraglutide (a GLP1 receptor agonist), with or without continuous positive airway pressure (CPAP), in patients with Type 2 Diabetes Mellitus (T2DM) and Obstructive Sleep Apnoea (OSA)

    Summary
    EudraCT number
    		 2014-000988-41
    Trial protocol
    		 GB  
    Global end of trial date
    10 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Oct 2020
    First version publication date
    25 Oct 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UoL000977
    Additional study identifiers
    ISRCTN number
    		 ISRCTN16250774
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1139-0677
    Sponsors
    Sponsor organisation name
    Liverpool Clinical Trials Centre, University of Liverpool
    Sponsor organisation address
    1-3 Brownlow Street, Liverpool, United Kingdom, L69 3GL
    Public contact
    Charlotte Rawcliffe Liverpool Clinical Trials Centre University of Liverpool L69 3GL, Charlotte Rawcliffe Liverpool Clinical Trials Centre University of Liverpool L69 3GL, 0151 794 8167, clr001@liverpool.ac.uk
    Scientific contact
    Charlotte Rawcliffe Liverpool Clinical Trials Centre University of Liverpool L69 3GL, Charlotte Rawcliffe Liverpool Clinical Trials Centre University of Liverpool L69 3GL, 0151 794 8167, clr001@liverpool.ac.uk
    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 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective To determine whether twenty six weeks of Liraglutide treatment (up to 1.8mg) can provide a useful treatment for obese patients with T2DM and OSA, either as a stand-alone treatment or as an add-on treatment to continuous positive airway pressure (CPAP). We are primarily concerned with change from baseline in AHI (the principal measure of OSA severity).
    Protection of trial subjects
    Consent was obtained prior to each patient participating in the trial, after a full explanation had been given of the treatment options, including the conventional and generally accepted methods of treatment. All risks and potential benefits were explained to the patients, and all patients were provided with Patient Information Sheets prior to consent. Patients were given the right to refuse their consent to participate in the trial, and to withdraw at any time. The study also had a Trial Steering Committee that provided overall supervision of the trial, particularly focusing on the progress of the trial, adherence to the protocol, patient safety and consideration of new information. The TSC included experienced diabetes and sleep respiratory experts and clinical trialists. Meetings were held annually, but additional meetings could have been held if required.
    Background therapy
    		 N/A
    Evidence for comparator
    		 The co-existence of obesity and insulin resistance in Type 2 Diabetes Mellitus (T2DM) and Obstructive Sleep Apnoea (OSA) provide a robust and plausible rationale for the therapeutic administration of Liraglutide to T2DM patients with OSA. The study is being undertaken to understand possible effects of Liraglutide, both as a monotherapy and in combination with continuous positive airway pressure (CPAP), on OSA symptoms and glycaemic control in obese OSA patients with T2DM. The data collected will help shape optimal treatment strategies for this challenging clinical population.
    Actual start date of recruitment
    11 Nov 2015
    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
    United Kingdom: 132
    Worldwide total number of subjects
    132
    EEA total number of subjects
    132
    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)
    120
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment was estimated to be over a period of 24 months and took place in one centre – Aintree University Hospital, England (UK) – which expected to recruit 5-6 patients per month. Aintree site opened to recruitment on 10/09/2015. First patient randomised 12/11/2015; Last patient randomised 18/02/2019. 132 participants were recruited in total.

    Pre-assignment
    Screening details
    		 232 patients were screened and 132 were randomised. Subjects were recruited from diabetes or sleep apnoea clinics within the Aintree. Eligible subjects attended a screening visit between 2-21 days prior to randomisation and included medical history, concomitant medications, physical exam, blood tests and overnight home study.

    Period 1
    Period 1 title
    Intervention Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Control Arm
    Arm description
    		 Control arm, comprising conventional care for existing T2DM patients with no intervention for OSA. This group did not use placebo medication. Patients were asked to continue with their usual anti-diabetes medications and if titration of any anti-diabetes drugs is necessary, due to worsening glycaemic control, this was achieved by avoiding the use of any Liraglutide and patients were given subcutaneous insulin (using either once daily or twice daily formulations). Patients were not be given CPAP for this period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Arm B: CPAP
    Arm description
    		 Will receive conventional care plus CPAP. The CPAP device that will be used will be ResMed S9 (or other similar device) fixed pressure device in accordance with the standard clinical protocols.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Victoza
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide was administered as a once-daily subcutaneous injection in the abdomen, thigh or upper arm. It was given at a starting dose of 0.6 mg once daily, increasing after one week to 1.2mg once daily. After at least one week of treatment with 1.2mg the patient was reviewed again and the dose increased to 1.8mg once daily. The patients who could not tolerate the increased dose after the first week were asked to continue at 0.6mg daily and were re-challenged with the higher dose (1.2mg) after 4-weeks. If the intolerance persisted, patients were asked to remain on the lowest, tolerated dose. The trial specific prescription would allow the prescriber to specify individual doses and quantities for those patients who did not tolerate the intended dose.

    Arm title
    		 Arm C: Liraglutide
    Arm description
    		 Will receive conventional care plus Liraglutide (up to 1.8mg).
    Arm type
    		 CPAP Device

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Arm D: Liraglutide + CPAP
    Arm description
    		 Will receive conventional care plus Liraglutide plus CPAP. The CPAP device that will be used will be ResMed S9 (or other similar device) fixed pressure device in accordance with the standard clinical protocols.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Victoza
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide was administered as a once-daily subcutaneous injection in the abdomen, thigh or upper arm. It was given at a starting dose of 0.6 mg once daily, increasing after one week to 1.2mg once daily. After at least one week of treatment with 1.2mg the patient was reviewed again and the dose increased to 1.8mg once daily. The patients who could not tolerate the increased dose after the first week were asked to continue at 0.6mg daily and were re-challenged with the higher dose (1.2mg) after 4-weeks. If the intolerance persisted, patients were asked to remain on the lowest, tolerated dose. The trial specific prescription would allow the prescriber to specify individual doses and quantities for those patients who did not tolerate the intended dose.

    Number of subjects in period 1
    		Arm A: Control Arm Arm B: CPAP Arm C: Liraglutide Arm D: Liraglutide + CPAP
    Started
    33
    33
    33
    33
    Completed
    33
    33
    33
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Control Arm
    Reporting group description
    		 Control arm, comprising conventional care for existing T2DM patients with no intervention for OSA. This group did not use placebo medication. Patients were asked to continue with their usual anti-diabetes medications and if titration of any anti-diabetes drugs is necessary, due to worsening glycaemic control, this was achieved by avoiding the use of any Liraglutide and patients were given subcutaneous insulin (using either once daily or twice daily formulations). Patients were not be given CPAP for this period.

    Reporting group title
    Arm B: CPAP
    Reporting group description
    		 Will receive conventional care plus CPAP. The CPAP device that will be used will be ResMed S9 (or other similar device) fixed pressure device in accordance with the standard clinical protocols.

    Reporting group title
    Arm C: Liraglutide
    Reporting group description
    		 Will receive conventional care plus Liraglutide (up to 1.8mg).

    Reporting group title
    Arm D: Liraglutide + CPAP
    Reporting group description
    		 Will receive conventional care plus Liraglutide plus CPAP. The CPAP device that will be used will be ResMed S9 (or other similar device) fixed pressure device in accordance with the standard clinical protocols.

    Reporting group values
    		 Arm A: Control Arm Arm B: CPAP Arm C: Liraglutide Arm D: Liraglutide + CPAP Total
    Number of subjects
    		 33 33 33 33 132
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: months
        median (inter-quartile range (Q1-Q3))
    		 52 (48 to 57) 57 (49 to 60) 55 (45 to 61) 54 (46 to 61) -
    Gender categorical
    Units: Subjects
        Female
    		 17 20 19 11 67
        Male
    		 16 13 14 22 65
    Ethnicity
    Units: Subjects
        Other
    		 1 2 0 0 3
        White
    		 32 31 33 33 129
    Smoking Status
    Units: Subjects
        Current Smoker
    		 5 3 5 9 22
        Ex Smoker
    		 15 7 13 13 48
        Never Smoked
    		 13 23 15 11 62
    Height
    Units: cm
        median (inter-quartile range (Q1-Q3))
    		 165 (161 to 177) 165 (160 to 174) 168 (164 to 172) 173 (165 to 177) -
    Weight
    Units: kg
        median (inter-quartile range (Q1-Q3))
    		 106.9 (97.7 to 127.3) 107.8 (97.4 to 130.9) 105.9 (93.7 to 115.2) 106.9 (93.6 to 124.4) -
    Waist
    Units: cm
        median (inter-quartile range (Q1-Q3))
    		 124 (120 to 134) 127 (117 to 136) 121 (111 to 132) 123 (116 to 131) -
    Waist:Hip Ratio
    Units: cm
        median (inter-quartile range (Q1-Q3))
    		 1.035 (.99 to 1.073) 1.02 (.98 to 1.07) 1.03 (0.992 to 1.07) 1.02 (.99 to 1.058) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Control Arm
    Reporting group description
    		 Control arm, comprising conventional care for existing T2DM patients with no intervention for OSA. This group did not use placebo medication. Patients were asked to continue with their usual anti-diabetes medications and if titration of any anti-diabetes drugs is necessary, due to worsening glycaemic control, this was achieved by avoiding the use of any Liraglutide and patients were given subcutaneous insulin (using either once daily or twice daily formulations). Patients were not be given CPAP for this period.

    Reporting group title
    Arm B: CPAP
    Reporting group description
    		 Will receive conventional care plus CPAP. The CPAP device that will be used will be ResMed S9 (or other similar device) fixed pressure device in accordance with the standard clinical protocols.

    Reporting group title
    Arm C: Liraglutide
    Reporting group description
    		 Will receive conventional care plus Liraglutide (up to 1.8mg).

    Reporting group title
    Arm D: Liraglutide + CPAP
    Reporting group description
    		 Will receive conventional care plus Liraglutide plus CPAP. The CPAP device that will be used will be ResMed S9 (or other similar device) fixed pressure device in accordance with the standard clinical protocols.

    Subject analysis set title
    Intention To Treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Full analysis set following the intention-to-treat principle with 18 patients removed as data not available for final analysis

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Analysis of all patients to receive treatment (1 patient ended study prior to receiving treatment)

    Subject analysis set title
    Full Analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Being the set of patients recruited into the study

    Primary: AHI (i.e. OSA severity).

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    End point title
    		 AHI (i.e. OSA severity).
    End point description
    To determine whether twenty six weeks of Liraglutide treatment (up to 1.8mg) can provide a useful treatment for obese patients with T2DM and OSA, either as a stand-alone treatment or as an add-on treatment to continuous positive airway pressure (CPAP). We are primarily concerned with change from baseline in AHI (the principal measure of OSA severity).
    End point type
    Primary
    End point timeframe
    Change in AHI between baseline and Twenty six weeks
    End point values
    		 Arm A: Control Arm Arm B: CPAP Arm C: Liraglutide Arm D: Liraglutide + CPAP
    Number of subjects analysed
    29
    28
    31
    26
    Units: AHI
        median (inter-quartile range (Q1-Q3))
    -5.2 (-12.3 to 5.6)
    -7.95 (-15.825 to 1.725)
    -10.4 (-12.5 to -3.65)
    -10.9 (-19.525 to -7.525)
    Attachments
    		 AHI by arm
    Statistical analysis title
    		 Primary Outcome (CPAP)
    Comparison groups
    Arm A: Control Arm v Arm B: CPAP v Arm C: Liraglutide v Arm D: Liraglutide + CPAP
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.028 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.35
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -13.722
         upper limit
    		 1.019
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.861
    Notes
    [1] - Analysis of Covaraince
    [2] - Adjusted for multiple comparisons, a value of <0.01 required to determine statistical significance
    Statistical analysis title
    		 Primary Outcome (Liraglutide)
    Comparison groups
    Arm A: Control Arm v Arm B: CPAP v Arm C: Liraglutide v Arm D: Liraglutide + CPAP
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.1
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -15.518
         upper limit
    		 -0.692
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.878
    Notes
    [3] - Adjusted for multiple comparisons, a value of <0.01 required to determine statistical significance

    Secondary: HbA1c

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    End point title
    		 HbA1c
    End point description
    Assess the change from baseline in HbA1c.
    End point type
    Secondary
    End point timeframe
    Change in HbA1c between baseline and Twenty six weeks
    End point values
    		 Arm A: Control Arm Arm B: CPAP Arm C: Liraglutide Arm D: Liraglutide + CPAP
    Number of subjects analysed
    31
    27
    31
    28
    Units: HbA1c
        median (inter-quartile range (Q1-Q3))
    -1 (-5 to 4.5)
    1 (-4.5 to 4)
    -10 (-15.5 to -5)
    -11 (-19 to -4.25)
    Statistical analysis title
    		 HbA1C (CPAP)
    Comparison groups
    Arm A: Control Arm v Arm B: CPAP v Arm C: Liraglutide v Arm D: Liraglutide + CPAP
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.405
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.395
         upper limit
    		 5.954
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.13
    Statistical analysis title
    		 HbA1c (Liraglutide)
    Comparison groups
    Arm D: Liraglutide + CPAP v Arm A: Control Arm v Arm B: CPAP v Arm C: Liraglutide
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.861
         upper limit
    		 -6.524
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.127

    Secondary: Body Weight

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    End point title
    		 Body Weight
    End point description
    Assess the change from baseline in body weight.
    End point type
    Secondary
    End point timeframe
    Change between baseline and twenty six weeks
    End point values
    		 Arm A: Control Arm Arm B: CPAP Arm C: Liraglutide Arm D: Liraglutide + CPAP
    Number of subjects analysed
    31
    25
    31
    28
    Units: kg
        median (inter-quartile range (Q1-Q3))
    -1.8 (-3.525 to 0.65)
    -0.3 (-5.6 to 1.8)
    -6.9 (-10.4 to -2.35)
    -4.05 (-6.275 to -2.6)
    Statistical analysis title
    		 Body Weight (CPAP)
    Comparison groups
    Arm A: Control Arm v Arm B: CPAP v Arm C: Liraglutide v Arm D: Liraglutide + CPAP
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.404
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.339
         upper limit
    		 3.336
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.193
    Statistical analysis title
    		 Body Weight (Liraglutide)
    Comparison groups
    Arm A: Control Arm v Arm B: CPAP v Arm C: Liraglutide v Arm D: Liraglutide + CPAP
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.094
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.17
         upper limit
    		 -2.487
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.195

    Secondary: Oxygen Desturation Index

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    End point title
    		 Oxygen Desturation Index
    End point description
    End point type
    Secondary
    End point timeframe
    Change between baseline and twenty=six weeks
    End point values
    		 Arm A: Control Arm Arm B: CPAP Arm C: Liraglutide Arm D: Liraglutide + CPAP
    Number of subjects analysed
    27
    26
    30
    21
    Units: ODI
        median (inter-quartile range (Q1-Q3))
    -6.5 (-14.05 to 2.05)
    -7.65 (-14.875 to 4.3)
    -7.2 (-12.275 to 0.825)
    -12.2 (-19.7 to 5)
    Statistical analysis title
    		 ODI (CPAP)
    Comparison groups
    Arm B: CPAP v Arm A: Control Arm v Arm C: Liraglutide v Arm D: Liraglutide + CPAP
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.614
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.479
         upper limit
    		 4.996
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.437
    Statistical analysis title
    		 ODI (Liraglutide)
    Comparison groups
    Arm A: Control Arm v Arm B: CPAP v Arm C: Liraglutide v Arm D: Liraglutide + CPAP
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.151
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.041
         upper limit
    		 3.943
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.491

    Secondary: Waist:Hip Ratio

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    End point title
    		 Waist:Hip Ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Change between baseline and twenty-six weeks
    End point values
    		 Arm A: Control Arm Arm B: CPAP Arm C: Liraglutide Arm D: Liraglutide + CPAP
    Number of subjects analysed
    31
    25
    31
    28
    Units: ratio
        median (inter-quartile range (Q1-Q3))
    -0.01 (-0.04 to -0.01)
    -0.02 (-0.04 to 0.05)
    -0.04 (-0.075 to -0.01)
    -0.01 (-0.04 to 0.03)
    Statistical analysis title
    		 Wast:HIP (CPAP)
    Comparison groups
    Arm A: Control Arm v Arm B: CPAP v Arm C: Liraglutide v Arm D: Liraglutide + CPAP
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.711
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.033
         upper limit
    		 0.048
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.021
    Statistical analysis title
    		 Waist:Hip (Liraglutide)
    Comparison groups
    Arm A: Control Arm v Arm B: CPAP v Arm C: Liraglutide v Arm D: Liraglutide + CPAP
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.094
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.075
         upper limit
    		 0.006
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.021

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Reported for the duration of the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Arm A:
    Reporting group description
    		 Control arm, comprising conventional care for existing T2DM patients with no intervention for OSA. This group did not use placebo medication. Patients were asked to continue with their usual anti-diabetes medications and if titration of any anti-diabetes drugs is necessary, due to worsening glycaemic control, this was achieved by avoiding the use of any Liraglutide and patients were given subcutaneous insulin (using either once daily or twice daily formulations). Patients were not be given CPAP for this period.

    Reporting group title
    Arm B:
    Reporting group description
    		 Will receive conventional care plus Liraglutide (up to 1.8mg).

    Reporting group title
    Arm C:
    Reporting group description
    		 Will receive conventional care plus CPAP. The CPAP device that will be used will be ResMed S9 (or other similar device) fixed pressure device in accordance with the standard clinical protocols.

    Reporting group title
    Arm D:
    Reporting group description
    		 Will receive conventional care plus Liraglutide plus CPAP. The CPAP device that will be used will be ResMed S9 (or other similar device) fixed pressure device in accordance with the standard clinical protocols.

    Serious adverse events
    		 Arm A: Arm B: Arm C: Arm D:
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 33 (3.03%)
    1 / 33 (3.03%)
    1 / 32 (3.13%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Thoracotomy
    Additional description: Bronchoscopy and dianostic frozen section of right lower lobe
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperglycaemia
    Additional description: Hyperglycaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Tendon Rupture
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
    Additional description: Urosepsis (Renal infection E-coli bladder)
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A: Arm B: Arm C: Arm D:
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 33 (45.45%)
    22 / 33 (66.67%)
    16 / 33 (48.48%)
    12 / 32 (37.50%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Sinus polyp
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Patent ductus arteriosus
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Inflammation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    Mass
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Immune system disorders
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 33 (12.12%)
    2 / 33 (6.06%)
    1 / 32 (3.13%)
         occurrences all number
    0
    4
    2
    1
    Dyspnoea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 33 (3.03%)
    8 / 33 (24.24%)
    4 / 32 (12.50%)
         occurrences all number
    4
    1
    8
    4
    Nasopharyngitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    0
    0
    Vocal cord disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wheezing
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Blister
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Atrial septal defect
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    Splenic cyst
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Middle ear effusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye disorders
    eye infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 33 (9.09%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    0
    1
    0
    3
    Diarrhoea
         subjects affected / exposed
    1 / 33 (3.03%)
    9 / 33 (27.27%)
    2 / 33 (6.06%)
    4 / 32 (12.50%)
         occurrences all number
    1
    9
    2
    4
    Dyspepsia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Food poisoning
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    nausea
         subjects affected / exposed
    0 / 33 (0.00%)
    5 / 33 (15.15%)
    1 / 33 (3.03%)
    4 / 32 (12.50%)
         occurrences all number
    0
    5
    1
    4
    Oropharyngeal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    1 / 33 (3.03%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    1
    1
    Salivary gland cyst
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Salivary gland disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 33 (0.00%)
    7 / 33 (21.21%)
    1 / 33 (3.03%)
    4 / 32 (12.50%)
         occurrences all number
    0
    7
    1
    4
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatic cyst
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    2 / 33 (6.06%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Eczema
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    0
    2
    Rash
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    0
    1
    Carbuncle
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rosacea
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thyroid cyst
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 33 (6.06%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    Rib fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    0
    1
    Localised infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sepsis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    0
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 33 (0.00%)
    1 / 33 (3.03%)
    0 / 32 (0.00%)
         occurrences all number
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2015
    Amendment 2: (2&3 combined) - Protocol, PIS, ICF and SmPC updates Change 1: Protocol updated from V2 (15/09/2014) to V3 (12/02/2015) Amendments to the protocol included changes to the following sections: - 1 PROTOCOL SUMMARY - Main Exclusion Criteria - Number of Sites 5 STUDY POPULATION - 5.2 Exclusion Criteria - 1.Medical History and Concurrent Diseases: - 5. Prohibited Treatments and/or Therapies 6 ENROLMENT AND RANDOMISATION - 6.2 Enrolment/Baseline: 7 TRIAL TREATMENTS - 7.1 Introduction - 7.3.1 Handling and Dispensing - 7.3.2 Preparation, Dosage and Administration of Study Treatment - 7.3.4 Accountability Procedures for Study Treatment - 7.5.1 Medications Not Permitted/Precautions Required 8 ASSESSMENTS AND PROCEDURES - 8.1 Schedule of Trial Procedures - 8.1 Screening Assessments (Visit 1) - 8.1.2 Baseline Assessments 9 STATISTICAL CONSIDERATIONS - 9.3 Sample Size: Planned recruitment rate added 10 PHARMACOVIGILANCE - 10.6 Reference Safety Information - Link to SmPC added 16 TRIAL OVERSIGHT - 16.1 Trial Management Group - corrections of typographical errors Change 2: PIS updated from V3 (15/09/2014) to V4 (12/02/2015) Change 3: ICF updated from V3 (15/09/2014) to V4 (12/02/2015) Change 4: GP Letter updated from V2 (17/10/2014) to V3 (12/02/2015)
    28 May 2015
    Amendment 1: Submitted with Amendment 2 Change 1: Protocol updated from V1 (May 2014) to V2 (15/09/2014) Amendments to the protocol included: Main Inclusion Criteria: *caveat inserted to include patients currently treated with DPP-IV inhibitors Exclusion criteria 12: clarified to patients with residual neurological deficit Screening Assessments: • Introductory paragraph inserted • All participants to have a standard multichannel overnight sleep study (limited respiratory polysomngram) to confirm the diagnosis of OSA in a consistent manner. • Pathway for patients identified from the Diabetes Clinic added. • 24 hour blood pressure monitoring deleted • Patient Treatment Diary added 8.1.2 Visit 2 • Participants to attend fasted 8.1.3 Visit 5 • Additional Visit added to collect prescription and/or CPAP device (ARMs B, C & D only) • Optional visit for Arm A patients who should be given the choice of a visit or telephone consultation. 8.1.4 Treatment Intervention (26 weeks) • Clarification of follow-up visits and support telephone calls to reflect internal templates, as well 9.2.2 Secondary Outcome Measures • Oxygen desaturation index (ODI) added • Left ventricular tissue function updated to tissue velocity 10.8 Adverse Events - Reporting Procedures • In accordance with LCTU standard practice, reporting requirements reduced from 70 days to 28 days after discontinuation of IMP Change 2: PIS updated from V1 (July 2014) to V2 (15/09/2014) Amendments to the PIS includes the following additional visits added • Visit 5 added – additional visit to collect CPAP/prescription/trial Arm review • Visits 6, 7 & 8 added plus fortnightly support telephone calls Total number of visits for all Arm’s increased from 8 to 11 • Drug dispensing: visits added Change 3: ICF updated from V1 (July 2014) to V2 (15/09/2014) Researcher(s) anonymised and amended to PI only Change 4: GP Letter updated from V1 (May 2014) to V2 (17/10/2014)
    29 Jan 2016
    Amendment 3 (2&3 combined): Protocol, PIS, ICF update, advert Change 1: Protocol updated from V3 (12/02/2015) to V3 (27/03/2015) Amendments to the protocol included changes to the following sections: 8 ASSESSMENTS AND PROCEDURES - 8.1 Schedule of trial procedure - 8.1.3 Visit 5 - 8.1.6 Optional Research Samples Change 2: PIS updated from V4 (12/02/2015) to V4 (27/03/2015) Change 3: ICF updated from V4 (12/02/2015) to V4 (27/03/2015) Submission: Recruitment Poster Diabetes V2 (04/12/2015) Submission: Recruitment Poster Sleep V2 (04/12/2015) Submission: Recruitment Advert V3 (05/01/2016) Submission: Screening Form/Checklist V1 (16/10/2015)
    18 Mar 2016
    Amendment 4: Protocol update Change 1: Protocol updated from V3 (27/03/2015) to V4 (25/11/2015) Amendments to the protocol included changes to the following sections: Inclusion criteria: - Section 1 - Protocol Summary - 5.1 Detailed Inclusion Criteria Exclusion Criteria - Section 5.2 2.3 Objectives 6.1 Screening: 7.3.1 Formulation, Packaging, Labelling, Storage and Stability 7.4 Continuous Positive Airway Pressure (CPAP) 8.1 Schedule of Trial Procedures - 8.1.1 Screening Assessments (Visit 1 - Clinical Sciences, UHA) 13.4.7 Recruitment: Section updated to include the provision for advertising.
    29 Jun 2016
    29/06/2016 Amendment 5: Protocol and PIS update Change 1: Protocol updated from V4 (25/05/2015) to V5 (12/05/2016) Amendments to the protocol included changes to the following sections: - 5.2 Detailed Exclusion Criteria - 5.3.3 Withdrawal from Trial Completely: Sentence added - 6.2 Enrolment/Randomisation - 8.1 Schedule of Trial Procedures - 8.1.1 Screening Assessments/Randomisation (Visit 1 - Clinical Sciences, UHA) - 8.1.2 Baseline Assessments/Randomisation (Visits 2, 3 & 4) - 8.1.5 Follow-up Investigations (Visits 9, 10 & 11) 9 Statistical Considerations: - 9.2.2 Secondary - 9.3 Sample Size - 9.5 Outline of analysis plan Change 2: PIS updated from V4 (27/03/2015) to V5 (12/05/2016)
    17 Oct 2017
    Amendment 7: Protocol and PIS update (Patients needing to re-consent) Change 1: Protocol updated from V5 (12/05/2016) to V6 (26/07/2017) Amendments to the protocol included changes to the following pages: All references to MARIARC have been changed to Liverpool Magnetic Resonance Imaging Centre (LiMRIC) Page 14: Schematic of study design updated Page 24: Criteria specific to MRI removed from main criteria and specific section for MRI scanning created as below Additional Exclusion Criteria for MRI Scanning Page 27: Randomisation information changed to allow patient not eligible for scanning to be randomised to main study Page 37: Information added regarding Oral Glucose Tolerance Test Page 38: Information for Duplex Ultrasnography moved to visit 2 Page 39: Follow up visits at weeks 2, 4 and 6 amended to allow optional of telephone calls or visits: Page 40: The specific number of 8 from each treatment arm for adipose tissue biopsy removed.
    23 Nov 2017
    Amendment 8: RSI Update Cholelithiasis and Cholecystitis added to RSI
    03 Jun 2019
    Amendment 9: Protocol update Novo Nordisk (study funder) has agreed a reduction in the number of patients needed to be recruited to the study. They have agreed that in each of the four arms they need 32 patients to analyse (128 in total). Due to the dropout rate being only 2.5% instead of the anticipated 10% it has been agreed that only 132 patients in total need to be recruited. Change 1: Protocol updated from V6 (26/07/2017) to V7 (21/01/2019) Amendments to the protocol included changes to the following sections: Section: Contact Details Section 1: Protocol Summary Section 4: Overall Design Section 3: Sample Size Section 6.2: Enrolment/Randomisation Section 10.2.3: Reporting of Pregnancy Section 10.6: Reference Safety Information

    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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