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    Clinical Trial Results:
    A 48-WEEK PHASE II, RANDOMISED, DOUBLE BLINDED PLACEBO CONTROLLED, PARALLEL-GROUP, MULTI-CENTRE TRIAL ON LIRAGLUTIDE’S SAFETY, EFFICACY AND ACTION ON LIVER HISTOLOGY AND METABOLISM IN OVERWEIGHT PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS, WITH OR WITHOUT TYPE II DIABETES

    Summary
    EudraCT number
    		 2009-016761-29
    Trial protocol
    		 GB  
    Global end of trial date
    02 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Sep 2020
    First version publication date
    26 Sep 2020
    Other versions
    Summary report(s)
    		 Lean Study Protocol V7.0

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RG_09-190
    Additional study identifiers
    ISRCTN number
    		 ISRCTN85774727
    US NCT number
    		 NCT01237119
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 UK Competent authority (MHRA) Reference: 21761/0247/001-0001, NHS (UK) Ethics Ref number: 10/H0402/32
    Sponsors
    Sponsor organisation name
    The University of Birmingham
    Sponsor organisation address
    Research Support Group, Finance Office, Aston Webb building, Birmingham, United Kingdom, B15 2TT
    Public contact
    Dr Sean Jennings, The University of Birmingham, +44 (0)121 415 8011, s.jennings@bham.ac.uk
    Scientific contact
    Professor Philip Newsome, The University of Birmingham, +44 (0)121 414 5614, p.n.newsome@bham.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
    20 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the safety and efficacy of 48 weeks treatment with once-daily injections of liraglutide in damaged liver tissue in overweight patients with non-alcoholic steatohepatitis [NASH] (i.e. the more severe, inflammatory form of fatty liver disease). To investigate whether the effect of liraglutide on NASH warrants further investigation.
    Protection of trial subjects
    No specific measures were included within the study protocol specifically for the protection of trial subjects outside the normal safety monitoring that is included in a phase II (safety and efficacy) study. This monitoring included, but not limited to blood tests (Full blood counts and Biochemistry panel); physical exam and collection/evaluation of adverse event and serious adverse event data.These procedures were performed/repeated at multiple visits throughout the treatment period (monthly - 3 monthly visits) and the results of these procedures were recorded in the Case Report Form (CRF) In addition a facility for 24/7 unblinding of study medication was available for medical physicians if required. This could be accessed by any physician who was treating a patient irrespective of whether they were directly involved in the clinical study. Trial subjects were provided with a participant study card which included details of the clinical trial and 24/7 emergency number. Limited medical advice was also available from this resource.
    Background therapy
    		 The study did not include any Non-Investigational Medicinal Products (NIMPS). A full record of any medications that a trial subject was taking during the study period was recorded in the individual subjects Case Report Form (Concomitant medication page).
    Evidence for comparator
    		 This clinical trial was a randomised, double blind phase II safety and efficacy study. The comparator was a liraglutide-matched Placebo provided by Novo-Nordisk Ltd (UK). The placebo included everything except the active ingredient.
    Actual start date of recruitment
    19 Oct 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 52
    Worldwide total number of subjects
    52
    EEA total number of subjects
    52
    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)
    49
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All trial participants were recruited / randomised into the clinical study between 19th October 2010 and 3rd May 2013. The trial participants were all recruited in the united kingdom from 4 participating centres; Queen Elizabeth Hospital: Birmingham, Queens Medical Centre: Nottingham, Hull royal infirmary: Hull, St James University Hospital: Leeds

    Pre-assignment
    Screening details
    		 Patients were screened using study inclusion and exclusion criteria detailed in the study protocol. Key screening inclusion criteria were: 1. Age >/= 18 2. BMI >/= 25 3. Non-alcoholic steatohepatitis (NASH): Kleiner classification on liver biopsy within </= 6 months prior to randomisation. Presence of any other liver aetiologies were excluded

    Period 1
    Period 1 title
    Randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    After screening and completion of the inclusion / exclusion criterion patients were randomly assigned to either treatment or placebo on a 1:1 basis using a computer generated randomisation. This randomisation was stratified to insure equal numbers in each treatment group. Stratification variables were; 1. Type II diabetes (vs. non-diabetics) 2. Trial/ participating centre All randomised patients were allocated a unique trial identification number.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 Control group: Treatment with once daily subcutaneous injection of inactive treatment (liraglutide placebo) - supplied by Novo Nordisk Ltd, UK.
    Arm type
    		 Placebo

    Investigational medicinal product name
    liraglutide placebo - supplied by Novo Nordisk Ltd, UK.
    Investigational medicinal product code
    PLACEBO
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.8mg daily after a 14 day dose escalation period

    Arm title
    		 Group 2
    Arm description
    		 Group 2: Experimental group. Treatment with once daily subcutaneous injections 1.8 mg active liraglutide (Victoza) supplied by Novo Nordisk Ltd, UK
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Active
    Other name
    Victoza
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.8mg Subcutaneous daily injection after a 2 week dose escalation period for a period of 48 weeks.

    Number of subjects in period 1
    		Group 1 Group 2
    Started
    26
    26
    Completed
    26
    26
    Period 2
    Period 2 title
    On Study Treatment and Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    After screening and completion of the inclusion / exclusion criterion patients were randomly assigned to either treatment or placebo on a 1:1 basis using a computer generated randomisation. This randomisation was stratified to insure equal numbers in each treatment group. Stratification variables were; 1. Type II diabetes (vs. non-diabetics) 2. Trial/ participating centre All randomised patients were allocated a unique trial identification number which was used to identify the patient.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 - Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    liraglutide placebo - supplied by Novo Nordisk Ltd, UK.
    Investigational medicinal product code
    PLACEBO
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.8mg daily after a 14 day dose escalation period

    Arm title
    		 Group 2 - Liraglutide - Active Treatment Group
    Arm description
    		 Active- experimental
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Active
    Other name
    Victoza
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.8mg Subcutaneous daily injection after a 2 week dose escalation period for a period of 48 weeks.

    Number of subjects in period 2
    		Group 1 - Placebo Group 2 - Liraglutide - Active Treatment Group
    Started
    26
    26
    Completed
    22
    23
    Not completed
    4
    3
         end Trt / No end of study biopsy- Patient choice
    3
    -
         patient choice- end Trt/ No biospy @ 48 week
    -
    3
         No Treatment received / ineligible after entry
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Control group: Treatment with once daily subcutaneous injection of inactive treatment (liraglutide placebo) - supplied by Novo Nordisk Ltd, UK.

    Reporting group title
    Group 2
    Reporting group description
    		 Group 2: Experimental group. Treatment with once daily subcutaneous injections 1.8 mg active liraglutide (Victoza) supplied by Novo Nordisk Ltd, UK

    Reporting group values
    		 Group 1 Group 2 Total
    Number of subjects
    		 26 26 52
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 24 25 49
        From 65-84 years
    		 2 1 3
        85 years and over
    		 0 0 0
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 52 ± 12 50 ± 11 -
    Gender categorical
    Units: Subjects
        Female
    		 13 8 21
        Male
    		 13 18 31
    Race
    Units: Subjects
        Asian (south Asian or oriental)
    		 1 1 2
        Black (African or caribbean)
    		 0 1 1
        Other (Including Mixed)
    		 2 1 3
        White
    		 23 23 46
    Smoking History
    Units: Subjects
        current smoker
    		 2 2 4
        ex-smoker
    		 13 8 21
        never smoked
    		 11 16 27
    Sex
    Units: Subjects
        Male
    		 18 13 31
        Female
    		 8 13 21
    Definite NASH
    Definite NASH
    Units: Subjects
        Positive
    		 26 26 52
    Kleiner fibrosis stages
    Kleiner fibrosis stages F0-F2 and F3-F4
    Units: Subjects
        F0-F2
    		 11 14 25
        F3-F4
    		 15 12 27
    Comorbidity - Type II Diabetes
    Units: Subjects
        Yes
    		 8 9 17
        No
    		 18 17 35
    Comorbidity - Hyperlipidaemia
    Units: Subjects
        Yes
    		 7 9 16
        No
    		 19 17 36
    Comorbidity - Hypertension
    Units: Subjects
        Yes
    		 14 13 27
        No
    		 12 13 25
    Comorbidity - Cardiovascular disease
    Units: Subjects
        Yes
    		 3 0 3
        No
    		 23 26 49
    Comorbidity - Thyroid Disease
    Units: Subjects
        Yes
    		 4 3 7
        No
    		 22 23 45
    Concomitant Drug Use - Metformin
    Units: Subjects
        Yes
    		 8 9 17
        No
    		 18 17 35
    Concomitant Drug Use - Sulfonylurea
    Units: Subjects
        Yes
    		 1 1 2
        No
    		 25 25 50
    Concomitant Drug Use - Anti-lipidaemic
    Units: Subjects
        Yes
    		 7 10 17
        No
    		 19 16 35
    Concomitant Drug Use - Anti-hypertensive
    Units: Subjects
        Yes
    		 12 13 25
        No
    		 14 13 27
    Concomitant Drug Use - Anti-platelet
    Units: Subjects
        Yes
    		 5 5 10
        no
    		 21 21 42
    Glucose
    Glucose (mmol/L)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 6.1 ± 1.5 6.0 ± 1.7 -
    Insulin
    Insulin (pmol/L)
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 257 ± 289 166 ± 80 -
    HOMA-IR
    HOMA-IR (mmol.IU.L) (glucose [mmol/L] × insulin[mmol × U/L])
    Units: mmol.IU.L
        arithmetic mean (standard deviation)
    		 9.6 ± 9.8 6.7 ± 4.7 -
    HbA1c
    HbA1c mmol/mol
    Units: mmol/mol
        arithmetic mean (standard deviation)
    		 42.4 ± 9.3 6.0 ± 0.9 -
    HbA1c (%)
    HbA1c (%)
    Units: Percent %
        arithmetic mean (standard deviation)
    		 6.0 ± 0.9 5.9 ± 0.7 -
    NEFA
    NEFA
    Units: Micro mol / L
        arithmetic mean (standard deviation)
    		 836 ± 368 967 ± 535 -
    ADIPO-IR
    ADIPO-IR (mmol.IU.L)
    Units: mmol.IU.L
        arithmetic mean (standard deviation)
    		 30.5 ± 42.7 22.2 ± 12.7 -
    Weight (kg)
    Weight (kg)
    Units: kg
        arithmetic mean (standard deviation)
    		 108 ± 18 101 ± 18 -
    Body mass index
    Body mass index (Kg/m2)
    Units: Kg/m2
        arithmetic mean (standard deviation)
    		 37.7 ± 6.2 34.2 ± 4.7 -
    Waist circumference
    Waist circumference (cm)
    Units: cm
        arithmetic mean (standard deviation)
    		 120 ± 15 110 ± 11 -
    Systolic blood pressure
    Systolic blood pressure (mmHg)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 133 ± 12 130 ± 13 -
    Diastolic blood pressure
    Diastolic blood pressure (mmHg)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 78 ± 9 79 ± 11 -
    Total cholesterol
    Total cholesterol (mmol/L)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 5.0 ± 1.2 4.5 ± 1.1 -
    High density lipoprotein
    High density lipoprotein (mmol/L)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.3 ± 0.2 1.1 ± 0.4 -
    Low density lipoprotein
    Low density lipoprotein (mmol/L) Low density lipoprotein (LDL) calculated using the Friedwald formula. LDL= Total Cholesterol –HDL-(Triglycerides / 2.1929).
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.9 ± 1.0 2.6 ± 0.8 -
    Triglycerides
    Triglycerides (mmol/L)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.8 ± 0.8 1.9 ± 1.1 -
    Creatinine
    Creatinine (μmol/L)
    Units: micro mol/L
        arithmetic mean (standard deviation)
    		 71 ± 15 83 ± 20 -
    Alanine aminotransferase
    Alanine aminotransferase (IU/L)
    Units: IU/L
        arithmetic mean (standard deviation)
    		 66 ± 42 77 ± 34 -
    Aspartate aminotransferase
    Aspartate aminotransferase (IU/L)
    Units: IU/L
        arithmetic mean (standard deviation)
    		 51 ± 27 51 ± 22 -
    Gamma-glutamyl transferase
    Gamma-glutamyl transferase (IU/L)
    Units: IU/L
        arithmetic mean (standard deviation)
    		 115 ± 174 91 ± 69 -
    Alkaline phosphatase
    Alkaline phosphatase (IU/L)
    Units: IU/L
        arithmetic mean (standard deviation)
    		 87 ± 41 76 ± 25 -
    Total bilirubin
    Total bilirubin (μmol/L)
    Units: μmol/L
        arithmetic mean (standard deviation)
    		 13 ± 7 13 ± 5 -
    Albumin
    Albumin (g/L)
    Units: g/L
        arithmetic mean (standard deviation)
    		 43 ± 5 45 ± 6 -
    Cytokeratin-18 M30
    Cytokeratin-18 M30 (IU/L)
    Units: IU/L
        arithmetic mean (standard deviation)
    		 352 ± 370 394 ± 304 -
    Enhanced Liver Fibrosis (ELF) test
    Enhanced Liver Fibrosis (ELF) test
    Units: Enhanced Liver Fibrosis (ELF) test
        arithmetic mean (standard deviation)
    		 9.4 ± 1.3 9.3 ± 0.9 -
    SF-36, physical component
    SF-36, physical component Quality of Life
    Units: Score
        arithmetic mean (standard deviation)
    		 40 ± 13 45 ± 11 -
    SF-36, mental component
    SF-36, mental component Quality of Life
    Units: Score
        arithmetic mean (standard deviation)
    		 45 ± 14 51 ± 10 -
    Dietary consumption Total calories
    Dietary consumption (Block FFQ) Total calories (Kcal)
    Units: Kcal
        arithmetic mean (standard deviation)
    		 1926 ± 677 1885 ± 700 -
    Dietary consumption Total protein
    Dietary consumption (Block FFQ) Total protein (g)
    Units: grams
        arithmetic mean (standard deviation)
    		 70 ± 25 72 ± 34 -
    Dietary consumption Total fat
    Dietary consumption (Block FFQ) Total fat (g)
    Units: grams
        arithmetic mean (standard deviation)
    		 74 ± 35 71 ± 30 -
    Dietary consumption Total carbohydrate
    Dietary consumption (Block FFQ) Total carbohydrate (g)
    Units: grams
        arithmetic mean (standard deviation)
    		 248 ± 89 240 ± 87 -
    Dietary consumption Caffeine
    Dietary consumption (Block FFQ) Caffeine (mg)
    Units: mg
        arithmetic mean (standard deviation)
    		 26 ± 45 21 ± 30 -
    Dietary consumption Alcohol
    Dietary consumption (Block FFQ) Alcohol (g)
    Units: grams
        arithmetic mean (standard deviation)
    		 4.8 ± 8.4 6.3 ± 8.3 -
    NAFLD activity score
    Liver histology Total NAFLD activity score (0-8)
    Units: Score
        arithmetic mean (standard deviation)
    		 4.8 ± 0.9 4.9 ± 0.9 -
    Hepatocyte ballooning score
    Liver histology Hepatocyte ballooning score (0-2)
    Units: Score
        arithmetic mean (standard deviation)
    		 1.5 ± 0.4 1.5 ± 0.5 -
    Steatosis score
    Liver histology Steatosis score (0-3)
    Units: Score
        arithmetic mean (standard deviation)
    		 1.9 ± 0.7 2.1 ± 0.7 -
    Lobular inflammation score
    Liver histology Lobular inflammation score (0-3)
    Units: Score
        arithmetic mean (standard deviation)
    		 1.4 ± 0.4 1.4 ± 0.3 -
    Kleiner fibrosis stage
    Liver histology Kleiner fibrosis stage (0-4)
    Units: Score
        arithmetic mean (standard deviation)
    		 2.3 ± 1.3 2.3 ± 0.9 -
    Liver biopsy length
    Liver biopsy length
    Units: mm
        arithmetic mean (standard deviation)
    		 19.7 ± 5.7 21.0 ± 7.6 -
    Number of portal tracts
    Liver Histology Number of portal tracts
    Units: Count
        arithmetic mean (standard deviation)
    		 16.2 ± 5.3 18.5 ± 7.1 -

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Control group: Treatment with once daily subcutaneous injection of inactive treatment (liraglutide placebo) - supplied by Novo Nordisk Ltd, UK.

    Reporting group title
    Group 2
    Reporting group description
    		 Group 2: Experimental group. Treatment with once daily subcutaneous injections 1.8 mg active liraglutide (Victoza) supplied by Novo Nordisk Ltd, UK
    Reporting group title
    Group 1 - Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Group 2 - Liraglutide - Active Treatment Group
    Reporting group description
    		 Active- experimental

    Subject analysis set title
    Evaluable Patient Set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomised patients that were evaluable with biopsy at the 48 weeks endpoint irrespective of treatment received.

    Subject analysis set title
    Safety patient cohort (ITT)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomised patients as per intention to treat.

    Primary: Histology: clearence of NASH and no worsening of fibrosis

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    End point title
    		 Histology: clearence of NASH and no worsening of fibrosis
    End point description
    Action number is the proportion of patients with an improvement in liver histology between biopsy at baseline and biopsy after 48 weeks of treatment: The definition of an improvement in in liver histology requires both of the following; - Disappearance of NASH (defined as a disappearance of hepatocyte ballooning) AND No worsening of fibrosis. Liver biopsy results were reviewed by two independent pathologists that were blinded to the study group/ treatment.
    End point type
    Primary
    End point timeframe
    Baseline (Screening within 6 months of randomisation) - End of treatment (within 14 days). A protocol defined treatment (completion of) is 48 weeks
    End point values
    		 Group 1 - Placebo Group 2 - Liraglutide - Active Treatment Group
    Number of subjects analysed
    22
    23
    Units: number
    2
    9
    Statistical analysis title
    		 Histological
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 17.7
    Variability estimate
    Standard error of the mean

    Secondary: Effect of treatment on individual histological features of Non-alcoholic steatohepatitits (NASH)

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    End point title
    		 Effect of treatment on individual histological features of Non-alcoholic steatohepatitits (NASH)
    End point description
    The liver biopsy's (baseline and end of treatment) were reviewed by two independent pathologists and the individual features of NASH including; 1. Steatosis 2. Hepatocyte inflammation and injury 3. Fibrosis Histological measures (change between baseline and end of treatment biopsy for individual patients) included; 1. Calculation of the mean changes in NAFLD activity score (NAS) between the two treatment groups. 2. Changes in the independent features of NAS; Steatosis, lobular inflammation and hepatocyte ballooning between the two treatment groups. 3. Changes in fibrosis stage according to Kleiner Non-Alcoholic Fatty Liver Disease (NAFLD) fibrosis score (F0-F4) between the two treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline (within 6 months of randomisation date) and within 7 days of end of study treatment (maximum protocol defined treatment duration 48 weeks)
    End point values
    		 Group 1 - Placebo Group 2 - Liraglutide - Active Treatment Group
    Number of subjects analysed
    22
    23
    Units: Pateint numbers / percentage
    22
    23
    Attachments
    		 Histology Data
    Statistical analysis title
    		 Changes from baseline for NAS.
    Statistical analysis description
    Changes from baseline in histopathological parameters - Total NAFLD activity score
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24 [1]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.3
    Notes
    [1] - From linear regression (equivalent to ANCOVA).
    Statistical analysis title
    		 Patients with improvement in NAS
    Statistical analysis description
    Changes from baseline in histopathological parameters - Patients with improvement in NAS
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.7
    Statistical analysis title
    		 Hepatocyte ballooning score - mean change
    Statistical analysis description
    Changes from baseline in histopathological parameters
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.1
    Statistical analysis title
    		 Patients with improved Hepatocyte ballooning
    Statistical analysis description
    Changes from baseline in histopathological parameters Hepatocyte ballooning score - N improved Patients with improvement
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 3.8
    Statistical analysis title
    		 Steatosis - Change in Score
    Statistical analysis description
    Changes from baseline in histopathological parameters Steatosis Change in score
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.2
    Statistical analysis title
    		 Patients with improvement in Steatosis
    Statistical analysis description
    Changes from baseline in histopathological parameters Steatosis Patients with improvement
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 3
    Statistical analysis title
    		 Lobular inflammation score - mean change
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.3
    Statistical analysis title
    		 Patients with improvement in Lobular Inflammation
    Statistical analysis description
    Changes from baseline in histopathological parameters Lobular inflammation - Patients with improvement
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.6
    Statistical analysis title
    		 Kleiner Fibrosis score - mean change
    Statistical analysis description
    Changes from baseline in histopathological parameters
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.1
    Statistical analysis title
    		 Patients with improvement in Kleiner Fibrosis
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 6.7
    Statistical analysis title
    		 Patients with worsening in Kleiner Fibrosis
    Statistical analysis description
    Changes from baseline in histopathological parameters Patients with worsening LIRAGLUTIDE - 2 (9%) PLACEBO - 8 (36%)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 1

    Secondary: Change to weight, BMI and waist: hip Circumference

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    End point title
    		 Change to weight, BMI and waist: hip Circumference
    End point description
    Each participants weight (kg), height (cm), waist and hip circumferences were measured at visits 1-8 (except visit 2) in order to calculate each individual patients body mass index (BMI) (Kg/m2) and waist: hip circumference.
    End point type
    Secondary
    End point timeframe
    Data recorded during the clinical trial at multiple time points between baseline (visit 1) and 3 months post end of treatment visit.
    End point values
    		 Group 1 - Placebo Group 2 - Liraglutide - Active Treatment Group
    Number of subjects analysed
    22
    23
    Units: Numbers and percentage
    22
    23
    Attachments
    		 Untitled (Filename: Fig 3a Abs Weight.pdf)
    Untitled (Filename: Fig 2a Weight.pdf)
    Physical Data
    Statistical analysis title
    		 Changes from baseline for Weight
    Statistical analysis description
    Absolute weight (kg) Lira change –5·3 (4·7) Placebo change –0·6 (4·4)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [2]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.19
         upper limit
    		 -1.59
    Notes
    [2] - *p values and adjusted treatment changes determined by linear regression analysis regressing change on the baseline characteristic score and treatment
    Statistical analysis title
    		 Changes from baseline for BMI
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [3]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.66
         upper limit
    		 -0.51
    Notes
    [3] - *p values and adjusted treatment changes determined by linear regression analysis regressing change on the baseline characteristic score and treatment
    Statistical analysis title
    		 Changes from baseline for Waist circumference
    Statistical analysis description
    Waist circumference (cm)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29 [4]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.32
         upper limit
    		 2.25
    Notes
    [4] - *p values and adjusted treatment changes determined by linear regression analysis regressing change on the baseline characteristic score and treatment.

    Secondary: Quality of LIfe (SF-36) / AUDIT

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    End point title
    		 Quality of LIfe (SF-36) / AUDIT
    End point description
    The SF36 (version 2.0) was used /requested at three protocol defined time points (Visit 1, 7 and 8).
    End point type
    Secondary
    End point timeframe
    Data recorded during the clinical trial at multiple time points between baseline (visit 1) and 3 months post end of treatment visit.
    End point values
    		 Group 1 - Placebo Group 2 - Liraglutide - Active Treatment Group
    Number of subjects analysed
    22
    23
    Units: SF-36 score
        arithmetic mean (standard deviation)
    -0.5 ± 8.0
    1.9 ± 5.1
    Attachments
    		 Questionnaires
    Statistical analysis title
    		 Quality of Life Physical Component
    Statistical analysis description
    Quality of life (SF-36v2) Mean (SD) change from baseline to 48 weeks Physical component
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 7.9
    Statistical analysis title
    		 Quality of life Mental component
    Statistical analysis description
    Quality of life (SF-36v2) Mean (SD) change from baseline to 48 weeks Physical component
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.64
         upper limit
    		 7.65

    Secondary: A reduction in non-invasive inflammatory and fibrosis markers

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    End point title
    		 A reduction in non-invasive inflammatory and fibrosis markers
    End point description
    Changes in Liver function measured by the use of non invasive biomarker (Fibroscan) and multiple Blood Tests including; Liver function Tests (LFTs), and Cytokeratin-18. Glycaemic Control measurements relating to A reduction in global (hepatic, adipose and muscle) insulin resistance and A reduction in hepatic de-novo lipogenesis (DNL) Reporting details the Mean (SD) from baseline to 48weeks
    End point type
    Secondary
    End point timeframe
    Baseline to end of Treatment / Study follow up
    End point values
    		 Group 1 - Placebo Group 2 - Liraglutide - Active Treatment Group
    Number of subjects analysed
    22
    23
    Units: Numerical
    arithmetic mean (standard deviation)
        Bilirubin
    -1.1 ± 3.1
    -1.7 ± 3.1
        Alkaline Phosphatase
    -1.2 ± 19.1
    -5.1 ± 11.7
        Alanine Transferase
    -10.2 ± 35.8
    -26.6 ± 34.4
        Aspartate Transferase
    -8.6 ± 28.3
    -15.8 ± 21.8
        CytoKeratin-18 (CK)
    -92 ± 327
    -185 ± 295
        HbA1c
    0.0 ± 8.7
    -5.7 ± 6.9
        Glucose
    0.72 ± 2.3
    -1.0 ± 1.5
        HOMA-IR
    0.70 ± 9.49
    -1.8 ± 3.7
        Triglycerides
    0.18 ± 1.29
    -0.02 ± 0.64
        Total Cholesterol
    -0.13 ± 0.91
    0.01 ± 0.60
        HDL
    -0.04 ± 0.13
    0.07 ± 0.19
        LDL
    -0.1 ± 0.9
    -0.1 ± 0.7
    Attachments
    		 Clinical Data
    Statistical analysis title
    		 Glucose
    Statistical analysis description
    Mean (95% CI) changes from baseline
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.81
         upper limit
    		 -0.53
    Statistical analysis title
    		 HOMA-IR
    Statistical analysis description
    Mean (95% CI) changes from baseline
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.23
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.24
         upper limit
    		 1.76
    Statistical analysis title
    		 Glycated haemoglobin A1c
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.91
         upper limit
    		 -0.44
    Statistical analysis title
    		 Total Cholesterol
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.066
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.427
         upper limit
    		 0.56
    Statistical analysis title
    		 HDL
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.134
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.029
         upper limit
    		 0.238
    Statistical analysis title
    		 LDL
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo) - LDL (mmol/L)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.126
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.622
         upper limit
    		 0.371
    Statistical analysis title
    		 Triglycerides
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo) - Triglycerides (mmol/L)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.197
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.834
         upper limit
    		 0.439
    Statistical analysis title
    		 Alanine aminotransferase
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo) - Alanine aminotransferase (U/L) - ALT
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -10.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.9
         upper limit
    		 4.5
    Statistical analysis title
    		 Aspartate aminotransferase
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo) - Aspartate aminotransferase (U/L) AST
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.29
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.3
         upper limit
    		 5.9
    Statistical analysis title
    		 γ-glutamyl transferase (U/L)
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo) - Gamma-glutamyl transferase (U/L) - GGT
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -22.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.4
         upper limit
    		 -5.2
    Statistical analysis title
    		 Alkaline phosphatase
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo) - Alkaline phosphatase (U/L)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.36
         upper limit
    		 3.43
    Statistical analysis title
    		 Bilirubin
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo) - Total bilirubin (μmol/L)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.52
         upper limit
    		 1.26
    Statistical analysis title
    		 CK-18
    Statistical analysis description
    Mean (95% CI) changes from baseline (liraglutide vs placebo) - Caspase-cleaved cytokeratin-18 fragment M30 (U/L)
    Comparison groups
    Group 1 - Placebo v Group 2 - Liraglutide - Active Treatment Group
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -188
         upper limit
    		 16

    Secondary: Non Serious Adverse Events

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    End point title
    		 Non Serious Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    AEs reported over the course of the trial will be attached as a pdf to this end point analysis.
    End point values
    		 Safety patient cohort (ITT)
    Number of subjects analysed
    52
    Units: Patients
    52
    Attachments
    		 Adverse Events
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Date of consent to end of study visit (3 months post end of treatment) for non-serious adverse events. Date of consent to 30 days post end of study treatment (48 weeks) or 30 days post last administration of IMP for serious adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Group 1: Placebo
    Reporting group description
    		 Control group. Treatment with once-daily subcutaneous injection of inactive treatment (liraglutide placebo) (Supplied by Novo Nordisk Ltd, UK)

    Reporting group title
    Group 2: Active
    Reporting group description
    		 Experimental group. Treatment with once-daily subcutaneous injections 1.8mg active liraglutide (Victoza ®) (Supplied by Novo Nordisk Ltd, UK)

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Results are posted in outcome section as validation error prevented uploading despite correct information- had to set number of patients not affected by non serious AE as `0` to post result as unable to over-ride validation warning to post results- group 1 is 24 and group 2 is 23.
    Serious adverse events
    		 Group 1: Placebo Group 2: Active
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 26 (7.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Calcitonin stimulation test
    Additional description: Calcitonin levels found to be abnormal
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Conduct disorder
    Additional description: ECG showed completed Heart Block and patient subsequently fitted with ventricular pacemaker. Occurred prior to any treatment being given. Ref: HE2013/0010/01
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
    Additional description: Patient admitted with headache and associated nausea and dizziness. MRI and CT scan of head showed no abnormalities SAE ref: HE2013/0049/01
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Granulomatous liver disease
    Additional description: End of trial biopsy showed incidental finding of multiple granulomas. Patient was found to have active tuberculosis and treated with 6 months of antibiotics ref: HE2013/0012/01
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
    Additional description: Patient diagnosed with REACTIVE HYPOGLYCAEMIA. REF: HE2013/0010/02
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 1: Placebo Group 2: Active
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2010
    Amendment 2.0 The following statements were added to the exclusion criteria (p38 & p39): • Patients with Multiple Endocrine Neoplasia Syndrome 2 (MEN2) • Family history of medullary thyroid cancer Reason: These additional exclusion criteria are in keeping with the current recommended contraindications of Liraglutide (Victoza®) use in patients. Non-Substantial Amendments to the Protocol Throughout the protocol a number of non substantial amendments were made, specifically the contact details (p66) of Novo Nordisk Ltd offices have been updated. The central contact point between the sponsor (The University of Birmingham) and the Drug Manufacturer and Holder of the IMP MA (Novo Nordisk). In addition the current national ethical and regulatory approval status of study has been updated in the protocol sponsor section as well as some additional information in the finance section (p75) of the protocol concerning the supply of pen-injection needles for use on the study. 1. Changes to IMP Labelling 2. Change to Patient Card: Inclusion of DUN Numbers (Prescribed study drug number)
    20 Nov 2010
    Amendment 3.0: Change to exclusion criteria: - No upper cut-off for BMI - removal of exclusion of patients that have had a significant change in dose of Angiotensin converting enzymes and (ACE) inhibitors and/or Angiotensin Receptor Blockers (ARBs) from exclusion criteria and inclusion of Multi-vitamins / vitamin E (containing > 200% recommended daily amount;>30mg/day). -Addition of a new participating site.
    20 Jan 2011
    Amendment 4.0 - addition of new participating site - New wording added to protocol in relation to the requirement for sites to report pregnancies to study office. - New wording added to protocol in relation to the time period for reporting adverse events
    28 Apr 2011
    Amendment 5.0 Change to clinical trial protocol 1. Trial Site addition of Hull Royal Infirmary 2. Change to Target dates for trial completion. 3. Amendment to visit schedule - Amendment to visit 8, with regards to 12 weeks post visit 7 rather 24 weeks
    01 Sep 2011
    Amendment 6.0: Addition of new participating centre and update to study protocol (protocol version 7.0) - site addition only.

    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.
    The information / data contained in this report is constrained /limited by the reporting structure of this report- for additional information and content please review the published articles and contact the corresponding author: Prof Philip Newsome.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24189085
    http://www.ncbi.nlm.nih.gov/pubmed/26608256
    http://www.ncbi.nlm.nih.gov/pubmed/26394161
    http://www.ncbi.nlm.nih.gov/pubmed/23163663
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