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    Clinical Trial Results:
    A randomised, double blind, placebo controlled, single centre, 60 week trial of Exenatide once weekly for the treatment of moderate severity Parkinson’s disease.

    Summary
    EudraCT number
    		 2013-003363-64
    Trial protocol
    		 GB  
    Global end of trial date
    12 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2018
    First version publication date
    22 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13/0384
    Additional study identifiers
    ISRCTN number
    		 ISRCTN75891427
    US NCT number
    		 NCT01971242
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 FoxTrialFinder: Exenatide-pd
    Sponsors
    Sponsor organisation name
    Comprehensive Clinical Trials Unit at UCL
    Sponsor organisation address
    Institute of Clinical Trials and Methodology, 90 High Holborn , London, United Kingdom, WC1V 6LJ
    Public contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.ac.uk
    Scientific contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.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
    27 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To generate further data to explore whether 48 weeks exposure to Exenatide has an advantage over placebo based on a standard validated assessment of Parkinson's disease severity (the MDS UPDRS part 3 motor subscale). This was measured during the “practically defined OFF medication state” i.e. after patients had withheld their conventional PD medication overnight. The hypothesis was that Exenatide would be associated with reduced MDS UPDRS part 3 scores at the study end.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, UCL CCTU Standard Operating Procedures, the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act, the EU Tissue and Cells Directives 2004/23/EC, 2006 17/EC and 2006/86/EC, and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). Protocol pre-defined reasons for a temporary halt of trial medication were in place in the event of participants experiencing abdominal pain consistent with a clinical diagnosis of pancreatitis or excessive/undesirable weight loss (>10% of body weight during a 12 week interval). Protocol pre-defined reasons for discontinuation of trial medication were in place in the event of participants experiencing any of the following: diagnosis of acute pancreatitis; an elevation in serum Amylase (>50% above baseline); developing clinical suspicion of thyroid malignancy; accelerated disease progression (defined as greater than 50% (and absolute value of 20 points) decline in MDS UPDRS part 3 motor sub-score from baseline in both the ON medication and the practically defined OFF medication states). Broader protocol pre-defined reasons for discontinuation of trial medication: unacceptable treatment toxicity or adverse event; inter-current illness that prevented further treatment; any change in the participant’s condition that in the clinician’s opinion justifies the discontinuation of treatment. All participants could choose to discontinue trial treatment at any time, without giving a reason, without penalty or loss of benefits to which they would otherwise be entitled. Investigation and treatment of adverse events were as per NHS standard of care.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2014
    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: 62
    Worldwide total number of subjects
    62
    EEA total number of subjects
    62
    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)
    41
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with moderate Parkinson’s disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. The trial was done at the Leonard Wolfson Experimental Neuroscience Centre (London, UK).

    Pre-assignment
    Screening details
    		 Inclusion: Patients aged 25–75 years, idiopathic Parkinson’s disease as measured by Queen Square Brain Bank criteria, on dopaminergic treatment with wearing-off effects, judged able to administer the trial drug, and at Hoehn and Yahr stage 2·5 or less when on treatment. Exclusion: concurrent dementia (MATTIS DRS<120), BMI<18.5 and diabetes.

    Pre-assignment period milestones
    Number of subjects started
    		 68 [1]
    Number of subjects completed
    		 62

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 Protocol deviation: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported in the pre-assignment period are the numbers who were screened for the trial but not randomised into the trial. The worldwide number enrolled is the number of patients who were eligible, consented and randomised into the trial.
    Period 1
    Period 1 title
    Main Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    The trial statistician generated and uploaded unique three-digit identifiers for every active and placebo drug kit to the randomisation service to allow allocation of masked study drug kits (sufficient for 12 weeks) at randomisation and follow-up visits by assessing clinicians. The randomisation service then provided the relevant kit numbers that were to be dispensed to the patient from the hospital pharmacy.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Exenatide
    Arm description
    		 Exenatide extended release 2mg subcutaneous injection (Bydureon) once weekly for 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Exenatide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of Exenatide extended release is supplied as a vial containing the Exenatide powder and an inactive ingredient called polylactide-co-glycolide and sucrose. This is supplied together with diluent (sterile water containing carboxymethylcellulose sodium, polysorbate 20, sodium phosphate monobasic monohydrate, sodium phosphate dibasic heptahydrate and sodium chloride) to allow reconstitution of the powder in solution for subcutaneous administration by the patient on a weekly basis. 2mg once weekly for 48 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Each dose of Placebo - Exenatide extended release is supplied as a vial containing a powder together with diluent to allow reconstitution of solution for subcutaneous administration by the patient on a weekly basis.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each dose of Placebo- Exenatide extended release is supplied as a vial containing a powder together with diluent to allow reconstitution of solution for subcutaneous administration by the patient on a weekly basis. Once weekly for 48 weeks.

    Number of subjects in period 1
    		Exenatide Placebo
    Started
    32
    30
    Completed
    31
    29
    Not completed
    1
    1
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Exenatide
    Reporting group description
    		 Exenatide extended release 2mg subcutaneous injection (Bydureon) once weekly for 48 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Each dose of Placebo - Exenatide extended release is supplied as a vial containing a powder together with diluent to allow reconstitution of solution for subcutaneous administration by the patient on a weekly basis.

    Reporting group values
    		 Exenatide Placebo Total
    Number of subjects
    		 32 30 62
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 18 23 41
        From 65-84 years
    		 14 7 21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.9 ( 8.2 ) 58.3 ( 8.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 7 16
        Male
    		 23 23 46
    Hoehn & Yahr
    Units: Subjects
        Stage 1.0 - 2.0
    		 30 30 60
        Stage 2.5
    		 2 0 2
    Age at Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    		 56.2 ( 7.9 ) 52.5 ( 7.8 ) -
    Duration of diagnosis at baseline
    Units: Years
        arithmetic mean (standard deviation)
    		 6.3 ( 3.3 ) 6.5 ( 3.4 ) -
    Levodoa equivalent dose
    Units: mg
        arithmetic mean (standard deviation)
    		 760 ( 268.4 ) 816.8 ( 203.4 ) -
    MDS UPDRS part 3 Off medication
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 32.8 ( 9.7 ) 27.1 ( 10.3 ) -
    MDS UPDRS Part 1 On medication
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 9.8 ( 4.8 ) 9.2 ( 3.8 ) -
    MDS UPDRS part 2 On medication
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 12.5 ( 6.7 ) 10.7 ( 5.3 ) -
    MDS UPDRS part 3 On medication
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 19.4 ( 8.4 ) 14.4 ( 8.2 ) -
    MDS UPDRS part 4 On medication
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 4.7 ( 3.1 ) 5.3 ( 3.0 ) -
    MATTIS Dementia Rating scale
    Units: unit(s)
        arithmetic mean (standard deviation)
    		 138.0 ( 5.0 ) 139.8 ( 3.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Exenatide
    Reporting group description
    		 Exenatide extended release 2mg subcutaneous injection (Bydureon) once weekly for 48 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Each dose of Placebo - Exenatide extended release is supplied as a vial containing a powder together with diluent to allow reconstitution of solution for subcutaneous administration by the patient on a weekly basis.

    Primary: Change from baseline in MDS UPDRS part 3 Off medication at 60 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 3 Off medication at 60 weeks
    End point description
    The primary endpoint measure for this trial is the MDS UPDRS (part 3) motor sub-score in the practically defined OFF medication state at 60 weeks.
    End point type
    Primary
    End point timeframe
    At 60 weeks from randomisation
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    28
    Units: units
        arithmetic mean (standard deviation)
    31.9 ( 12.0 )
    29.2 ( 12.0 )
    Statistical analysis title
    		 Primary outcome analysis
    Statistical analysis description
    We used an analysis of covariance (ANCOVA) model to estimate the difference in MDS UPDRS part 3 subscore between treatments (Exenatide - placebo) at 60 weeks together with a two-sided 95% confidence interval, adjusting for the Hoehn and Yahr score and baseline MDS UPDRS scores which were included as covariates.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0318
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 -0.3

    Secondary: Change from baseline in MDS UPDRS part 3 Off medication at 48 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 3 Off medication at 48 weeks
    End point description
    Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 3 Motor Examination subsection score.
    End point type
    Secondary
    End point timeframe
    At 48 weeks post randomisation
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    30
    29
    Units: units
        arithmetic mean (standard deviation)
    30.2 ( 11.1 )
    28.8 ( 10.8 )
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    For secondary outcomes, the differences between the two groups were summarised using estimates and confidence intervals, using the ANCOVA approach.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0026
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 -1.6

    Secondary: Change from baseline in MDS UPDRS part 1 On medication at 60 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 1 On medication at 60 weeks
    End point description
    Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 1 non-Motor Experiences of Daily Living subsection score.
    End point type
    Secondary
    End point timeframe
    At 60 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    28
    Units: Units
        arithmetic mean (standard deviation)
    9.3 ( 4.0 )
    10.1 ( 5.3 )
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    For secondary outcomes, the differences between the two groups were summarised using estimates and confidence intervals, using the ANCOVA approach. Outcome measures in the ON medication state were additionally adjusted for change from baseline in LED to account for the possible confounding effect of increased Parkinson’s medication during the trial.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 0.8

    Secondary: Change from baseline in MDS UPDRS part 1 On medication at 48 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 1 On medication at 48 weeks
    End point description
    Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 1 non-Motor Experiences of Daily Living subsection score.
    End point type
    Secondary
    End point timeframe
    At 48 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    29
    Units: Units
        arithmetic mean (standard deviation)
    8.8 ( 4.4 )
    9.7 ( 5.6 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 1.5

    Secondary: Change from baseline in MDS UPDRS part 2 On medication at 60 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 2 On medication at 60 weeks
    End point description
    Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 2 Motor Experiences of Daily Living subsection score.
    End point type
    Secondary
    End point timeframe
    At 60 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    28
    Units: Units
        arithmetic mean (standard deviation)
    11.6 ( 6.6 )
    11.0 ( 6.7 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 1.5

    Secondary: Change from baseline in MDS UPDRS part 2 On medication at 48 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 2 On medication at 48 weeks
    End point description
    Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 2 Motor Experiences of Daily Living subsection score.
    End point type
    Secondary
    End point timeframe
    At 48 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    29
    Units: Units
        arithmetic mean (standard deviation)
    11.7 ( 6.3 )
    10.8 ( 5.6 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 1.5

    Secondary: Change from baseline in MDS UPDRS part 3 On medication at 60 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 3 On medication at 60 weeks
    End point description
    Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 3 Motor Examination subsection score.
    End point type
    Secondary
    End point timeframe
    at 60 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    28
    Units: unit(s)
        arithmetic mean (standard deviation)
    19.9 ( 10.3 )
    14.5 ( 7.1 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 0.9

    Secondary: Change from baseline in MDS UPDRS part 3 On medication at 48 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 3 On medication at 48 weeks
    End point description
    Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 3 Motor Examination subsection score.
    End point type
    Secondary
    End point timeframe
    At 48 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    29
    Units: unit(s)
        arithmetic mean (standard deviation)
    20.5 ( 9.5 )
    15.7 ( 7.1 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 2.4

    Secondary: Change from baseline in MDS UPDRS part 4 On medication at 60 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 4 On medication at 60 weeks
    End point description
    Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 4 Motor Complications subsection score.
    End point type
    Secondary
    End point timeframe
    At 60 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    28
    Units: unit(s)
        arithmetic mean (standard deviation)
    5.2 ( 2.3 )
    6.1 ( 3.7 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 0.9

    Secondary: Change from baseline in MDS UPDRS part 4 On medication at 48 weeks

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    End point title
    		 Change from baseline in MDS UPDRS part 4 On medication at 48 weeks
    End point description
    Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 4 Motor Complications subsection score.
    End point type
    Secondary
    End point timeframe
    At 48 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    29
    Units: unit(s)
        arithmetic mean (standard deviation)
    4.9 ( 2.5 )
    5.6 ( 3.0 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 0.9

    Secondary: Change from baseline in MATTIS Dementia Rating scale at 60 weeks

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    End point title
    		 Change from baseline in MATTIS Dementia Rating scale at 60 weeks
    End point description
    The Mattis Dementia Rating Scale (DRS-2) assesses a patient’s overall level of cognitive functioning with respect to five abilities: Attention, Initiation/Perseveration, Construction, Conceptualization, and Memory using a series of 36 tasks and 32 stimulus cards.
    End point type
    Secondary
    End point timeframe
    At 60 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    28
    Units: unit(s)
        arithmetic mean (standard deviation)
    139.9 ( 3.6 )
    140.2 ( 4.6 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 2.5

    Secondary: Change from baseline in MATTIS Dementia rating scale at 48 weeks

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    End point title
    		 Change from baseline in MATTIS Dementia rating scale at 48 weeks
    End point description
    The Mattis Dementia Rating Scale (DRS-2) assesses a patient’s overall level of cognitive functioning with respect to five abilities: Attention, Initiation/Perseveration, Construction, Conceptualization, and Memory using a series of 36 tasks and 32 stimulus cards.
    End point type
    Secondary
    End point timeframe
    At 48 weeks post randomisation.
    End point values
    		 Exenatide Placebo
    Number of subjects analysed
    31
    29
    Units: unit(s)
        arithmetic mean (standard deviation)
    139.7 ( 4.1 )
    140.2 ( 3.9 )
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.57
    Method
    		 ANCOVA
    Parameter type
    		 Slope
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation to 60 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Exenatide
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Exenatide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 30 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Collapse
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Faecal Impaction
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute urinary retention
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Unintentional weight loss
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Exenatide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 32 (96.88%)
    29 / 30 (96.67%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 32 (12.50%)
    3 / 30 (10.00%)
         occurrences all number
    5
    3
    Nervous system disorders
    Increased time off medication
         subjects affected / exposed
    8 / 32 (25.00%)
    11 / 30 (36.67%)
         occurrences all number
    8
    12
    Sleep disorder
         subjects affected / exposed
    3 / 32 (9.38%)
    6 / 30 (20.00%)
         occurrences all number
    3
    6
    Increased dystonia
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 30 (16.67%)
         occurrences all number
    3
    5
    Dyskinesia
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Freezing
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    9 / 32 (28.13%)
    6 / 30 (20.00%)
         occurrences all number
    13
    11
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    12 / 32 (37.50%)
    10 / 30 (33.33%)
         occurrences all number
    12
    11
    Nausea
         subjects affected / exposed
    16 / 32 (50.00%)
    8 / 30 (26.67%)
         occurrences all number
    16
    10
    Diarrhoea
         subjects affected / exposed
    7 / 32 (21.88%)
    4 / 30 (13.33%)
         occurrences all number
    8
    6
    Abdominal pain
         subjects affected / exposed
    5 / 32 (15.63%)
    3 / 30 (10.00%)
         occurrences all number
    5
    3
    Loss of appetite
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Indigestion
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Bloating
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 30 (10.00%)
         occurrences all number
    4
    3
    Skin and subcutaneous tissue disorders
    Injection site reaction
         subjects affected / exposed
    25 / 32 (78.13%)
    22 / 30 (73.33%)
         occurrences all number
    27
    26
    Renal and urinary disorders
    Lower urinary tract symptoms
         subjects affected / exposed
    6 / 32 (18.75%)
    6 / 30 (20.00%)
         occurrences all number
    6
    7
    Urinary tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 32 (6.25%)
    5 / 30 (16.67%)
         occurrences all number
    2
    5
    Metabolism and nutrition disorders
    Weight loss
         subjects affected / exposed
    24 / 32 (75.00%)
    18 / 30 (60.00%)
         occurrences all number
    24
    18
    Weight gain
         subjects affected / exposed
    7 / 32 (21.88%)
    11 / 30 (36.67%)
         occurrences all number
    7
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jan 2015
    Protocol updated to v3.0 to add patients with Type 1 or Type 2 Diabetes mellitus to the exclusion criteria. Other corrections and clarifications throughout.
    22 May 2015
    Protocol updated to v4.0 with changes in withheld PD medication, participants not being shown an instructional video re lumbar puncture and clarifications throughout.
    20 Aug 2015
    Protocol updated to v5.0 with the additional dispensing of a kit to maintain sufficient IMP supply after a high number of vial breakages.
    13 Nov 2015
    Protocol updated to v6.0 with the following: excessive weight loss resulting in dose temporarily stopped not discontinued and becoming a notifiable event; exploratory outcomes added; additional blood test at visit seven; clarifications.

    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 small size of our study meant that, despite randomisation with a block design according to Hoehn and Yahr status, the Exenatide group had higher MDS-UPDRS part 3 scores and lower LED at baseline than the placebo group.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28781108
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