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    Clinical Trial Results:
    Multicentre UK Study of the Acetylcholinesterase Inhibitor Donepezil in Early Dementia Associated with Parkinson's Disease (MUSTARDD-PD)

    Summary
    EudraCT number
    		 2009-015170-35
    Trial protocol
    		 GB  
    Global end of trial date
    01 Sep 2014

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    5137
    Additional study identifiers
    ISRCTN number
    		 ISRCTN30151023
    US NCT number
    		 NCT01014858
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Newcastle upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Freeman Hospital, Freeman Road, Newcastle upon Tyne, United Kingdom, NE7 7DN
    Public contact
    Professor David Burn, Newcastle University, 44 0191 208 3357, david.burn@ncl.ac.uk
    Scientific contact
    Professor David Burn, Newcastle University, 44 0191 208 3357, david.burn@ncl.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
    15 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Is the cholinesterase inhibitor drug donepezil hydrochloride superior to placebo in improving cognitive function, neuropsychiatric burden and functional ability in people with Parkinson’s disease and mild dementia after 24 months of treatment?
    Protection of trial subjects
    No actions required.
    Background therapy
    		 Stable doses of atypical anti-psychotic medication (i.e. dose unchanged for 6 weeks prior to study entry) were permitted, as it was acknowledged that many patients with PDD experience psychotic features (especially visual hallucinations) prior to the onset of cognitive decline which may require atypical anti-psychotic medication. It was felt that it would be both impractical and unethical to exclude the use, or require the withdrawal, of these agents in a placebo-controlled study. Patients receiving a non-selective centrally acting anticholinergic drug for control of parkinsonian motor symptoms or other indication (e.g. urinary urgency) were excluded and use of these medications were forbidden throughout the duration of the study. Previous exposure to any cholinesterase inhibitor also excluded a patient. Patients receiving the N-methyl-d-aspartate antagonist memantine were also excluded; no exposure, previous or current, was permitted.
    Evidence for comparator
    		 This was a placebo-controlled study.
    Actual start date of recruitment
    30 Mar 2012
    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)
    7
    From 65 to 84 years
    52
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited between February 2013 and May 2014. This typically took place in clinic or a research unit. Sites were asked to consider all subjects seen consecutively with Parkinson’s disease and mild dementia as being suitable for randomisation, and to indicate in a log the reason(s) why screened patients were not randomised.

    Pre-assignment
    Screening details
    		 At the time of potential consideration for the study, the direct medical team caring for the potential participant determined if they were potentially eligible for the study with a consideration of the patient (and their records) in order to determine whether they met the inclusion criteria and if it was appropriate to approach the patient.

    Pre-assignment period milestones
    Number of subjects started
    		 64 [1]
    Number of subjects completed
    		 62

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 randomised in error: 1
    Reason: Number of subjects
    		 did not attend baseline visit: 1
    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: One subject was 'randomised in error' and withdrawn by site; no study data available. A second participant did not attend their baseline appointment.
    Period 1
    Period 1 title
    Visit 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Assignment to active or placebo arm was blinded to both the participant and investigator/assessor (double-blind) through the use of matched placebo. The assessor at each visit for the Mattis DRS-2, NPI-10 and BADLS was independent, and thus blinded not only to the treatment arm, but also to reports of general symptoms, progress and adverse events, as it was acknowledged that the latter, in particular, could potentially influence the assessor as to which treatment the participant was taking.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Donepezil hydrochloride
    Arm description
    		 Starting dose 5mg/day, increased to 10mg/day after 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Donepezil hydrochloride
    Investigational medicinal product code
    70676/18-12-2009, 87750/18-12-2009
    Other name
    Aripezil, Pridia
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Starting dose 5mg/day, increased to 10mg/day after 8 weeks

    Arm title
    		 Placebo
    Arm description
    		 Placebo was a gelatin capsule (swedish orange, size AAA) containing microcrystalline cellulose
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    N/A
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule daily for first 8 weeks, 2 capsules daily between weeks 9 and 26, then one capsule daily until week 104.

    Number of subjects in period 1
    		Donepezil hydrochloride Placebo
    Started
    32
    30
    Completed
    32
    30
    Period 2
    Period 2 title
    Visit 4
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Assignment to active or placebo arm was blinded to both the participant and investigator/assessor (double-blind) through the use of matched placebo. The assessor at each visit for the Mattis DRS-2, NPI-10 and BADLS was independent, and thus blinded not only to the treatment arm, but also to reports of general symptoms, progress and adverse events, as it was acknowledged that the latter, in particular, could potentially influence the assessor as to which treatment the participant was taking.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Donepezil hydrochloride
    Arm description
    		 Starting dose 5mg/day, increased to 10mg/day after 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Donepezil hydrochloride
    Investigational medicinal product code
    70676/18-12-2009, 87750/18-12-2009
    Other name
    Aripezil, Pridia
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Starting dose 5mg/day, increased to 10mg/day after 8 weeks

    Arm title
    		 Placebo
    Arm description
    		 Placebo was a gelatin capsule (swedish orange, size AAA) containing microcrystalline cellulose
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    N/A
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    One capsule daily for first 8 weeks, 2 capsules daily between weeks 9 and 26, then one capsule daily until week 104.

    Number of subjects in period 2
    		Donepezil hydrochloride Placebo
    Started
    32
    30
    Completed
    14
    14
    Not completed
    18
    16
         Consent withdrawn by subject
    5
    3
         Study terminated early
    13
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Donepezil hydrochloride
    Reporting group description
    		 Starting dose 5mg/day, increased to 10mg/day after 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was a gelatin capsule (swedish orange, size AAA) containing microcrystalline cellulose

    Reporting group values
    		 Donepezil hydrochloride Placebo Total
    Number of subjects
    		 32 30 62
    Age categorical
    Age of participants
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 5 2 7
        From 65-84 years
    		 26 26 52
        85 years and over
    		 1 2 3
    Age continuous
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 73 ± 9 74.6 ± 7 -
    Gender categorical
    People with Parkinson’s Disease and mild dementia residing in the UK.
    Units: Subjects
        Female
    		 5 9 14
        Male
    		 27 21 48
    MATTIS-DRS-2
    Mattis Dementia Rating Scale, Age-and-education-corrected Scaled Score
    Units: None
        arithmetic mean (standard deviation)
    		 7.9 ± 3 7 ± 2.9 -
    10-item NPI score
    10-item Neuropsychiatric Inventory
    Units: None
        median (inter-quartile range (Q1-Q3))
    		 2.5 (0.3 to 6.8) 4 (1 to 5.8) -
    NPI caregiver distress score
    Validated Questionnaire
    Units: None
        median (inter-quartile range (Q1-Q3))
    		 3 (0 to 6) 3.5 (0.3 to 5) -
    BADLS score
    Bristol Activities of Daily Living Scale
    Units: None
        median (inter-quartile range (Q1-Q3))
    		 5 (3 to 11) 2.5 (1 to 6.5) -
    MDS-UPDRS score
    Motor Subsection of the 2008 Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale
    Units: None
        median (inter-quartile range (Q1-Q3))
    		 40 (34 to 49.5) 34 (29 to 42) -
    ABC scale score
    Activities-specific balance confidence scale
    Units: None
        median (inter-quartile range (Q1-Q3))
    		 70 (57.3 to 81) 75.9 (66.8 to 85) -
    EQ5D
    Validated Quality of Life Questionnaire
    Units: None
        median (inter-quartile range (Q1-Q3))
    		 65 (60 to 75) 70 (60 to 80) -
    DEMQOL
    Validated Quality of Life Questionnaire
    Units: None
        median (inter-quartile range (Q1-Q3))
    		 93 (84 to 98) 95 (90 to 100) -
    DEMQOL-proxy
    Validated Quality of Life Questionnaire
    Units: None
        median (inter-quartile range (Q1-Q3))
    		 104 (95 to 113) 108 (99 to 115) -

    End points

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    End points reporting groups
    Reporting group title
    Donepezil hydrochloride
    Reporting group description
    		 Starting dose 5mg/day, increased to 10mg/day after 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was a gelatin capsule (swedish orange, size AAA) containing microcrystalline cellulose
    Reporting group title
    Donepezil hydrochloride
    Reporting group description
    		 Starting dose 5mg/day, increased to 10mg/day after 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was a gelatin capsule (swedish orange, size AAA) containing microcrystalline cellulose

    Subject analysis set title
    Donepezil hydrochloride
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    People with Parkinson’s Disease and mild dementia residing in the UK. Starting dose 5mg/day, increased to 10mg/day after 8 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    People with Parkinson’s Disease and mild dementia residing in the UK. One capsule daily for first 8 weeks, 2 capsules daily between weeks 9 and 26, then one capsule daily until week 104.

    Primary: MATTIS-DRS-2

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    End point title
    		 MATTIS-DRS-2 [1]
    End point description
    Mattis Dementia Rating Scale, Age-and-education-corrected Scaled Score
    End point type
    Primary
    End point timeframe
    26 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical testing carried out as study terminated early.
    End point values
    		 Donepezil hydrochloride Placebo
    Number of subjects analysed
    14
    14
    Units: None
        median (inter-quartile range (Q1-Q3))
    8 (5 to 12.5)
    6 (5.3 to 8.8)
    No statistical analyses for this end point

    Primary: MATTIS-DRS-2

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    End point title
    		 MATTIS-DRS-2 [2]
    End point description
    Mattis Dementia Rating Scale, Raw Scores
    End point type
    Primary
    End point timeframe
    26 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical testing was able to be carried out as the study was terminated early.
    End point values
    		 Donepezil hydrochloride Placebo
    Number of subjects analysed
    14
    14
    Units: None
        median (inter-quartile range (Q1-Q3))
    133 (123 to 141)
    130 (122 to 134)
    No statistical analyses for this end point

    Primary: 10-item NPI score

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    End point title
    		 10-item NPI score [3]
    End point description
    10-item Neuropsychiatric Inventory
    End point type
    Primary
    End point timeframe
    26 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical testing was able to be carried out as the study was terminated early.
    End point values
    		 Donepezil hydrochloride Placebo
    Number of subjects analysed
    12
    14
    Units: None
        median (inter-quartile range (Q1-Q3))
    2.5 (0.8 to 6.8)
    4.5 (1.3 to 7)
    No statistical analyses for this end point

    Primary: BADLS score

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    End point title
    		 BADLS score [4]
    End point description
    Bristol Activities of Daily Living Score
    End point type
    Primary
    End point timeframe
    26 weeks
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical testing was able to be carried out as the study was terminated early.
    End point values
    		 Donepezil hydrochloride Placebo
    Number of subjects analysed
    14
    14
    Units: None
        median (inter-quartile range (Q1-Q3))
    5 (2.3 to 8.5)
    4.5 (2 to 7.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All non-serious adverse events were reported from visit 3 until final visit. Serious adverse events were reported throughout the trial until 2 weeks after trial medication was stopped.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 As reported
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Donepezil hydrochloride
    Reporting group description
    		 Starting dose 5mg/day, increased to 10mg/day after 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was a gelatin capsule (swedish orange, size AAA) containing microcrystalline cellulose

    Serious adverse events
    		 Donepezil hydrochloride Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 30 (6.67%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Aortic dissection
    Additional description: Death due to haemopericardium, aortic dissection and hypertension
         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 / 1
    0 / 0
    Transient ischaemic attack
         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
    Blood and lymphatic system disorders
    Acute leukaemia
    Additional description: Death due to acute leukaemia
         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 / 1
    0 / 0
    General disorders and administration site conditions
    Confusional state
    Additional description: Confused, has falls, severe offs with freezing so lost confidence walking and panicked. Refused to walk due to panic and this caused chest pain, so ambulance called.
         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
    Dehydration
    Additional description: Patient increased trial medication from 1 to 2 tablets. This caused excessive tiredness. Patient felt dehydrated, cold and faint. Patient took dioralyte to rehydrate self. Phoned 999 and taken to A&E.
         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
    Urinary retention
    Additional description: Postural hypotension and urinary retention: collapsed at party, taken to A&E. Abdomen soft, suprapubic mass - bladder 999mls - catheterised.
         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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Donepezil hydrochloride Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 32 (59.38%)
    23 / 30 (76.67%)
    Injury, poisoning and procedural complications
    Bleed post tooth extraction
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Burnt throat
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    dislocated finger when fell
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Grazed hand following fall
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Head Injury
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Injury to right elbow
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    injury to left thumb
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Laceration of scalp (due to fall)
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Wound on left arm
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Corrective surgery right middle finger
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Surgery for skin cancer
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Surgical procedure to right shoulder with post-operative pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    TIA lasting 30 minutes
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dyskensias
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    dystonia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Increased episodes of freezing
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    increased freezing
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    increased neuropathic pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Increased PD tremor
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Worsening of Parkinson's symptoms
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Achy legs
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Apathy
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Back ache
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Back pain increased
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Breathlessness going upstairs
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Bruising to head and shoulders
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Chestiness with cough
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Chesty cough
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Choked on IMP
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Confusion
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    confusion/disorentation
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    coughing at night
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Dizziness on standing and sudden movement
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Dizziness when taking pain medication
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Drowsiness
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Excessive saliva
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    face twisted
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    10 / 32 (31.25%)
    12 / 30 (40.00%)
         occurrences all number
    10
    12
    Fall/loss of consciousness
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    falls
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Fell
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    frequent falls
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    further deterioration in memory
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Generally unwell
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Grip in right hand weaker
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hallucinations
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Headaches
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hip pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    hypotension
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    increase in falls
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    increased anxiety
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Increased balance problem
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Increased confusion and drowsiness
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Increased confusion and agitation
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Increased day time somnolence
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Increased sleepiness
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    intermittent neck pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    intermittent tinnitus
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Itchy scalp
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Itchy skin
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Legs aching when walking
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    legs aching whilst walking
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Lesion on chest
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Light headedness
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Loss of consciousness
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Loss of balance
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    low mood
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    muddled head
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Nightmares
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Nose bleed
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Pain in back worsening
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Pain in right and left wrists worsening
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Pain in right knee on extension
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    painful right knee on exertion
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Painful right leg
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Panic attack
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Postural hypertension
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    productive cough
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Reduced apetite
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Reduction in semen/burning
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    right shoulder worsening
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    runny nose
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Shoulder pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Significant behavioural changes
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    sleepiness
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    slight euphoria
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Some choking
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Sweating
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Swollen feet
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Three falls when getting out of chair
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Tiredness
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Unable to eat or drink
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    vaginal discharge
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Very bad nightmares
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Weakness
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Weight loss
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    woolly head
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    worsening memory
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Worsening of back pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Worsening of confusion
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    worsening of cramps in feet
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    worsening of cramps in hands
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    worsening of cramps in legs
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    worsening of pain in left calf
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Worsening of REM/sleep disorder
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Myelodysplasia syndrome
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Tiredness due to reduced platelet count
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    5 / 32 (15.63%)
    1 / 30 (3.33%)
         occurrences all number
    5
    1
    Flatulence
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hiatus hernia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Loose stools
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    lower abdominal cramps
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Worsening constipation
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Worsening of urinary frequency/urgency
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Chest infection
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    infected wound
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2012
    Update of protocol to version 4.0; bringing REC application up to date with MHRA/CSP applications.
    01 Aug 2012
    Update of protocol to version 5.0; removal of CT scan, DRS stratification and general protocol maintenance.
    26 Jun 2013
    Update of protocol to version 6.0 and PIS.
    22 Aug 2013
    Update to protocol version 7.0; change to DRS and removal of neurosurgery exclusion criteria.
    07 Mar 2014
    Addition of a study specific poster and leaflet.
    23 Apr 2014
    PI change at Norfolk & Norwich; PI change at Derby.
    18 Jun 2014
    Temporary halt to recruitment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    29 May 2014
    Temporary halt to recruitment.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Recruitment to the trial proved difficult, so the trial was terminated early. It was originally intended to recruit 500 participants, however only 62 patients were recruited over 19 months. The last results were therefore collected at 26 weeks.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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