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    Clinical Trial Results:
    A randomised, double blind, placebo controlled trial to evaluate the effect of Rivastigmine on gait in people with Parkinson’s disease who have fallen.

    Summary
    EudraCT number
    		 2011-003053-25
    Trial protocol
    		 GB  
    Global end of trial date
    10 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2018
    First version publication date
    07 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1466
    Additional study identifiers
    ISRCTN number
    		 ISRCTN19880883
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1124-0244
    Sponsors
    Sponsor organisation name
    University of Bristol
    Sponsor organisation address
    Senate House, Tyndall Ave, Bristol , United Kingdom, BS8 1TH
    Public contact
    N/A, Parkinson's UK , +44 0808 800 0303,
    Scientific contact
    Dr Emily Henderson , University of Bristol , the-respond-trial@bristol.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
    02 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study sought to assess the benefit of rivastigmine (a drug which augments mental function) on gait (walking) dysfunction in patients with Parkinson’s disease (PD) with a past history of a fall. The primary aim was to determine the effect of the cholinesterase inhibitor (ChEi) rivastigmine on step time variability in patients with PD. Step time variability is a marker of how stable an individual's walking is and a prognostic marker for future falls risk.
    Protection of trial subjects
    Ethics approval was granted from the South West Research Ethics Committee on 28th September 2011 and a Clinical Trial Authorisation (CTA) granted from the Medicines and Healthcare Regulatory Agency (MHRA) on 18th June 2012. The trial was performed in accordance with the UK 2004 Medicines for Human Use (Clinical Trials) Regulations and its subsequent amendments
    Background therapy
    		 Usual dopaminergic Parkinson's medication.
    Evidence for comparator
    		 We searched PubMed for randomized control trials (RCTs), limited only to humans using “Parkinson disease” and “Cholinesterase inhibitors” as MeSH terms. This identified twenty studies, of which, 5 reported a falls outcome. Only one randomised crossover trial sought primarily to determine the effect of a cholinesterase inhibitor – donepezil, on falls in PD. In this trial 23 subjects who reported falling or near falling more than two times a week were given donepezil for 6 weeks. Donepezil treatment was associated with a reduction in fall rate from 0.25 falls/day (SEM=0.08) on placebo to 0.13 falls/day (SEM 0.03) on donepezil (p=0.05). However, frequent fallers drove the observed benefit and the finding was reported using a per-protocol, as opposed to an intention-to-treat, analysis. The study was small and of short duration. Two RCT’s of rivastigmine versus placebo reported falls as adverse events. Both reported lower proportions of falls occurring in the cholinesterase inhibitor groups (7/211 (3.3%) versus 9/123 (7.3%) and 21/362 (5.8%) versus 11/179 (6.1%)) although in both cases the absolute numbers were small. One study reported that galantamine was associated with a decrease in falls, freezing and gait domains of the UPDRS. The fifth trial stated that ‘increased number of falls’ contributed to withdrawal of a participant. No other gait outcome measures were reported in any of the trials.
    Actual start date of recruitment
    04 Oct 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 130
    Worldwide total number of subjects
    130
    EEA total number of subjects
    130
    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)
    31
    From 65 to 84 years
    94
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were identified from community and hospital settings. Patient Identification Centres (PICs) were set-up to identify patients in other local centres and DeNDRoN (Dementias and Neurodegenerative Diseases Research Network) nurses performed pre-screening of potential participants in hospital clinics. We also recruited participants from the

    Pre-assignment
    Screening details
    		 931 were assessed for eligiblity. 500 were ineligible (did not meet inclusion criteria) and 301 declined to participate.

    Period 1
    Period 1 title
    Baseline period
    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
    Patients were randomly assigned (1:1) to rivastigmine (acetylcholinesterase inhibitor) or identically matched placebo capsules. Participants were enrolled and tested by an investigator (EH) who had no access to the randomisation sequence that was generated by Bristol Randomised Trials Collaboration (BRTC) clinical trials unit using a web-based program. A treatment pack number was issued via a secure website that matched a drug pack held in the pharmacy to ensure concealment of allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rivastigmine
    Arm description
    		 Participants treated with the active medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rivasigmine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1.5mg bd for 4 weeks 3mg bd for 4 weeks 4.5mg bd for 4 weeks 6mg bd for 4 weeks Highest tolerated dose for 16 weeks.

    Arm title
    		 Placebo arm
    Arm description
    		 Patients treated with placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1.5mg bd for 4 weeks 3mg bd for 4 weeks 4.5mg bd for 4 weeks 6mg bd for 4 weeks Highest tolerated dose for further 16 weeks.

    Number of subjects in period 1
    		Rivastigmine Placebo arm
    Started
    65
    65
    Completed
    65
    65
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rivastigmine
    Arm description
    		 Participants treated with the active medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rivasigmine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1.5mg bd for 4 weeks 3mg bd for 4 weeks 4.5mg bd for 4 weeks 6mg bd for 4 weeks Highest tolerated dose for 16 weeks.

    Arm title
    		 Placebo arm
    Arm description
    		 Patients treated with placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1.5mg bd for 4 weeks 3mg bd for 4 weeks 4.5mg bd for 4 weeks 6mg bd for 4 weeks Highest tolerated dose for further 16 weeks.

    Number of subjects in period 2
    		Rivastigmine Placebo arm
    Started
    65
    65
    Completed
    65
    65

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rivastigmine
    Reporting group description
    		 Participants treated with the active medication.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients treated with placebo

    Reporting group values
    		 Rivastigmine Placebo arm Total
    Number of subjects
    		 65 65 130
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        geometric mean (full range (min-max))
    		 71 (54 to 90) 69 (46 to 88) -
    Gender categorical
    Units: Subjects
        Female
    		 30 19 49
        Male
    		 35 46 81
    Have experienced freezing of gait in previous month
    Units: Subjects
        Experienced FoG
    		 42 48 90
        Not experienced FoG
    		 23 17 40
    Falls in previous year
    Units: Number
        median (inter-quartile range (Q1-Q3))
    		 5 (2 to 12) 5.5 (2 to 12.5) -
    Gait speed
    Units: m/s
        geometric mean (standard deviation)
    		 1 ± 0.3 1 ± 0.3 -
    Step time variability (normal walking)
    Units: sec
        median (inter-quartile range (Q1-Q3))
    		 0.026 (0.02 to 0.047) 0.024 (0.018 to 0.039) -
    Step time variability (walking with simple task)
    Units: sec
        median (inter-quartile range (Q1-Q3))
    		 0.053 (0.028 to 0.138) 0.049 (0.03 to 0.11) -
    Step time variability (walking plus complex task)
    Units: sec
        median (inter-quartile range (Q1-Q3))
    		 0.078 (0.035 to 0.167) 0.068 (0.036 to 0.149) -
    MoCA
    Montreal Cognitive Assessment
    Units: Units
        median (inter-quartile range (Q1-Q3))
    		 24 (22 to 27) 26 (23 to 27) -
    Frontal Assessment Battery
    Units: Units
        median (inter-quartile range (Q1-Q3))
    		 15 (12 to 16) 14 (12 to 16) -
    Geriatric depression Scale
    Units: Units
        median (inter-quartile range (Q1-Q3))
    		 3 (2 to 6) 3 (1 to 5) -
    Cognitive Failures Questionnaire
    Units: Units
        median (inter-quartile range (Q1-Q3))
    		 41 (30 to 48) 39 (30 to 47) -
    MDS-UPDRS
    Units: Units
        median (inter-quartile range (Q1-Q3))
    		 87 (64 to 99) 90 (74 to 106) -
    Levodopa equivalent dose
    Units: mg
        median (inter-quartile range (Q1-Q3))
    		 710 (450 to 1075) 980 (650 to 1298) -
    Duration of Parkinson’s disease (years)
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 8 (5 to 13) 9 (5 to 13) -
    Quality-of-life EQ-5D-5L index score
    Quality-of-life EQ-5D-5L index score
    Units: Units
        arithmetic mean (standard deviation)
    		 0.72 ± 0.19 0.71 ± 0.18 -
    Quality-of-life EQ-5D-5L visual analogue score
    Quality-of-life EQ-5D-5L visual analogue score
    Units: units
        arithmetic mean (standard deviation)
    		 64 ± 17 65 ± 17 -
    ICON-FES
    (fear of falling)
    Units: Units
        arithmetic mean (standard deviation)
    		 22.9 ± 6.72 24 ± 5.17 -
    PPA falls risk score
    PPA=Physiological Profile Assessment
    Units: Units
        arithmetic mean (standard deviation)
    		 1.9 ± 1.9 1.9 ± 1.4 -

    End points

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    End points reporting groups
    Reporting group title
    Rivastigmine
    Reporting group description
    		 Participants treated with the active medication.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients treated with placebo
    Reporting group title
    Rivastigmine
    Reporting group description
    		 Participants treated with the active medication.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients treated with placebo

    Subject analysis set title
    Set 1 (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT analysis set

    Primary: 8 month follow-up

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    End point title
    		 8 month follow-up
    End point description
    End point type
    Primary
    End point timeframe
    8 months
    End point values
    		 Rivastigmine Placebo arm Set 1 (ITT)
    Number of subjects analysed
    65
    65
    130
    Units: number / month
        number (not applicable)
    65
    65
    130
    Statistical analysis title
    		 Falls per month
    Statistical analysis description
    Negative binomial regression
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Regression, negative binomial
    Parameter type
    		 Incident rate ratio
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.18
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Primary (step time variability normal walk)
    Statistical analysis description
    Adjusted for centred age, centred baseline cognition (MoCA score), centred log baseline step time variability of condition, and previous falls categorised as (1, 2–3, 4–6, 7–19, ≥20)
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076
    Statistical analysis title
    		 Primary (step time variability simple task)
    Statistical analysis description
    Adjusted for centred age, centred baseline cognition (MoCA score), centred log baseline step time variability of condition, and previous falls categorised as (1, 2–3, 4–6, 7–19, ≥20)
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.093
    Statistical analysis title
    		 Primary (step time variability complex task)
    Statistical analysis description
    Adjusted for centred age, centred baseline cognition (MoCA score), centred log baseline step time variability of condition, and previous falls categorised as (1, 2–3, 4–6, 7–19, ≥20)
    Comparison groups
    Rivastigmine v Placebo arm v Set 1 (ITT)
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.122
    Statistical analysis title
    		 Gait speed (normal walking)
    Statistical analysis description
    for baseline outcome, centred age, centred baseline cognition (MoCA score), centred baseline log step time variability during normal walking, and previous falls (categorised as 1, 2–3, 4–6, 7–19, ≥20).
    Comparison groups
    Placebo arm v Rivastigmine
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.18
    Statistical analysis title
    		 Gait speed (simple task)
    Statistical analysis description
    for baseline outcome, centred age, centred baseline cognition (MoCA score), centred baseline log step time variability during normal walking, and previous falls (categorised as 1, 2–3, 4–6, 7–19, ≥20).
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.16
    Statistical analysis title
    		 Gait speed (complex task)
    Statistical analysis description
    adjusted for baseline outcome, centred age, centred baseline cognition (MoCA score), centred baseline log step time variability during normal walking, and previous falls (categorised as 1, 2–3, 4–6, 7–19, ≥20).
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.16
    Statistical analysis title
    		 FOG episode previous month
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.22
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 1.6
    Notes
    [1] - Adjusted for baseline outcome, centred age, centred baseline cognition (MoCA score), centred baseline log step time variability during normal walking, and previous falls (categorised as 1, 2–3, 4–6, 7–19, ≥20).
    Statistical analysis title
    		 MoCA
    Statistical analysis description
    Adjusted for baseline outcome, centred age, centred baseline cognition (MoCA score), centred baseline log step time variability during normal walking, and previous falls (categorised as 1, 2–3, 4–6, 7–19, ≥20).
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.06
    Statistical analysis title
    		 MDS-UPDRS
    Comparison groups
    Placebo arm v Rivastigmine
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.6
         upper limit
    		 3
    Statistical analysis title
    		 Quality of life EQ-5D score
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.007
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.051
         upper limit
    		 0.066
    Statistical analysis title
    		 PPA falls risk score
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Geometric mean ratio.
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.39
    Statistical analysis title
    		 Fear of falling
    Statistical analysis description
    ICON-FES Iconographical Falls Efficacy Scale
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric mean ratio
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.03
         upper limit
    		 1.53
    Statistical analysis title
    		 Controlled leaning balance score
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Relative risk ratio
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.57
    Notes
    [2] - Logistic regression
    Statistical analysis title
    		 Mood (Geriatric Depression Scale score)
    Statistical analysis description
    Adjusted for baseline outcome, centred age, centred baseline cognition (MoCA score), centred baseline log step time variability during normal walking, and previous falls (categorised as 1, 2–3, 4–6, 7–19, ≥20).
    Comparison groups
    Rivastigmine v Placebo arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.19

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Over 8 months of treatment
    Adverse event reporting additional description
    Minimum monthly phone call to participants plus falls diaries returned on a monthly basis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Rivastigmine
    Reporting group description
    		 Participants treated with the active medication.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients treated with placebo

    Serious adverse events
    		 Rivastigmine Placebo arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 65 (21.54%)
    13 / 65 (20.00%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Biopsy of cervix
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic cancer metastatic
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    5 / 65 (7.69%)
    4 / 65 (6.15%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Foot operation
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia repair
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb operation
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    3 / 65 (4.62%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroid disorder
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Peritonitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 65 (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: 5%
    Non-serious adverse events
    		 Rivastigmine Placebo arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 65 (98.46%)
    62 / 65 (95.38%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 65 (21.54%)
    6 / 65 (9.23%)
         occurrences all number
    17
    7
    Parkinsonism
         subjects affected / exposed
    26 / 65 (40.00%)
    22 / 65 (33.85%)
         occurrences all number
    36
    28
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    20 / 65 (30.77%)
    3 / 65 (4.62%)
         occurrences all number
    24
    3
    Vomiting
         subjects affected / exposed
    11 / 65 (16.92%)
    3 / 65 (4.62%)
         occurrences all number
    15
    3
    Salivary hypersecretion
         subjects affected / exposed
    4 / 65 (6.15%)
    2 / 65 (3.08%)
         occurrences all number
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Please refer to http://www.ncbi.nlm.nih.gov/pubmed/26795874 for exact n for each outcome measure listed.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26795874
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    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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