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    Clinical Trial Results:
    Does Co-careldopa treatment in combination with routine NHS occupational and physical therapy, delivered early after stroke within a stroke service, improve functional recovery including walking and arm function?

    Summary
    EudraCT number
    		 2009-017925-20
    Trial protocol
    		 GB  
    Global end of trial date
    18 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 May 2016
    First version publication date
    08 May 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RR08/8789
    Additional study identifiers
    ISRCTN number
    		 ISRCTN99643613
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Leeds
    Sponsor organisation address
    Hyde Terrace, Leeds, United Kingdom, LS2 9LN
    Public contact
    QA Department, University of Leeds, ctruq@leeds.ac.uk
    Scientific contact
    QA Department, University of Leeds, ctruq@leeds.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
    18 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if combining Co-careldopa with routine occupational and physical therapy during early rehabilitation in people with new stroke admitted to a stroke unit enhances the effect of conventional rehabilitation treatments in terms of physical functioning. The primary objective compared the proportion of patients walking independently at eight weeks post-randomisation. Secondary objectives were to assess the impact on physical functioning, mood and cognition at eight weeks, six months and 12 months post randomisation comparing between treatment groups.
    Protection of trial subjects
    Protection of trial subjects: The trial subjects were recruited as in patients at acute stroke rehabilitation facilities within hospital Trusts. They were monitored closely as part of their hospital inpatient care plan. Where appropriate some services enabled patients to be discharged into the community where they were supported by the early discharge team. Administration of the first two doses of the trial IMP (Co-careldopa/placebo tablets) were taken whilst the patient was in hospital and under the supervision of a clinician. The first two doses were lower doses to reduce the risk of early adverse events. Follow up visits were conducted face to face in the patient's home, at hospital or at a research facility. When face to face contact was not possible, a telephone follow up was conducted. CTRU prepared 6-monthly safety reports during the recruitment and follow up period for review by the Data Monitoring Ethics Committee. Also, DMEC reviewed 3-monthly un-blinded reports which included a summary of SAEs, SARs and SUSARs summarised by treatment groups. Trial data was collected on paper CRFs and were sent to the CTRU where it was entered onto a trial database application - MACRO. The database is stored on a private network protected by a firewall. Access is restricted to trial staff by login and password. The trial data was then filed in locked filling cabinets. CTRU will comply with all aspects of Data Protection Act 1998. All information collected during the trial will be kept strictly confidential. Patient names were collected on the consent form. However, for all other data collection forms that were transferred to or from CTRU the data was coded with a trial number, the patient's initials and date of birth.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2011
    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: 593
    Worldwide total number of subjects
    593
    EEA total number of subjects
    593
    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)
    205
    From 65 to 84 years
    322
    85 years and over
    66

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patient admitted to stroke services after a new or recurrent stroke were approached and considered for enrolment from 5 to 42 days post stroke. Between May 2011 and March 2014, 593 patients (mean age 68.5 years, 364 (61.4%) male) and 165 carers (mean age 59.7 years, 47 (28.5%) male) were recruited.

    Pre-assignment
    Screening details
    		 During the recruitment period, 19509 patients were screened for eligibility. Of those screened, 1547 (7.9%) were deemed eligible, 599 (3.1%) were consented and 593 (3.0%) were randomised.

    Pre-assignment period milestones
    Number of subjects started
    		 19509 [1]
    Number of subjects completed
    		 593

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Ineligible: 17962
    Reason: Number of subjects
    		 Not consented: 948
    Reason: Number of subjects
    		 Not randomised: 6
    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: These are patients screened for eligibility and were not consented into the trial.
    Period 1
    Period 1 title
    Main trial (baseline-8 weeks)
    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
    A placebo tablet was manufactured to match the commercial Co-careldopa (Sinemet®), and the final assembly, packaging and labelling of the co-careldopa / placebo kit was performed by Sharp Clinical Services. The composition of the placebo was approved by the MHRA. Co-careldopa and matching placebo were labelled with a unique random 5 digit kit number, which was assigned to a participant upon randomisation by the central randomisation system at the CTRU.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Co-careldopa
    Arm description
    		 Active arm The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg). Patients were required to take it as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Co-careldopa
    Investigational medicinal product code
    Other name
    Sinemet®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomised to receive either Co-careldopa (Sinemet®) or matched Placebo tablet in addition to routine NHS physical therapy (PT) and occupational therapy (OT). The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg).

    Arm title
    		 Placebo
    Arm description
    		 Control arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were required to take placebo as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).

    Number of subjects in period 1
    		Co-careldopa Placebo
    Started
    308
    285
    Completed
    271
    261
    Not completed
    37
    24
         Moved out of area
    1
    1
         Withdrawn
    24
    11
         Not known
    -
    4
         Other
    1
    -
         Could not contact
    -
    2
         Lost in post
    -
    1
         Too unwell
    1
    2
         Lost at site
    4
    -
         Died
    6
    1
         Refused to complete
    -
    2
    Period 2
    Period 2 title
    6 months
    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
    		 Co-careldopa
    Arm description
    		 Active arm The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg). Patients were required to take it as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Co-careldopa
    Investigational medicinal product code
    Other name
    Sinemet®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomised to receive either Co-careldopa (Sinemet®) or matched Placebo tablet in addition to routine NHS physical therapy (PT) and occupational therapy (OT). The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg).

    Arm title
    		 Placebo
    Arm description
    		 Control arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were required to take placebo as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).

    Number of subjects in period 2
    		Co-careldopa Placebo
    Started
    271
    261
    Completed
    242
    250
    Not completed
    29
    11
         Withdrawn
    6
    4
         Other
    16
    1
         Died
    7
    6
    Period 3
    Period 3 title
    12 months
    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
    		 Co-careldopa
    Arm description
    		 Active arm The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg). Patients were required to take it as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Co-careldopa
    Investigational medicinal product code
    Other name
    Sinemet®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were randomised to receive either Co-careldopa (Sinemet®) or matched Placebo tablet in addition to routine NHS physical therapy (PT) and occupational therapy (OT). The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg).

    Arm title
    		 Placebo
    Arm description
    		 Control arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were required to take placebo as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).

    Number of subjects in period 3
    		Co-careldopa Placebo
    Started
    242
    250
    Completed
    222
    221
    Not completed
    20
    29
         Withdrawn
    12
    7
         Other
    -
    12
         Died
    8
    10

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Co-careldopa
    Reporting group description
    		 Active arm The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg). Patients were required to take it as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).

    Reporting group title
    Placebo
    Reporting group description
    		 Control arm

    Reporting group values
    		 Co-careldopa Placebo Total
    Number of subjects
    		 308 285 593
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 113 92 205
        From 65-84 years
    		 161 161 322
        85 years and over
    		 34 32 66
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.5 ( 13.65 ) 69.6 ( 12.68 ) -
    Gender categorical
    Units: Subjects
        Female
    		 121 108 229
        Male
    		 187 177 364
    Type of stroke
    Units: Subjects
        Infarction
    		 270 238 508
        Primary haemorrhage
    		 38 47 85
    Education
    Units: Subjects
        </= 12 years
    		 134 139 273
        >12 years
    		 168 140 308
        Missing
    		 6 6 12
    Thrombolysis received
    Units: Subjects
        Yes
    		 62 59 121
        No
    		 208 178 386
        Missing
    		 0 1 1
        Not applicable
    		 38 47 85
    Type of scan
    Units: Subjects
        CT brain scan
    		 299 281 580
        brain MRI
    		 9 4 13
        Missing
    		 0 0 0
        Not applicable
    		 0 0 0
    Digital scans
    Units: Subjects
        Yes
    		 263 250 513
        No
    		 35 31 66
        Missing
    		 1 0 1
        Not applicable
    		 9 4 13
    Rivermead Mobility Index (RMI) - researcher completed
    RMI assesses ability to walk independently. It was completed by researchers prior to randomisation to inform the stratification of patients. It has 15 items (score range 0-15), with higher scores indicating increased ability to walk independently.
    Units: Subjects
        Score 0-3
    		 237 223 460
        Score >3 but <7
    		 71 62 133
    General health questionnaire 12 (GHQ12)
    GHQ-12 assesses emotional health. It contains 12 questions (score range 0-36) addressing issues of decision making, loss of sleep and confidence, feelings of strain, enjoyment of daily activities, confidence and happiness. A higher score indicates worse emotional health. The scores can also be categorised into: no sign of psychological distress; evidence of distress (score >15); severe problems and psychological distress (score >20).
    Units: Subjects
        No sign of psychological distress
    		 91 94 185
        Evidence of distress
    		 85 68 153
        Severe problems and psychological distress
    		 117 115 232
        Missing
    		 15 8 23
    Montreal Cognitive Assessment (MoCA)
    MoCA is a researcher-administered instrument that assesses cognitive function. It contains 10 items and the scores range from 0 to 30; a score <26 indicates cognitive impairment.
    Units: Subjects
        Normal
    		 57 63 120
        Cognitive impairment
    		 242 218 460
        Missing
    		 9 4 13
    Rivermead Mobility Index (RMI score) - researcher completed
    RMI assesses ability to walk independently. It was completed by researchers prior to randomisation to inform the stratification of patients at baseline. It has 15 items (score range 0-15), with higher scores indicating increased ability to walk independently
    Units: Score
        arithmetic mean (standard deviation)
    		 2.2 ( 1.8 ) 2.3 ( 1.8 ) -
    Montreal Cognitive Assessment (MoCA)
    MoCA is a researcher-administered instrument that assesses cognitive function. It contains 10 items and the scores range from 0 to 30; a score <26 indicates cognitive impairment.
    Units: Score
        arithmetic mean (standard deviation)
    		 20 ( 6.6 ) 20.5 ( 6 ) -
    Rivermead Mobility Index (RMI score) - patient completed
    RMI assesses ability to walk independently. It was completed by participants at baseline and follow-up to see how they assessed their own mobility. It has 15 items (score range 0-15), with higher scores indicating increased ability to walk independently
    Units: Score
        arithmetic mean (standard deviation)
    		 2.4 ( 2.2 ) 2.5 ( 2.2 ) -
    ABILHAND Scale
    The ABILHAND questionnaire measures upper limb impairment by asking participants to rate 23 items relating to their manual ability on a 3 level scale (impossible, difficult, easy). The raw scores are converted into a linear measure of ability using Rasch analysis. The scores are thus expressed as logits on an interval scale ranging from plus to minus with the centre of the scale set to zero. A higher number logit indicates greater patient’s perceived ability. The baseline score in DARS is based on participant’s own assessment of their manual ability in the month before their stroke.
    Units: Logits
        arithmetic mean (standard deviation)
    		 0.8 ( 3.9 ) 0.3 ( 1.8 ) -
    Nottingham Extended Activities of Daily Living (NEADL) Scale
    Physical and social independence were assessed using NEADL. It assesses aspects of physical and social independence performance across 22 items (score range 0-66) grouped into four categories (mobility, kitchen, domestic and leisure activities); a higher score indicates greater independence. At baseline, participants were asked to consider their independence before their stroke and in the last month at the follow-up.
    Units: Score
        arithmetic mean (standard deviation)
    		 59 ( 11 ) 58.6 ( 12.4 ) -
    Barthel Index
    Activities of daily living, disability and mobility were assessed using the Barthel Index. Ten items (score range 0-20) evaluate the patient’s functional ability; higher scores indicate a greater degree of functional independence.
    Units: Score
        arithmetic mean (standard deviation)
    		 7.7 ( 8.3 ) 7.8 ( 3.7 ) -
    Montreal Cognitive Assessment (MoCA)
    MoCA is a researcher-administered instrument that assesses cognitive function. It contains 10 items and the scores range from 0 to 30; a score <26 indicates cognitive impairment.
    Units: score
        arithmetic mean (standard deviation)
    		 20 ( 6.6 ) 20.5 ( 6 ) -
    General health questionnaire 12 (GHQ12)
    GHQ-12 assesses emotional health. It contains 12 questions (score range 0-36) addressing issues of decision making, loss of sleep and confidence, feelings of strain, enjoyment of daily activities, confidence and happiness. A higher score indicates worse emotional health.
    Units: Score
        arithmetic mean (standard deviation)
    		 19.4 ( 6.7 ) 19.3 ( 7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Co-careldopa
    Reporting group description
    		 Active arm The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg). Patients were required to take it as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).

    Reporting group title
    Placebo
    Reporting group description
    		 Control arm
    Reporting group title
    Co-careldopa
    Reporting group description
    		 Active arm The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg). Patients were required to take it as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).

    Reporting group title
    Placebo
    Reporting group description
    		 Control arm
    Reporting group title
    Co-careldopa
    Reporting group description
    		 Active arm The initial two doses of Co-careldopa were 62.5mg (Levodopa 50mg and carbidopa 12.5mg) and the remaining doses were 125mg (Levodopa 100mg and carbidopa 25mg). Patients were required to take it as a single oral tablet 45-60 minutes before PT or OT sessions (this also includes programmed rehabilitation delivered by rehabilitation assistants). Rehabilitation treatment appropriate for drug administration within DARS was defined as active physical treatment (i.e. most physical and occupational therapy directed at motor skills such as walking, transfers, and dressing but not psychological input sessions or speech and language therapy).

    Reporting group title
    Placebo
    Reporting group description
    		 Control arm

    Primary: Rivermead Mobility Index (RMI) categorical - 8 weeks

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    End point title
    		 Rivermead Mobility Index (RMI) categorical - 8 weeks
    End point description
    The primary endpoint is the ability to walk independently at 8 weeks post-randomisation (defined by a score of 7 or above and who also answer 'yes' to item number 7 on the Rivermead Mobility Index questionnaire. For the primary outcome ITT (intention to treat)analysis, it was assumed that patients who died or were lost to follow-up were unable to walk independently.
    End point type
    Primary
    End point timeframe
    Number of patients walking independently at 8 weeks post randomisation.
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    308
    285
    Units: number of patients
        Able to walk independently at 8 weeks
    125
    127
        Not able to walk independently at 8 weeks
    183
    158
    Statistical analysis title
    		 Stepwise multilevel logistic regression analysis
    Statistical analysis description
    For the primary outcome ITT analysis, it was assumed that patients who died or were lost to follow-up were unable to walk independently. The planned analyses for estimating differences in walking ability between treatment groups (Co-careldopa and placebo) were to use a multi-level logistic regression model adjusted for stratification variables: gender, type of stroke, researcher-completed RMI baseline score (continuous) and centre (the latter fitted as a random effect). Continued, see comment.
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    593
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.212
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.528
         upper limit
    		 1.153
    Notes
    [1] - inspection of the residuals, influence and model fit statistics and the diagnostic plots suggested poor model fit, therefore stepwise regression that additionally included age, baseline scores for Barthel Index, ABILHAND, NEADL, MoCA and GHQ-12, number of days between stroke and randomisation, and total number of sufficient motor therapy sessions was used to build a more robust model.

    Secondary: Modified Rankin Scale - 8 weeks

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    End point title
    		 Modified Rankin Scale - 8 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    at 8 weeks
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    271
    261
    Units: number of patients
        cat 0
    3
    1
        cat 1
    15
    11
        cat 2
    24
    30
        cat 3
    101
    114
        cat 4
    95
    79
        cat 5
    34
    34
        cat 6
    6
    1
    Statistical analysis title
    		 stepwise multilevel ordinal logistic regression
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, age, baseline NEADL score, baseline Barthel index and days between stroke and randomisation
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.404
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.871
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.629
         upper limit
    		 1.206

    Secondary: Montreal Cognitive Assessment (MOCA) - 8 weeks

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    End point title
    		 Montreal Cognitive Assessment (MOCA) - 8 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    at 8 weeks
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    271
    261
    Units: Points
        arithmetic mean (standard deviation)
    22.4 ( 6.26 )
    22.9 ( 5.51 )
    Statistical analysis title
    		 stepwise multilevel regression analysis
    Statistical analysis description
    covariates in the model: treatment arm, gender, stroke type, RMI score at randomisation, baseline MoCA, age, baseline NEADL, baseline ABILHAND and days between stroke and randomisation
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.592
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.747
         upper limit
    		 0.427

    Secondary: ABILHAND Scale - 8 week

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    End point title
    		 ABILHAND Scale - 8 week
    End point description
    End point type
    Secondary
    End point timeframe
    at 8 weeks
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    271
    261
    Units: logits
        arithmetic mean (standard deviation)
    3.2 ( 7.8 )
    2.1 ( 6.5 )
    Statistical analysis title
    		 Stepwise multilevel linear regression analysis
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, baseline ABILHAND, baseline Barthel index, baseline MoCA, baseline NEADL, days between stroke and randomisation
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.585
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.458
         upper limit
    		 0.259

    Secondary: Nottingham Extended Activities of Daily Living (NEADL) Scale - 8 weeks

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    End point title
    		 Nottingham Extended Activities of Daily Living (NEADL) Scale - 8 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    at 8 weeks
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    271
    261
    Units: Points
        arithmetic mean (standard deviation)
    21 ( 17.7 )
    20 ( 15.8 )
    Statistical analysis title
    		 stepwise multilevel linear regression analysis
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, age, baseline NEADL score, baseline MoCA, baseline Barthel index and days between stroke and randomisation
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.382
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.238
         upper limit
    		 3.303

    Secondary: General Health Questionnaire 12 - at 8 weeks

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    End point title
    		 General Health Questionnaire 12 - at 8 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    at 8 weeks
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    271
    261
    Units: points
        arithmetic mean (standard deviation)
    16.9 ( 7.2 )
    16.4 ( 6.6 )
    Statistical analysis title
    		 stepwise multilevel linear regression analysis
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, age, baseline GHQ12 score, baseline NEADL and baseline Barthel index
    Comparison groups
    Placebo v Co-careldopa
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.677
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.238
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.884
         upper limit
    		 1.361

    Secondary: Barthel Index at 8 weeks

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    End point title
    		 Barthel Index at 8 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    8 weeks post randomisation
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    271
    261
    Units: points
        arithmetic mean (standard deviation)
    12.9 ( 5.09 )
    13.2 ( 4.9 )
    Statistical analysis title
    		 stepwise multilevel linear regression
    Statistical analysis description
    Model was adjusted for following covariates: treatment group, gender, stroke type, RMI score at randomisation, age, baseline NEADL score, baseline MoCA, baseline Barthel Index, days between stroke and randomisation.
    Comparison groups
    Placebo v Co-careldopa
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.511
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.218
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.868
         upper limit
    		 0.433

    Secondary: Fatigue Assessment Scale - 8 weeks

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    End point title
    		 Fatigue Assessment Scale - 8 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    at 8 weeks
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    271
    261
    Units: Points
        arithmetic mean (standard deviation)
    25.1 ( 7.6 )
    24.8 ( 7.4 )
    No statistical analyses for this end point

    Secondary: Rivermead Mobility Index (RMI) continuous - 6 months

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    End point title
    		 Rivermead Mobility Index (RMI) continuous - 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    Rivermead Mobility Index at 6 months as continuous
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    242 [2]
    250 [3]
    Units: points
        arithmetic mean (standard deviation)
    8.3 ( 4.6 )
    8.1 ( 4.5 )
    Notes
    [2] - Please, note that number of subjects that started the arm was 308 (baseline).
    [3] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 stepwise multilevel linear regression
    Statistical analysis description
    the same covariates in the model were used as per primary endpoint analysis
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.662
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.144
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.504
         upper limit
    		 0.791

    Secondary: Barthel Index at 6 months

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    End point title
    		 Barthel Index at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    Barthel Index - 6 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    242 [4]
    250 [5]
    Units: points
        arithmetic mean (standard deviation)
    12.9 ( 5.1 )
    13.2 ( 4.9 )
    Notes
    [4] - Please, note that number of subjects that started the arm was 308 (baseline).
    [5] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 Stepwise multilevel linear regression analysis
    Statistical analysis description
    Adjusted for gender, stroke type, RMI score at randomisation, age, baseline Barthel index, baseline MoCA score, baseline NEADL and days between stroke and randomisation
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.378
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.334
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.079
         upper limit
    		 0.41

    Secondary: ABILHAND Scale - 6 months

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    End point title
    		 ABILHAND Scale - 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    ABILHAND Scale - 6 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    242 [6]
    250 [7]
    Units: logits
        arithmetic mean (standard deviation)
    5.1 ( 9.4 )
    3.4 ( 8 )
    Notes
    [6] - Please, note that number of subjects that started the arm was 308 (baseline).
    [7] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 multilevel linear regression analysis
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.478
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.152
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.573
         upper limit
    		 0.269

    Secondary: Nottingham Extended Activities of Daily Living (NEADL) Scale - 6 months

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    End point title
    		 Nottingham Extended Activities of Daily Living (NEADL) Scale - 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    at 6 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    242 [8]
    250 [9]
    Units: points
        arithmetic mean (standard deviation)
    27.2 ( 18.2 )
    27.3 ( 18.1 )
    Notes
    [8] - Please, note that number of subjects that started the arm was 308 (baseline).
    [9] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 multilevel linear regression analysis
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, age, baseline NEADL score, baseline MoCA, baseline Barthel index and days between stroke and randomisation
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.985
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.724
         upper limit
    		 2.777

    Secondary: General Health Questionnaire 12 - at 6 months

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    End point title
    		 General Health Questionnaire 12 - at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    at 6 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    242 [10]
    250 [11]
    Units: points
        arithmetic mean (standard deviation)
    15.1 ( 7 )
    16.3 ( 6.8 )
    Notes
    [10] - Please, note that number of subjects that started the arm was 308 (baseline).
    [11] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 stepwise multilevel linear regression analysis
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, age, baseline GHQ12 score, baseline NEADL and baseline Barthel index
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.332
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.569
         upper limit
    		 -0.096

    Secondary: Modified Rankin Scale - 6 months

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    End point title
    		 Modified Rankin Scale - 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    at 6 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    242 [12]
    250 [13]
    Units: number of patients
        cat 0
    1
    2
        cat 1
    29
    25
        cat 2
    23
    30
        cat 3
    123
    128
        cat 4
    41
    47
        cat 5
    27
    16
        cat 6
    6
    4
    Notes
    [12] - Please, note that number of subjects that started the arm was 308 (baseline).
    [13] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 stepwise multilevel ordinal logistic regression
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, age, baseline NEADL score, baseline Barthel index and days between stroke and randomisation
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.226
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.808
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.571
         upper limit
    		 1.142

    Secondary: Fatigue Assessment Scale - 6 months

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    End point title
    		 Fatigue Assessment Scale - 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    at 6 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    242 [14]
    250 [15]
    Units: Points
        arithmetic mean (standard deviation)
    25.9 ( 8.1 )
    25.4 ( 7.6 )
    Notes
    [14] - Please, note that number of subjects that started the arm was 308 (baseline).
    [15] - Please, note that number of subjects that started the arm was 285(baseline).
    No statistical analyses for this end point

    Secondary: Montreal Cognitive Assessment (MOCA) - 6 months

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    End point title
    		 Montreal Cognitive Assessment (MOCA) - 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    Montreal Cognitive Assessment (MOCA) - 6 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    242 [16]
    250 [17]
    Units: Points
        arithmetic mean (standard deviation)
    23.1 ( 6.18 )
    23.6 ( 5.45 )
    Notes
    [16] - Please, note that number of subjects that started the arm was 308 (baseline).
    [17] - Please, note that number of subjects that started the arm was 285(baseline).
    Statistical analysis title
    		 stepwise multilevel regression analysis
    Statistical analysis description
    Model was adjusted for following covariates: treatment group, gender, stroke type, RMI score at randomisation, baseline MoCA score, age, baseline NEADL score, baseline ABILHAND, days between stroke and randomisation.
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    492
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.445
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.269
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.959
         upper limit
    		 0.419

    Secondary: Rivermead Mobility Index (RMI) continuous - 12 months

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    End point title
    		 Rivermead Mobility Index (RMI) continuous - 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Rivermead Mobility Index continuous - 12 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    222 [18]
    221 [19]
    Units: points
        arithmetic mean (standard deviation)
    8.7 ( 4.7 )
    8.5 ( 4.6 )
    Notes
    [18] - Please, note that number of subjects that started the arm was 308 (baseline).
    [19] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 multilevel linear regression
    Statistical analysis description
    model was adjusted for the same covariates as per primary endpoint analysis
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.637
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 0.881

    Secondary: Barthel Index at 12 months

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    End point title
    		 Barthel Index at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Barthel Index at 12 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    222 [20]
    221 [21]
    Units: Points
        arithmetic mean (standard deviation)
    14.4 ( 5.4 )
    14.6 ( 5.1 )
    Notes
    [20] - Please, note that number of subjects that started the arm was 308 (baseline).
    [21] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 Stepwise multilevel linear regression analysis
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, age, baseline Barthel index, baseline MoCA score, baseline NEADL score and days between stroke and randomisation
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.591
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.224
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.042
         upper limit
    		 0.594

    Secondary: ABILHAND Scale - 12 months

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    End point title
    		 ABILHAND Scale - 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    ABILHAND Scale - 12 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    222 [22]
    221 [23]
    Units: Logits
        arithmetic mean (standard deviation)
    6.5 ( 10.3 )
    5.3 ( 9.6 )
    Notes
    [22] - Please, note that number of subjects that started the arm was 308 (baseline).
    [23] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 multilevel linear regression analysis
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.479
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.157
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.592
         upper limit
    		 0.278

    Secondary: Nottingham Extended Activities of Daily Living (NEADL) Scale - 12 months

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    End point title
    		 Nottingham Extended Activities of Daily Living (NEADL) Scale - 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    222 [24]
    221 [25]
    Units: Points
        arithmetic mean (standard deviation)
    30.4 ( 19.4 )
    29.8 ( 18.9 )
    Notes
    [24] - Please, note that number of subjects that started the arm was 308 (baseline).
    [25] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 multilevel linear regression analysis
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, age, baseline NEADL score, baseline MoCA, baseline Barthel index and days between stroke and randomisation
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.434
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.036
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.564
         upper limit
    		 3.636

    Secondary: General Health Questionnaire 12 - at 12 months

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    End point title
    		 General Health Questionnaire 12 - at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    at 12 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    222 [26]
    221 [27]
    Units: Points
        arithmetic mean (standard deviation)
    14 ( 6.77 )
    14.4 ( 7.16 )
    Notes
    [26] - Please, note that number of subjects that started the arm was 308 (baseline).
    [27] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 stepwise multilevel linear regression analysis
    Statistical analysis description
    model was adjusted for gender, stroke type, RMI score at randomisation, age, baseline GHQ12 score, baseline NEADL and baseline Barthel index
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.241
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.769
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.006
         upper limit
    		 0.518

    Secondary: Fatigue Assessment Scale - 12 months

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    End point title
    		 Fatigue Assessment Scale - 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    at 12 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    222 [28]
    221 [29]
    Units: Points
        arithmetic mean (standard deviation)
    24.9 ( 8.3 )
    24.5 ( 8.2 )
    Notes
    [28] - Please, note that number of subjects that started the arm was 308 (baseline).
    [29] - Please, note that number of subjects that started the arm was 285 (baseline).
    No statistical analyses for this end point

    Secondary: Montreal Cognitive Assessment (MOCA) - 12 months

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    End point title
    		 Montreal Cognitive Assessment (MOCA) - 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Montreal Cognitive Assessment (MOCA) - 12 months
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    222 [30]
    221 [31]
    Units: Point
        arithmetic mean (standard deviation)
    23.1 ( 5.93 )
    23.5 ( 5.64 )
    Notes
    [30] - Please, note that number of subjects that started the arm was 308 (baseline).
    [31] - Please, note that number of subjects that started the arm was 285 (baseline).
    Statistical analysis title
    		 stepwise multilevel regression analysis
    Statistical analysis description
    Model was adjusted for following covariates: treatment group, gender, stroke type, RMI score at randomisation, baseline MoCA score, age, baseline NEADL score, baseline ABILHAND, days between stroke and randomisation.
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.613
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.194
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.949
         upper limit
    		 0.561

    Secondary: Rivermead Mobility Index (RMI) continuous - 8 weeks

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    End point title
    		 Rivermead Mobility Index (RMI) continuous - 8 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    at 8 weeks
    End point values
    		 Co-careldopa Placebo
    Number of subjects analysed
    271
    261
    Units: points
        arithmetic mean (standard deviation)
    6.8 ( 4.2 )
    7 ( 4.2 )
    Statistical analysis title
    		 stepwise multilevel linear regression
    Statistical analysis description
    model was adjusted for the same covariates in model for primary endpoint analysis
    Comparison groups
    Co-careldopa v Placebo
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.198
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.354
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.894
         upper limit
    		 0.186

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Randomisation until 30 days after the last dose of Co-careldopa/placebo.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Co-careldopa
    Reporting group description
    		 Active arm

    Reporting group title
    Placebo
    Reporting group description
    		 Control arm

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There are no non-serious adverse events recorded for these results. Leeds Institute of Clinical Trials Research is an academic trials unit where full MedDRA coding of non-serious adverse events is not the standard. It has therefore not been possible for adverse event data to be accurately entered into the full data view within EudraCT as all mandatory categories can not be completed. A summary of non-serious adverse events is available if required.
    Serious adverse events
    		 Co-careldopa Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    57 / 308 (18.51%)
    50 / 285 (17.54%)
         number of deaths (all causes)
    22
    17
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
    Additional description: Lung cancer with multiple PEs (Pulmonary Embolisms)
         subjects affected / exposed
    1 / 308 (0.32%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer metastatic
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioma - Brain
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PV bleed
         subjects affected / exposed
    0 / 308 (0.00%)
    2 / 285 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 308 (0.32%)
    2 / 285 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    10 / 308 (3.25%)
    5 / 285 (1.75%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faint, clammy unwell
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
    Additional description: Nausea & dizziness
         subjects affected / exposed
    2 / 308 (0.65%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unresponsive event
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid endarterectomy
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Epistaxis
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroids
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chest infection
         subjects affected / exposed
    5 / 308 (1.62%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 308 (0.97%)
    8 / 285 (2.81%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
    Additional description: Exacerbation of COPD
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shortness of breath
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart rate decreased
    Additional description: acute or chronic
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Self harm
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 308 (0.65%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hallucination
    Additional description: Hallucinations (drug induced)
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (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 fibrillation
    Additional description: Fast AF, Heart failure & chest infection
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
    Additional description: Angina
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    2 / 308 (0.65%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
    Additional description: Paroxymal atrial flutter & hypotension
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
    Additional description: Pain - chest/thorax
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    5 / 308 (1.62%)
    5 / 285 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
    Additional description: Right sided Cerebral haemorrhage Left occipital haemorrhage
         subjects affected / exposed
    1 / 308 (0.32%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
    Additional description: Post Stroke Epilepsy, epilepsy
         subjects affected / exposed
    2 / 308 (0.65%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 308 (0.32%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Numbness
    Additional description: Pain and left hand Numbness
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
    Additional description: ?Transient ischaemic attack ? Postural Hypertension
         subjects affected / exposed
    0 / 308 (0.00%)
    2 / 285 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Falls
         subjects affected / exposed
    1 / 308 (0.32%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasovagal attack
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Severe anaemia and low albumin and chest infection.
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Diarrhoea and C. Difficile
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    Additional description: Nausea and vomiting
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
    Additional description: Intra-abdominal fluid (free). Pleural effusion. Positive blood cultures.
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Cholecystitis
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
    Additional description: Melaena/PR bleed and dehydration
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver scan abnormal
    Additional description: Liver neoplasm - suspected.
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallstone ileus
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Kidney failure
    Additional description: Acute Kidney failure secondary to lower respiratory tract infection/Pneumonia with sepsis
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
    Additional description: Fracture left neck of femur Radial head fracture of right arm, displaced intracapsular fracture of neck of femur, fracture of rich acetabulum.
         subjects affected / exposed
    2 / 308 (0.65%)
    3 / 285 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Staphylococcus test positive
    Additional description: Rigors - increased, stoma output, diagnosed as stpah aureus infection
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 308 (0.97%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 308 (0.65%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
    Additional description: Psoas abscess
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic clonic event
    Additional description: Tonic clonic event
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
    Additional description: Community acquired Pneumonia /Gastroenteritis
         subjects affected / exposed
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         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 / 308 (0.32%)
    2 / 285 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Headache
    Additional description: Headache/New onset diabetes
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
    Additional description: Dehydration & mild renal impairment
         subjects affected / exposed
    1 / 308 (0.32%)
    0 / 285 (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
    0 / 308 (0.00%)
    1 / 285 (0.35%)
         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
    		 Co-careldopa Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 308 (0.00%)
    0 / 285 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jun 2010
    Protocol version 3.0 dated 9 July 2010 Eligibility criteria updated with the following: •inclusion criteria amended to include patients with 'new' strokes. •Cannot walk 10 metres or more indoors independently •Professionally scored Rivermead Mobility Index score of <7. •Expected to be able to comply with treatment schedule post randomisation (e.g. swallow whole tablets) •Expected to be in hospital for at least their first two doses trial medication •Diagnosis of Parkinson’s disease, dementia, severe medical or surgical illness, severe psychosis or glaucoma •Symptomatic orthostatic hypotension •Patients currently participating in other interventional drug or treatment therapy trials Defined end of trial as the date of the last patient’s last 8 week follow-up visit for the purpose of safety reporting. Primary endpoint measure clarified to '...as measured by a score of 7 or higher and who also answer ‘yes’ to item number 7 on the Rivermead Mobility Index'.
    25 Jul 2011
    Protocol v4.0 - amended eligibility criteria to include new clinically 'first' diagnosed ischaemic or haemorrhagic stroke in the 2 weeks prior to randomisation. Removed dementia from exclusion criteria and aligned criteria to match Co-careldopa SPC.
    20 Dec 2011
    Protocol v5.0 - trial design changed to the following: - to enable participants to receive either Co-careldopa/placebo within 7-28 days post stroke. -to enable co-enrolment for participants taking part in other non-CTIMP/observational trials Consent forms amended to enable an annonymised copy of the CT/MRI scan to be transferred to CTRU. -Sufficient motor therapy defined as at least 20 mins of motor therapy in at least 80% of therapy sessions. Patients complying with medication are those receiving treatment 45-60 mins before therapy begins in at least 80% of therapy sessions.
    30 Mar 2012
    Protocol v6.0 - eligibility criteria amended to: -new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke within 5 to 42 days prior to randomisation -able to access continuity of rehabilitation treatment following discharge

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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