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    Clinical Trial Results:
    Methylphenidate versus placebo for fatigue in advanced cancer (MePFAC)

    Summary
    EudraCT number
    		 2017-001950-33
    Trial protocol
    		 GB  
    Global end of trial date
    03 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2024
    First version publication date
    16 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15/0592
    Additional study identifiers
    ISRCTN number
    		 ISRCTN79478762
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Priment CTU, Marie Curie Palliative Care Research Department, UCL, priment@ucl.ac.uk
    Scientific contact
    Paddy Stone, Marie Curie Palliative Care Research Department, UCL, p.stone@ucl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jul 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    What is the clinical effectiveness of methylphenidate versus placebo for cancer-related fatigue in patients receiving palliative care?
    Protection of trial subjects
    During the trial participants were treated in accordance with routine clinical care and under supervision of a consultatant in palliative medicine (Principal Investigators at each site). Participants were contacted on a weekly basis to elicit adverse effects. Non-serious adverse events were recorded weekly and assessed for severity. Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions (SUSARS) were additionally assessed for causality and expectedness and were reported to the sponsor within 24 hours.
    Background therapy
    		 Participants received usual care in both study arms in addition to the trial intervention
    Evidence for comparator
    		 Methylphenidate is a psychostimulant drug that is widely used as part of the management of people with Attention Deficit Hyperactivity Disorder. It has also been evaluated as a potential treatment for cancer-related fatigue. Some trials and meta-analyses have suggested that this medication may also be effective for relief of cancer related fatigue, but the evidence is mixed with many trials showing no benefit. In the context of ongoing uncertainty about its role, this research was conducted in response to a commissioned call by the NIHR, and placebo was considered to be a suitable comparator.
    Actual start date of recruitment
    29 Jun 2018
    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: 159
    Worldwide total number of subjects
    159
    EEA total number of subjects
    0
    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)
    81
    From 65 to 84 years
    76
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Across 17 active sites (hopsices, hosptial and community palliative care teams), 162 participants were randomised (73 men; mean 65.8 [SD 10.3] years). The first patient was enrolled on 29th June 2018 and the last patient randomised on 27th April 2023. The last visit for the last patient was 3rd July 2023, which is when the trial ended.

    Pre-assignment
    Screening details
    		 297 patients were screened 54 did not meet the inclusion criteria 78 met an exclusion criterion 3 died before consent/randomisation

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    Identical appearance between methyphenidate and placebo

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 Methylphenidate arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylphenidate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Initially participants were prescribed 1 tablet twice daily (=methylphenidate 10mgs/day) or matching placebo. Participants were contacted every week and the dose of medication was adjusted (either up or down) over the course of the first six weeks of the study (dose titration phase), up to a maximum of 12 tablets/day (=60mgs/day). Thereafter, for the next two weeks (dose maintenance phase), the dose of medication was not increased any further (although it could be reduced in response to adverse effects). During the next week (dose tapering phase) the dose was reduced and then the medication was stopped completely for the last week of the trial.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablets individually dose-titrated in same manner as in active 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
    Initially participants were prescribed 1 tablet twice daily. Participants were contacted every week and the dose of medication was adjusted (either up or down) over the course of the first six weeks of the study (dose titration phase), up to a maximum of 12 tablets/day. Thereafter, for the next two weeks (dose maintenance phase), the dose of medication was not increased any further (although it could be reduced in response to adverse effects). During the next week (dose tapering phase) the dose was reduced and then the medication was stopped completely for the last week of the trial.

    Number of subjects in period 1
    		Intervention Placebo
    Started
    82
    77
    Completed
    82
    77
    Period 2
    Period 2 title
    Week 6
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    Identical appearance to methylphenidate and placebo

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 Methylphenidate arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylphenidate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Initially participants were prescribed 1 tablet twice daily (=methylphenidate 10mgs/day) or matching placebo. Participants were contacted every week and the dose of medication was adjusted (either up or down) over the course of the first six weeks of the study (dose titration phase), up to a maximum of 12 tablets/day (=60mgs/day). Thereafter, for the next two weeks (dose maintenance phase), the dose of medication was not increased any further (although it could be reduced in response to adverse effects). During the next week (dose tapering phase) the dose was reduced and then the medication was stopped completely for the last week of the trial.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablets individually dose-titrated in same manner as in active 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
    Initially participants were prescribed 1 tablet twice daily. Participants were contacted every week and the dose of medication was adjusted (either up or down) over the course of the first six weeks of the study (dose titration phase), up to a maximum of 12 tablets/day. Thereafter, for the next two weeks (dose maintenance phase), the dose of medication was not increased any further (although it could be reduced in response to adverse effects). During the next week (dose tapering phase) the dose was reduced and then the medication was stopped completely for the last week of the trial.

    Number of subjects in period 2
    		Intervention Placebo
    Started
    82
    77
    Completed
    72
    67
    Not completed
    10
    10
         Adverse event, serious fatal
    2
    -
         Lost to follow-up
    8
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Methylphenidate arm

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets individually dose-titrated in same manner as in active arm

    Reporting group values
    		 Intervention Placebo Total
    Number of subjects
    		 82 77 159
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 43 38 81
        From 65-84 years
    		 37 39 76
        85 years and over
    		 2 0 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.7 ( 11.9 ) 62.6 ( 11.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 44 42 86
        Male
    		 38 35 73
    FACIT-Fatigue score
    Units: FACIT-F fatigue score
        arithmetic mean (standard deviation)
    		 20 ( 9 ) 22 ( 10 ) -
    EORTC QLQc15 - Pain score
    Units: EORTC QLQc15-Pain score
        arithmetic mean (standard deviation)
    		 52 ( 19 ) 53 ( 20 ) -
    EORTC QLQc15 - Physical functioning
    Units: EORTC QLQc15-Physical functioning score
        arithmetic mean (standard deviation)
    		 50 ( 18 ) 50 ( 17 ) -
    EORTC QLQc15 - Emotional Functioning
    Note that only 81/82 in methylphenidate group provided a baseline score
    Units: EORTC QLQc15-Emotional Functioning score
        arithmetic mean (standard deviation)
    		 44 ( 17 ) 42 ( 17 ) -
    EORTC QLQc15 - Quality of life
    Units: EORTC-QLQc15 Quality of life score
        arithmetic mean (standard deviation)
    		 30 ( 13 ) 31 ( 14 ) -
    EORTC QLQc15 - Nausea
    Units: EORTC QLQc15 - Nausea
        arithmetic mean (standard deviation)
    		 44 ( 22 ) 39 ( 22 ) -
    EORTC QLQc15 - Anorexia
    Units: EORTC QLQc15 - anorexia
        arithmetic mean (standard deviation)
    		 52 ( 25 ) 52 ( 26 ) -
    EORTC QLQc15 - Dyspnoea
    Units: EORTC QLQc15 - Dyspnoea
        arithmetic mean (standard deviation)
    		 52 ( 21 ) 53 ( 24 ) -
    EORTC QLQc15 - Constipation
    Units: EORTC QLQc15 - Constipation
        arithmetic mean (standard deviation)
    		 47 ( 24 ) 41 ( 21 ) -
    EORTC QLQc15 - Insomnia
    Units: EORTC QLQc15 - insomnia
        arithmetic mean (standard deviation)
    		 56 ( 25 ) 51 ( 27 ) -
    Utility score
    Units: EQ-5D-5L
        arithmetic mean (standard deviation)
    		 0.62 ( 0.21 ) 0.65 ( 0.18 ) -
    Depression score
    Hospital Anxiety and Depression Scale (HADS) - Depression (D) subscale score Note that baseline HADS-D score was only available for n=81 in the intervention group
    Units: HADS-D
        median (inter-quartile range (Q1-Q3))
    		 7 (5 to 11) 6 (4 to 9) -
    Anxiety score
    Hospital Anxiety and Depression Scale (HADS) - Anxiety (A) subscale scores
    Units: HADS-A
        median (inter-quartile range (Q1-Q3))
    		 6 (3 to 9) 4 (2 to 9) -
    EORTC QLQc15 - Fatigue
    This is a fatigue subscale of the EORTC QLQc15 and was used only as a secondary fatigue outcome measure in this study
    Units: EORTC QLQc15 - Fatigue
        arithmetic mean (standard deviation)
    		 74 ( 15 ) 72 ( 18 ) -

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Methylphenidate arm

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets individually dose-titrated in same manner as in active arm
    Reporting group title
    Intervention
    Reporting group description
    		 Methylphenidate arm

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets individually dose-titrated in same manner as in active arm

    Primary: FACIT-Fatigue at 6 +/- 2 weeks

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    End point title
    		 FACIT-Fatigue at 6 +/- 2 weeks
    End point description
    FACIT-F Fatigue score
    End point type
    Primary
    End point timeframe
    6 weeks - but if fatigue data were missing at 6 weeks then data from week 7, 8, 5 or 4 (in that order) could be used.
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [1]
    77 [2]
    75 [3]
    72 [4]
    Units: FACIT-F fatigue score
        arithmetic mean (standard deviation)
    20 ( 9 )
    22 ( 10 )
    32 ( 11 )
    31 ( 12 )
    Notes
    [1] - Baseline fatigue
    [2] - Baseline fatigue
    [3] - Week 6 +/- 2 weeks fatigue
    [4] - Week 6 +/- 2 weeks fatigue
    Statistical analysis title
    		 Baseline to week 6 +/- 2
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    1.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.95
         upper limit
    		 4.9

    Secondary: EORTC QLQ-C15-PAL Pain scores at 6 weeks

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    End point title
    		 EORTC QLQ-C15-PAL Pain scores at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 Weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [5]
    77 [6]
    72 [7]
    66 [8]
    Units: EORTC QLQc15-PAL Pain scores
        arithmetic mean (standard deviation)
    52 ( 19 )
    53 ( 20 )
    46 ( 18 )
    45 ( 18 )
    Notes
    [5] - Baseline pain
    [6] - Baseline pain
    [7] - Week 6 pain
    [8] - Weeks 6 pain
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    1.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.66
         upper limit
    		 6.93

    Secondary: EORTC QLQ-C15-PAL Physical functioning scores at 6 weeks

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    End point title
    		 EORTC QLQ-C15-PAL Physical functioning scores at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [9]
    77 [10]
    72 [11]
    66 [12]
    Units: EORTC QLQc15 Physical functioning score
        arithmetic mean (standard deviation)
    50 ( 18 )
    50 ( 17 )
    41 ( 16 )
    44 ( 17 )
    Notes
    [9] - Baseline physical functioning
    [10] - Baseline physical functioning
    [11] - Week 6 physical functioning
    [12] - Week 6 physical functioning
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    -2.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.28
         upper limit
    		 1.94

    Secondary: EORTC QLQ-C15-PAL Emotional functioning scores at 6 weeks

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    End point title
    		 EORTC QLQ-C15-PAL Emotional functioning scores at 6 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    81 [13]
    77 [14]
    72 [15]
    66 [16]
    Units: EORTC QLQ-C15-PAL Emotional functioning
        arithmetic mean (standard deviation)
    44 ( 17 )
    42 ( 17 )
    38 ( 17 )
    35 ( 17 )
    Notes
    [13] - Baseline Emotional functioning
    [14] - Baseline Emotional functioning
    [15] - Week 6 Emotional functioning
    [16] - Week 6 Emotional functioning
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    1.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.18
         upper limit
    		 6.59

    Secondary: EORTC QLQc15 - Quality of Life

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    End point title
    		 EORTC QLQc15 - Quality of Life
    End point description
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [17]
    77 [18]
    72 [19]
    66 [20]
    Units: EORTC QLQc15 Quality of life score
        arithmetic mean (standard deviation)
    30 ( 13 )
    31 ( 14 )
    26 ( 11 )
    28 ( 14 )
    Notes
    [17] - Baseline QoL
    [18] - Baseline QoL
    [19] - Week 6 QoL
    [20] - Week 6 QoL
    Statistical analysis title
    		 Baseline to week 6
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    -2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.91
         upper limit
    		 1.74

    Secondary: EORTC QLQc15 - Fatigue

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    End point title
    		 EORTC QLQc15 - Fatigue
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [21]
    77 [22]
    72 [23]
    66 [24]
    Units: EORTC QLQc15 - Fatigue scores
        arithmetic mean (standard deviation)
    74 ( 15 )
    72 ( 18 )
    54 ( 17 )
    55 ( 19 )
    Notes
    [21] - Baseline intervention
    [22] - Baseline placebo
    [23] - Week 6 intervention
    [24] - Week 6 placebo
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.79
         upper limit
    		 2.8

    Secondary: EORTC QLQc15 - Nausea

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    End point title
    		 EORTC QLQc15 - Nausea
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [25]
    77 [26]
    72 [27]
    66 [28]
    Units: EORTC QLQc15 - Nausea score
        arithmetic mean (standard deviation)
    44 ( 22 )
    39 ( 22 )
    41 ( 19 )
    35 ( 19 )
    Notes
    [25] - Baseline
    [26] - Baseline
    [27] - Week 6
    [28] - Week 6
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.07
         upper limit
    		 10.66

    Secondary: EORTC QLQc15 - Anorexia

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    End point title
    		 EORTC QLQc15 - Anorexia
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to six weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [29]
    77 [30]
    72 [31]
    66 [32]
    Units: EORTC QLQc15 - Anorexia scores
        arithmetic mean (standard deviation)
    52 ( 25 )
    52 ( 77 )
    47 ( 26 )
    41 ( 23 )
    Notes
    [29] - Baseline
    [30] - Baseline
    [31] - Week 6
    [32] - Week 6
    Statistical analysis title
    		 Baseline to week 6
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    6.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 14

    Secondary: EORTC QLQc15 - Dyspnoea

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    End point title
    		 EORTC QLQc15 - Dyspnoea
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to six weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [33]
    77 [34]
    72 [35]
    66 [36]
    Units: EORTC QLQc15 - Dyspnoea scores
        arithmetic mean (standard deviation)
    52 ( 21 )
    53 ( 24 )
    45 ( 23 )
    51 ( 26 )
    Notes
    [33] - Baseline
    [34] - Baseline
    [35] - Week 6
    [36] - Week 6
    Statistical analysis title
    		 Baseline to week 6
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    -6.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.78
         upper limit
    		 0.44

    Secondary: EORTC QLQc15 - Constipation

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    End point title
    		 EORTC QLQc15 - Constipation
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to six weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    81 [37]
    77 [38]
    72 [39]
    66 [40]
    Units: EORTC QLQc15 - Constipation
        arithmetic mean (standard deviation)
    47 ( 24 )
    41 ( 21 )
    43 ( 22 )
    36 ( 19 )
    Notes
    [37] - Baseline
    [38] - Baseline
    [39] - Week 6
    [40] - Week 6
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Coefficient
    Point estimate
    4.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.02
         upper limit
    		 11.29

    Secondary: EORTC QLQc15 - Insomnia

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    End point title
    		 EORTC QLQc15 - Insomnia
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to six weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [41]
    77 [42]
    72 [43]
    66 [44]
    Units: EORTC QLQc15 - Insomnia scores
        arithmetic mean (standard deviation)
    56 ( 25 )
    51 ( 27 )
    44 ( 24 )
    47 ( 25 )
    Notes
    [41] - Baseline
    [42] - Baseline
    [43] - Week 6
    [44] - Week 6
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    -5.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.96
         upper limit
    		 1.98

    Secondary: FACIT-F Fatigue at 6 weeks only

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    End point title
    		 FACIT-F Fatigue at 6 weeks only
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to six weeks only Note that this is different to the primary outcome for the study, which was FACIT-F scores at 6+/-2 weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [45]
    77 [46]
    72 [47]
    67 [48]
    Units: FACIT-F Fatigue scores
        arithmetic mean (standard deviation)
    20 ( 9 )
    22 ( 10 )
    33 ( 11 )
    31 ( 12 )
    Notes
    [45] - Baseline
    [46] - Baseline
    [47] - Week 6
    [48] - Week 6
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    3.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 6.05

    Secondary: Utility Score

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    End point title
    		 Utility Score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [49]
    77 [50]
    72 [51]
    66 [52]
    Units: EQ-5D-5L scores
        arithmetic mean (standard deviation)
    0.62 ( 0.21 )
    0.65 ( 0.18 )
    0.71 ( 0.23 )
    0.70 ( 0.22 )
    Notes
    [49] - Baseline
    [50] - Baseline
    [51] - Week 6
    [52] - Week 6
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    0.028
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.031
         upper limit
    		 0.086

    Secondary: Anxiety Score

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    End point title
    		 Anxiety Score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to six weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    82 [53]
    77 [54]
    72 [55]
    66 [56]
    Units: HADS-A score
        median (inter-quartile range (Q1-Q3))
    6 (3 to 9)
    4 (2 to 9)
    4 (2 to 6)
    4 (2 to 6)
    Notes
    [53] - Baseline
    [54] - Baseline
    [55] - Week 6
    [56] - Week 6
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    -0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.62

    Secondary: Depression score

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    End point title
    		 Depression score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to six weeks
    End point values
    		 Intervention Placebo Intervention Placebo
    Number of subjects analysed
    81 [57]
    77 [58]
    72 [59]
    66 [60]
    Units: HADS-D score
        median (inter-quartile range (Q1-Q3))
    7 (5 to 11)
    6 (4 to 9)
    4 (2 to 8)
    5 (3 to 9)
    Notes
    [57] - Baseline
    [58] - Baseline
    [59] - Week 6
    [60] - Week 6
    Statistical analysis title
    		 Baseline to 6 weeks
    Statistical analysis description
    Analysis of the outcome used a mixed effects linear model. Each participant provided two values, one for baseline and one for follow-up, with random intercepts for participant. Fixed effects were time point (baseline or follow up), randomized treatment, and the stratification factors (except site and fatigue severity).
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Coefficient
    Point estimate
    -1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.41
         upper limit
    		 -0.3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported across the 10-weeks of the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Study specific
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Methylphenidate arm
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Methylphenidate arm Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 82 (23.17%)
    16 / 77 (20.78%)
         number of deaths (all causes)
    6
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Progression of underlying cancer
         subjects affected / exposed
    5 / 82 (6.10%)
    4 / 77 (5.19%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 5
    0 / 1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 82 (3.66%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Worsening of heart failure
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Facial droop
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cord compression
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient loss of consciousness
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 77 (1.30%)
         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
    Bleeding or clotting
         subjects affected / exposed
    0 / 82 (0.00%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    2 / 82 (2.44%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis / diarrhoea
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 82 (1.22%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Impaired liver function
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney injury, haematuria, kidney pain
         subjects affected / exposed
    1 / 82 (1.22%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    5 / 82 (6.10%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Methylphenidate arm Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 82 (100.00%)
    77 / 77 (100.00%)
    Cardiac disorders
    Palpitations
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    26 / 82 (31.71%)
    25 / 77 (32.47%)
         occurrences all number
    57
    65
    Feeling of abnormal heart rhythms
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    11 / 82 (13.41%)
    12 / 77 (15.58%)
         occurrences all number
    15
    31
    Nervous system disorders
    Headache
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    46 / 82 (56.10%)
    46 / 77 (59.74%)
         occurrences all number
    203
    171
    Feeling dizzy
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    52 / 82 (63.41%)
    42 / 77 (54.55%)
         occurrences all number
    219
    203
    Feeling drowsy
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    62 / 82 (75.61%)
    61 / 77 (79.22%)
         occurrences all number
    307
    321
    General disorders and administration site conditions
    Insomnia
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    60 / 82 (73.17%)
    58 / 77 (75.32%)
         occurrences all number
    269
    293
    Feeling abnormally active
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    8 / 82 (9.76%)
    10 / 77 (12.99%)
         occurrences all number
    13
    17
    Fever
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    19 / 82 (23.17%)
    14 / 77 (18.18%)
         occurrences all number
    33
    20
    Flu-like symptoms
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    41 / 82 (50.00%)
    34 / 77 (44.16%)
         occurrences all number
    126
    70
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    47 / 82 (57.32%)
    45 / 77 (58.44%)
         occurrences all number
    257
    217
    Diarrhoea
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    40 / 82 (48.78%)
    41 / 77 (53.25%)
         occurrences all number
    113
    148
    Nausea
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    57 / 82 (69.51%)
    43 / 77 (55.84%)
         occurrences all number
    228
    167
    Vomiting
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    31 / 82 (37.80%)
    21 / 77 (27.27%)
         occurrences all number
    74
    56
    Dry mouth
    Additional description: Self-reported as "severe" at any time over the 10-week period
         subjects affected / exposed
    60 / 82 (73.17%)
    53 / 77 (68.83%)
         occurrences all number
    359
    300
    Other GI symptoms
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    43 / 82 (52.44%)
    42 / 77 (54.55%)
         occurrences all number
    101
    92
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    49 / 82 (59.76%)
    41 / 77 (53.25%)
         occurrences all number
    189
    145
    Sore throat
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    35 / 82 (42.68%)
    33 / 77 (42.86%)
         occurrences all number
    82
    76
    Other respiratory AEs
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    44 / 82 (53.66%)
    37 / 77 (48.05%)
         occurrences all number
    117
    121
    Skin and subcutaneous tissue disorders
    Hair loss
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    25 / 82 (30.49%)
    18 / 77 (23.38%)
         occurrences all number
    76
    67
    Itch
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    40 / 82 (48.78%)
    32 / 77 (41.56%)
         occurrences all number
    126
    108
    Skin rashes
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    27 / 82 (32.93%)
    22 / 77 (28.57%)
         occurrences all number
    65
    46
    Other skin or hair symptoms
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    11 / 82 (13.41%)
    16 / 77 (20.78%)
         occurrences all number
    16
    29
    Psychiatric disorders
    Anxiety
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    50 / 82 (60.98%)
    42 / 77 (54.55%)
         occurrences all number
    178
    175
    Depression
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    42 / 82 (51.22%)
    29 / 77 (37.66%)
         occurrences all number
    149
    102
    Irritability
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    51 / 82 (62.20%)
    50 / 77 (64.94%)
         occurrences all number
    211
    186
    Aggression
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    11 / 82 (13.41%)
    16 / 77 (20.78%)
         occurrences all number
    28
    32
    Mood swings
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    10 / 82 (12.20%)
    10 / 77 (12.99%)
         occurrences all number
    93
    87
    Abnormal beviour
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    6 / 82 (7.32%)
    5 / 77 (6.49%)
         occurrences all number
    6
    5
    Other mood or mental state symptoms
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    10 / 82 (12.20%)
    10 / 77 (12.99%)
         occurrences all number
    12
    14
    Musculoskeletal and connective tissue disorders
    Abnormal muscle movements (twitches)
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    36 / 82 (43.90%)
    37 / 77 (48.05%)
         occurrences all number
    138
    131
    Joint pain
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    53 / 82 (64.63%)
    52 / 77 (67.53%)
         occurrences all number
    251
    243
    Metabolism and nutrition disorders
    Anorexia
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    63 / 82 (76.83%)
    55 / 77 (71.43%)
         occurrences all number
    279
    231
    Weight loss
    Additional description: Self-reported as "mild, moderate or severe" at any time over the 10-week period
         subjects affected / exposed
    38 / 82 (46.34%)
    43 / 77 (55.84%)
         occurrences all number
    125
    99

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Oct 2018
    CHANGES TO INCLUSION CRITERIA Prognosis of 2-12 months removed as an inclusion criterion Requirement to be under care of Specialist Palliative Care team changed to requirement to be receiving generalist or specialist palliative care CHANGES TO EXCLUSION CRITERIA Cardiovascular exclusions modified so that it was only uncontrolled heart failure, uncontrolled angina or myocardial infarction in the last one year that were regarded as exclusions Cerebrovascular exclusions modified so that it was only stroke in the last one year that was regarded as an exclusion Alcohol or drug dependency exclusion criterion was modified so that it was only dependency within last one year that was regarded as an exclusion Estimated Glomerular Filtration Rate (eGFR) exclusion was reduced from <60mls/hr to <45mls/hr Alkaline Phosphatase (ALP) levels no longer regarded as an exclusion Exclusion of inpatient hospital or hospice patients was removed
    20 May 2019
    CHANGES TO EXCLUSION CRITERIA Exclusion of patients who are currently in another Clinical Trial of an Investigational Medicinal Product (CTIMP) expanded to include patients who have been on a CTIMP within last four weeks CHANGES TO TRIAL PROCEDURES Window for dose titration increased from ±3 days to ±4 days
    22 Aug 2019
    CHANGES TO TRIAL PROCEDURES Collection of cancer diagnosis and Eastern Cooperative Oncology Group Performance Status from participants at screening/baseline Collection of baseline Adverse Event data
    17 Mar 2020
    CHANGES MADE IN RESPONSE TO COVID PANDEMIC Emergency action to stop new recruitment, taper the dose of methylphenidate for patients already on trial and then withdrawal of medication. Enrolled participants remained on follow-up but did not take investigational medicinal product or placebo.
    06 Jul 2020
    CHANGES MADE IN RESPONSE TO COVID PANDEMIC Telephone assessments permitted to replace face-to-face visits at weeks 3, 6 and 10 Home delivery of IMP permitted Need for separate face-to-face screening visit (with written informed consent) was removed. Consent for screening tests (blood tests, blood pressure and pulse) could now be verbal rather than written Screening and enrolment visits could be merged CHANGES TO SAMPLE SIZE Sample size for randomised participants changed from 230 to 215-230
    09 Jan 2023
    CHANGES TO SECONDARY OUTCOMES References to carer satisfaction as an outcome were removed from the protocol - Inclusion of carer satisfaction in the original protocol was an error, no data were collected on this outcome. Anxiety and depression were specified as secondary outcomes - Data on anxiety and depression had not previously been explicitly specified as secondary outcomes. CHANGES TO SAMPLE SIZE Sample size reduced from 215-230 randomised participants to 162-230 randomised participants. Estimated number of evaluable participants changed from 172 to 130-172: In light of below expected recruitment rates, funder agreed to extend trial to achieve at least 130 evaluable participants (estimated to require at least 162 randomised participants).

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Mar 2020
    Recruitment suspended nationally due to COVID pandemic
    31 Oct 2020

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38757263
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