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    Clinical Trial Results:
    A multicentre randomised trial to establish the effect(s) of routine administration of Fluoxetine for six months in patients with a recent stroke.

    Summary
    EudraCT number
    2011-005616-29
    Trial protocol
    GB  
    Global end of trial date
    16 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jul 2019
    First version publication date
    02 Jul 2019
    Other versions
    Summary report(s)
    FOCUS trial_Lancet publication

    Trial information

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    Trial identification
    Sponsor protocol code
    FOCUS2012
    Additional study identifiers
    ISRCTN number
    ISRCTN83290762
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    CTA Number: 01384/0221/001-0001, NIHR Funding code: 13/04/30, REC Number: 11/SS/0100
    Sponsors
    Sponsor organisation name
    Academic and Central Office for Research and Development (ACCORD)
    Sponsor organisation address
    QMRI, 47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Professor Martin Dennis, University of Edinburgh, 0131 465 9617, martin.dennis@ed.ac.uk
    Scientific contact
    Professor Martin Dennis, University of Edinburgh, 0131 465 9617, martin.dennis@ed.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
    21 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective: Is there a difference in the functional outcome, measured with the modified Rankin score, at 6 months between those treated with fluoxetine (20mg daily) for 6 months after stroke, and those treated with placebo? Secondary objectives: To establish whether there a difference in: the long term survival; functional outcome; motor function at 6 and 12 months; communication; cognition; aspects of quality of life (mood, fatigue, participation) at 6 and 12 months; cost of health and social care over 6 and 12 months; risk of serious adverse events at 6 and 12 months and number of new diagnosis of depression between those patients treated with fluoxetine versus placebo?
    Protection of trial subjects
    The trial was conducted in accordance with all relevant data protection, ethical and regulatory requirements to ensure the privacy and security of patient information and to ensure the rights, safety and well-being of the patients and the quality of the research data. We sought FOCUS group and public involvement opinion during the development of the protocol and participant materials and created an easy access patient information sheet and consent form for patients with aphasia. We sought to minimise risk and burden to the patient without compromising the scientific rigour of the trial. The side effects of fluoxetine are well recognised. We sought to minimise risk by excluding patients in whom the risks are likely to be greatest e.g. those with previous seizures. Patient follow-up questionnaires were kept to a minimum so that they would not be too burdensome for patients. Any unexpected deterioration in function between the 6 and 12 month assessments, or indication of depression or another post stroke complication, from the information provided in the questionnaire, was fed back to the GPs. We provided a 24/7 helpline for participants, their families and professionals. Also a 24/7 emergency unblinding service.
    Background therapy
    Participants received the background therapy determined by the clinical teams in each of our 103 centres.
    Evidence for comparator
    Many clinical and preclinical studies have suggested that fluoxetine might improve outcomes after stroke through a range of mechanisms, which include enhancing neuroplasticity and promoting neurogenesis. The results of the FLAME (FLuoxetine for motor recovery After acute ischaeMic strokE) trial indicated that fluoxetine enhanced motor recovery. A subsequent Cochrane systematic review3 of SSRIs for stroke recovery identified 52 randomised controlled trials of SSRIs versus controls (in 4060 patients) This review suggested that SSRIs might reduce post-stroke disability, although this estimate was based on a meta-analysis done across various measures of function and greater effects were seen if studies with increased risk of bias were retained and patients with depression were included. Although promising, data from the FLAME trial and the Cochrane review were not sufficiently compelling to alter stroke treatment guidelines or to alleviate concerns that any possible benefits might be offset by serious adverse reactions.4 The primary aim of the Fluoxetine Or Control Under Supervision (FOCUS) trial was to ascertain whether patients with a clinical stroke diagnosis would have improved functional outcomes with a 6-month course of fluoxetine compared with placebo. Important secondary aims were to identify any other benefits or harms and to assess whether any benefits persisted from the end of the treatment period to 12 months after stroke.
    Actual start date of recruitment
    10 Sep 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 3127
    Worldwide total number of subjects
    3127
    EEA total number of subjects
    3127
    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)
    849
    From 65 to 84 years
    1875
    85 years and over
    403

    Subject disposition

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    Recruitment
    Recruitment details
    Between Sept 10, 2012, and March 31, 2017, 3152 patients were consented in 103 UK hospitals and 3127 were enrolled. 25 patients were not enrolled; 15 were identified as ineligible between obtaining consent and randomisation and in nine cases the patients, carer or family member, or their treating clinician changed their mind about participating.

    Pre-assignment
    Screening details
    We did not require centres to collect information about patients screened for eligibility

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fluoxetine
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Oxactin 20mg
    Investigational medicinal product code
    PL 19611/0017
    Other name
    Fluoxetine 20mg
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    20mg daily for 6 months. Each capsule contains 22.36 mg fluoxetine hydrochloride equivalent to 20 mg fluoxetine. Each capsule contains 22.36 mg fluoxetine hydrochloride equivalent to 20 mg fluoxetine. Excipient with known effect: 58 mg of lactose monohydrate per capsule. List of excipients: Lactose monohydrate Microcrystalline cellulose Crospovidone Magnesium stearate Printing Ink – Shellac Black Iron Oxide E172 Propylene Glycol E1520 Ammonium Hydroxide E527 Capsule Shell: Body: Indigo carmine E132 Yellow Iron oxide E172 Black Iron oxide E172 Titanium dioxide E171 Gelatin

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule daily orally for 6 months

    Number of subjects in period 1
    Fluoxetine Placebo
    Started
    1564
    1563
    6 months
    1553
    1553
    12 months
    1539
    1544
    Completed
    1539
    1544
    Not completed
    25
    19
         Unable to obtain mRS
    5
    8
         Consent withdrawn by subject
    20
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fluoxetine
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Fluoxetine Placebo Total
    Number of subjects
    1564 1563 3127
    Age categorical
    Units: Subjects
        <=70 years
    666 664 1330
        >70 years
    898 899 1797
    Age continuous
    Mean age
    Units: years
        arithmetic mean (standard deviation)
    71.2 ± 12.4 71.5 ± 12.1 -
    Gender categorical
    Units: Subjects
        Female
    589 616 1205
        Male
    975 947 1922
    Ethnicity
    Units: Subjects
        Asian
    30 31 61
        Black
    35 29 64
        chinese
    0 1 1
        White
    1495 1493 2988
        Other
    4 9 13
    Marital Status
    Units: Subjects
        Married
    879 846 1725
        Partner
    93 91 184
        Divorced or separated
    109 100 209
        Widowed
    337 354 691
        Single
    124 150 274
        Other
    22 22 44
    Living arrangement
    Units: Subjects
        Living with someone else
    1057 1034 2091
        Lives alone
    485 516 1001
        Living in an institution
    10 4 14
        Other
    12 9 21
    Employment Status
    Units: Subjects
        Full-time employment
    287 258 545
        Part-time employment
    76 70 146
        Retired
    1122 1134 2256
        Unemployed or disabled
    53 60 113
        Other
    26 41 67
    Independent before stroke
    Units: Subjects
        Independent before stroke
    1431 1435 2866
        Dependent before stroke
    133 128 261
    Known coronary heart disease
    Units: Subjects
        Yes
    281 300 581
        No
    1283 1263 2546
    Stroke diagnosis
    Units: Subjects
        Non-stroke (final diagnosis)
    2 2 4
        Ischaemic stroke
    1408 1404 2812
        Intracerebral haemorrhage
    154 157 311
    OCSP classification of ischaemic strokes
    Units: Subjects
        Total anterior circulation infarct
    318 317 635
        Partial anterior circulation infarct
    561 553 1114
        Lacunar infarct
    307 283 590
        Posterior circulation infarct
    191 230 421
        Uncertain
    33 23 56
        Haemorrhagic so no OCSP
    154 157 311
    Cause of stroke, modified TOAST classification
    Units: Subjects
        Large artery disease
    278 234 512
        Small vessel disease
    252 218 470
        Embolism from heart
    377 411 788
        Another cause
    38 35 73
        Unknown or uncertain
    465 508 973
        Haemorrhagic so no TOAST
    154 157 311
    Ability to walk at baseline - predictive variable
    Units: Subjects
        Able to walk at time of randomisation
    435 412 847
        Unable to walk at time of randomisation
    1129 1151 2280
    Predicted 6m probability of a good outcome (mRS0-2)
    Predicted 6m probability of a good outcome (mRS0-2) using SSV
    Units: Subjects
        0·00 to ≤0∙15
    592 591 1183
        >0∙15 to 1·00
    972 972 1944
    Motor deficit at baseli
    Presence of motor deficit
    Units: Subjects
        Yes
    1361 1361 2722
        No
    203 202 405
    Depression at baseline
    Depression at baseline reported by patient or proxy
    Units: Subjects
        Yes
    26 18 44
        No
    1538 1545 3083
    Current mood on PHQ2 scale
    Current mood on PHQ2 scale
    Units: Subjects
        2 yes responses
    81 60 141
        1 yes response
    136 130 266
        0 yes response
    1347 1373 2720
    Details of enrolment
    Details of enrolment
    Units: Subjects
        Inpatient
    1544 1536 3080
        Outpatient
    20 27 47
    Able to lift both arms at baseline - predictive variable
    Units: Subjects
        Able
    924 935 1859
        Unable
    640 628 1268
    Able to talk and not confused at baseline
    Units: Subjects
        Able
    1166 1164 2330
        Unable
    398 399 797
    Known Ischaemic stroke or TIA
    Units: Subjects
        Yes
    274 294 568
        No
    1290 1269 2559
    Known diabetes mellitus
    Units: Subjects
        Yes
    337 303 640
        No
    1227 1260 2487
    Known hyponatraemia
    Units: Subjects
        Yes
    19 26 45
        No
    1545 1537 3082
    Previous intracranial bleed
    Units: Subjects
        Yes
    27 23 50
        No
    1537 1540 3077
    Previous upper GI bleed
    Units: Subjects
        Yes
    25 26 51
        No
    1539 1537 3076
    Previous bone fracture
    Units: Subjects
        Yes
    241 256 497
        No
    1323 1307 2630
    Previous depression
    Units: Subjects
        Yes
    130 123 253
        No
    1434 1440 2874
    Consent from
    Units: Subjects
        Patient
    1136 1118 2254
        Proxy
    428 445 873
    Aphasia at baseline
    Aphasia at baseline on NIHSS
    Units: Subjects
        Yes
    457 449 906
        No
    1107 1114 2221
    Taking non SSRI at baseline
    Units: Subjects
        Yes
    65 77 142
        No
    1499 1486 2985
    Probability of a good outcome (mRS0-2) on SSV
    Probability of a good outcome (mRS0-2) on SSV
    Units: proportion
        median (inter-quartile range (Q1-Q3))
    0.28 (0.07 to 0.63) 0.26 (0.07 to 0.63) -
    NIHSS score at baseline
    Total NIHSS score at baseline
    Units: points
        median (inter-quartile range (Q1-Q3))
    6 (3 to 11) 6 (3 to 11) -
    Delay since stroke onset to randomisation
    Delay since stroke onset to randomisation
    Units: Days
        arithmetic mean (standard deviation)
    6.9 ± 3.6 7.0 ± 3.6 -

    End points

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    End points reporting groups
    Reporting group title
    Fluoxetine
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Disability on the modified Rankin Scale (mRS) at 6 months

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    End point title
    Disability on the modified Rankin Scale (mRS) at 6 months
    End point description
    The primary outcome was functional status, measured with the modified Rankin Scale (mRS) at 6 months after randomisation. We performed an ordinal logistic regression adjusted for baseline variables included in our minimisation algorithm. We also carried out unadjusted analysis but this was a secondary analysis.
    End point type
    Primary
    End point timeframe
    At 6 months after randomisation (although we used data captured from 90 days to 12 months after date of randomisation).
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1564
    1563
    Units: 0 to 6
        mRS = 0
    114
    124
        mRS = 1
    302
    309
        mRS = 2
    156
    155
        mRS = 3
    518
    510
        mRS = 4
    121
    122
        mRS = 5
    213
    203
        mRS = 6
    129
    130
        Missing
    11
    10
    Statistical analysis title
    Ordinal analysis of the mRS adjusted
    Statistical analysis description
    Ordinal analysis of the modified Rankin Scale (mRS) adjusted with logistic regression for the variables included in our minimisation algorithm. 1553 patients had mRS data available in each group; 11 patients in the fluoxetine group and ten in the placebo group had missing mRS data. Common odds ratio 0·951 (95% CI 0·839–1·079), p=0·439; adjusted for baseline variables
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.439 [1]
    Method
    Ordinal logistic regression
    Parameter type
    Common odds ratio
    Point estimate
    0.951
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.839
         upper limit
    1.079
    Notes
    [1] - adjusted for baseline variables
    Statistical analysis title
    Ordinal analysis of 6m mRS unadjusted
    Statistical analysis description
    Ordinal analysis of 6m mRS unadjusted
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.531 [2]
    Method
    Ordinal logistic regression
    Parameter type
    Common odds ratio
    Point estimate
    0.961
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.848
         upper limit
    1.089
    Notes
    [2] - unadjusted

    Secondary: Adverse outcomes by 6 months

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    End point title
    Adverse outcomes by 6 months
    End point description
    The proportion of patients with each safety outcome by group
    End point type
    Secondary
    End point timeframe
    by 6 months
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1564
    1563
    Units: Patients
        Any stroke
    56
    64
        All thrombotic event
    78
    92
        Ischaemic Stroke
    43
    45
        Other thrombotic events
    20
    27
        Acute coronary events
    15
    23
        All bleeding events
    41
    38
        Haemorrhagic stroke
    7
    9
        Upper gastrointestinal bleed
    21
    16
        Other major bleeds
    13
    14
        Epiletic seizures
    58
    40
        Fall with Injury
    120
    94
        Fractured bone
    45
    23
        Hyponatraemia<125mmol/L
    22
    14
        Hyperglycaemia
    23
    16
        Symptomatic hypoglycaemia
    23
    13
        New depression
    210
    269
        New antidepressant
    280
    357
        attempted or actual suicide
    3
    2
    Statistical analysis title
    Any stroke at 6m
    Statistical analysis description
    Any stroke at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4543
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    0.8
    Statistical analysis title
    All Thrombotic events at 6m
    Statistical analysis description
    All Thrombotic events at 6m
    Comparison groups
    Placebo v Fluoxetine
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2677
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.49
         upper limit
    0.69
    Statistical analysis title
    Ischaemic Stroke at 6m
    Statistical analysis description
    Ischaemic Stroke at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8264
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    1
    Statistical analysis title
    Other thrombotic events at 6m
    Statistical analysis description
    Other thrombotic events at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3025
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.4
    Statistical analysis title
    Acute coronary events at 6m
    Statistical analysis description
    Acute coronary events at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.191
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.28
         upper limit
    0.26
    Statistical analysis title
    All bleeding events at 6m
    Statistical analysis description
    All bleeding events at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7346
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.91
         upper limit
    1.29
    Statistical analysis title
    Haemorrhagic stroke at 6m
    Statistical analysis description
    Haemorrhagic stroke at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6153
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.37
    Statistical analysis title
    Upper gastronomical bleed at 6m
    Statistical analysis description
    Upper gastronomical bleed at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4094
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.44
         upper limit
    1.08
    Statistical analysis title
    other major bleeds at 6m
    Statistical analysis description
    other major bleeds at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8454
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.71
         upper limit
    0.58
    Statistical analysis title
    Epileptic seizures at 6m
    Statistical analysis description
    Epileptic seizures at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0651
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    2.37
    Statistical analysis title
    Fall with injury at 6m
    Statistical analysis description
    Fall with injury at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0663
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    1.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.11
         upper limit
    3.43
    Statistical analysis title
    Fractured bone at 6m
    Statistical analysis description
    Fractured bone at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.007
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    1.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    2.43
    Statistical analysis title
    Hyponatraemia<125 mmol/L at 6m
    Statistical analysis description
    Hyponatraemia<125 mmol/L at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1805
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.24
         upper limit
    1.26
    Statistical analysis title
    Hyperglycaemia at 6m
    Statistical analysis description
    Hyperglycaemia at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2602
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.33
         upper limit
    1.22
    Statistical analysis title
    Symptomatic Hypoglycaemia at 6m
    Statistical analysis description
    Symptomatic Hypoglycaemia at 6m
    Comparison groups
    Placebo v Fluoxetine
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.094
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.11
         upper limit
    1.39
    Statistical analysis title
    New Depressiom at 6m
    Statistical analysis description
    New Depressiom at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0033
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -3.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.3
         upper limit
    -1.26
    Statistical analysis title
    New antidepressant at 6m
    Statistical analysis description
    New antidepressant at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -4.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.76
         upper limit
    -2.12
    Statistical analysis title
    attempted or actual suicide at 6m
    Statistical analysis description
    attempted or actual suicide at 6m
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.655
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.02
         upper limit
    0.34

    Secondary: Stroke impact scale at 6m

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    End point title
    Stroke impact scale at 6m
    End point description
    Stroke impact scale domains: each heading adjusted - missing pts: Fluoxetine Placebo Strength 1551 1549 Hand ability 1550 1545 mobility 1555 1556 motor 1552 1550 daily activities 1563 1550 physical function 1563 1551 memory 1541 1545 communication 1552 1552 emotion 1522 1534 participation 1552 1548 Recovery (VAS) 1548 1554
    End point type
    Secondary
    End point timeframe
    6 months from randomisation
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1564
    1563
    Units: units
    median (inter-quartile range (Q1-Q3))
        Strength
    56.25 (31.25 to 81.25)
    62.50 (37.50 to 81.25)
        Hand ability
    45.00 (0.00 to 90.00)
    50.00 (0.00 to 90.00)
        Mobility
    63.89 (36.11 to 86.11)
    63.89 (33.33 to 88.89)
        Motor
    54.86 (27.31 to 83.00)
    56.78 (28.75 to 82.64)
        Daily activities
    62.50 (37.50 to 90.00)
    65.00 (35.00 to 90.00)
        Physical function
    56.77 (30.38 to 84.31)
    58.82 (30.56 to 84.10)
        Memory
    82.14 (57.14 to 96.43)
    82.14 (57.14 to 96.43)
        Communication
    89.29 (67.86 to 100.00)
    92.86 (71.43 to 100.00)
        Emotion
    75.00 (58.33 to 88.89)
    75.00 (58.33 to 88.89)
        Participation
    62.50 (37.50 to 87.50)
    65.63 (40.63 to 87.50)
        Recovery (VAS)
    60.00 (40.00 to 80.00)
    60.00 (40.00 to 80.00)
    Statistical analysis title
    SIS - Strength 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7008
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Hand Ability 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4824
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Mobility 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5486
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Motor 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5125
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Daily Activities 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6235
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Physical function 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5154
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Memory 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.307
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Communication 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1919
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Emotion 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4687
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Participation 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2595
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS - Recover (VAS) 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.982
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Vitality - subscale of SF36

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    End point title
    Vitality - subscale of SF36
    End point description
    Vitality - subscale of SF36
    End point type
    Secondary
    End point timeframe
    by 6 months
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1545
    1542
    Units: units
    median (inter-quartile range (Q1-Q3))
        Vitality
    56.25 (37.50 to 75.00)
    56.25 (43.75 to 75.00)
    Statistical analysis title
    Vitality 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3087
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6726
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Mental Health Inventory - 5 item at 6m

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    End point title
    Mental Health Inventory - 5 item at 6m
    End point description
    Mental Health Inventory - 5 item at 6m
    End point type
    Secondary
    End point timeframe
    by 6 months
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1538
    1541
    Units: units
    median (inter-quartile range (Q1-Q3))
        MHI-5
    76.00 (60.00 to 88.00)
    72.00 (56.00 to 88.00)
    Statistical analysis title
    Mental Health Inventory -5
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3079
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Health related quality of life (EurQol - EQ5D-5L) at 6m

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    End point title
    Health related quality of life (EurQol - EQ5D-5L) at 6m
    End point description
    Health related quality of life (EurQol - EQ5D-5L) at 6m
    End point type
    Secondary
    End point timeframe
    by 6 months
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1552
    1559
    Units: units
    median (inter-quartile range (Q1-Q3))
        EQ5D-5L
    0.56 (0.21 to 0.74)
    0.56 (0.19 to 0.75)
    Statistical analysis title
    EQ5D -5L at 6m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5866
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Disability on the modified Rankin Scale at 12 months by treatment group

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    End point title
    Disability on the modified Rankin Scale at 12 months by treatment group
    End point description
    The primary outcome was functional status, measured with the modified Rankin Scale (mRS) at 12 months after randomisation.
    End point type
    Secondary
    End point timeframe
    by 12m
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1564
    1563
    Units: 0-6
        mRS = 0
    133
    145
        mRS =1
    251
    237
        mRS = 2
    178
    175
        mRS = 3
    494
    505
        mRS = 4
    90
    81
        mRS = 5
    211
    203
        mRS = 6
    182
    198
        Missing
    25
    19
    Statistical analysis title
    Ordinal analysis of the modified Rankin Scale(mRS)
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.82 [3]
    Method
    Ordinal logistic regression
    Parameter type
    common odds ratio
    Point estimate
    1.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.894
         upper limit
    1.151
    Notes
    [3] - Adjusted for minimisation variables
    Statistical analysis title
    Ordinal analysis of 12m mRS unadjusted
    Statistical analysis description
    Ordinal analysis of 12m mRS unadjusted
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.158 [4]
    Method
    Ordinal logistic regression
    Parameter type
    Common Odd ratio
    Point estimate
    1.033
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.879
         upper limit
    1.215
    Notes
    [4] - Unadjusted

    Secondary: Stroke impact Scale at 12m

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    End point title
    Stroke impact Scale at 12m
    End point description
    Stroke impact domains each heading adjusted - missing pts: Fluoxetine Placebo Strength 1529 1532 Hand ability 1530 1530 mobility 1536 1534 motor 1531 1532 daily activities 1534 1530 physical function 1534 1532 memory 1531 1531 communication 1532 1534 emotion 1518 1519 participation 1532 1530 Recovery (VAS) 1540 1539
    End point type
    Secondary
    End point timeframe
    by 12 months
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1564
    1563
    Units: Units
    median (inter-quartile range (Q1-Q3))
        SIS Strength
    56.25 (31.25 to 75.00)
    56.25 (37.50 to 75.00)
        SIS Hand ability
    50.00 (0.00 to 90.00)
    50.00 (5.00 to 90.00)
        SIS mobility
    66.67 (36.11 to 88.89)
    66.67 (38.89 to 88.89)
        SIS motor
    55.56 (28.80 to 83.33)
    58.61 (31.20 to 83.70)
        SIS Daily activities
    67.50 (40.00 to 90.00)
    67.50 (40.00 to 90.00)
        SIS Physical function
    57.81 (32.81 to 84.24)
    60.10 (33.54 to 85.28)
        SIS Memory
    78.57 (60.71 to 96.43)
    82.14 (57.14 to 96.43)
        SIS Communication
    89.29 (67.86 to 100.00)
    89.29 (71.43 to 100.00)
        SIS Emotion
    72.22 (58.33 to 86.11)
    73.61 (58.33 to 88.89)
        SIS Participation
    65.63 (40.63 to 90.63)
    65.63 (40.63 to 90.63)
        SIS Recovery (VAS)
    60.00 (40.00 to 80.00)
    60.00 (40.00 to 80.00)
    Statistical analysis title
    SIS Strength
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Placebo v Fluoxetine
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3844
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS Hand Ability at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2813
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS mobility at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5425
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS motor at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3286
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS Daily activities at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5808
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS Physical function at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.372
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS Memory at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4245
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS Communication at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3138
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS emotion at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7442
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS Participation at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9295
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    SIS Recovery (VAS) at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9333
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Vitality Median (IQR)

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    End point title
    Vitality Median (IQR)
    End point description
    Vitality Median (IQR)
    End point type
    Secondary
    End point timeframe
    by 12m
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1533
    1528
    Units: units
    median (inter-quartile range (Q1-Q3))
        Vitality Median (IQR)
    50.00 (37.50 to 75.00)
    50.00 (37.50 to 75.00)
    Statistical analysis title
    Vitality Median (IQR) at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3061
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9043
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Mental Health Inventory - 5 item at 12m

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    End point title
    Mental Health Inventory - 5 item at 12m
    End point description
    Mental Health Inventory - 5 item at 12m
    End point type
    Secondary
    End point timeframe
    by 12m
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1530
    1527
    Units: units
    median (inter-quartile range (Q1-Q3))
        MHI 5 Median (IQR)
    72.00 (56.00 to 88.00)
    76.00 (56.00 to 88.00)
    Statistical analysis title
    MHI 5 (Median IQR) at 12m
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3057
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.711
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Health related quality of life (EurQol - EQ5D-5L) at 12m excluding dead patients

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    End point title
    Health related quality of life (EurQol - EQ5D-5L) at 12m excluding dead patients
    End point description
    Health related quality of life (EurQol - EQ5D-5L) at 12m excluding dead patients
    End point type
    Secondary
    End point timeframe
    by 12m
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1546
    1550
    Units: units
    median (inter-quartile range (Q1-Q3))
        EQ5D-5L excluding dead patients
    0.59 (0.24 to 0.75)
    0.59 (0.27 to 0.77)
    Statistical analysis title
    EQ5D-5L exclusing dead patients
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Mann Whitney test
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3096
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3091
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Depression 12m

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    End point title
    Depression 12m
    End point description
    New Depression
    End point type
    Secondary
    End point timeframe
    by 12m
    End point values
    Fluoxetine Placebo
    Number of subjects analysed
    1564
    1563
    Units: patients
        New Depression
    292
    327
        New Antidepressant
    358
    410
    Statistical analysis title
    New Depression
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Chi squared
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1142
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -2.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.04
         upper limit
    0.54
    Statistical analysis title
    New Antidepressant
    Statistical analysis description
    Comparison of fluoxetine vs Placebo - Chi squared
    Comparison groups
    Fluoxetine v Placebo
    Number of subjects included in analysis
    3127
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.36
         upper limit
    -0.33

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    The trial systematically collected data on adverse events which may theoretically be associated with the IMP and the condition under investigation from randomisation to end of follow-up at 12 months.
    Adverse event reporting additional description
    Recruiting hospitals identified and reported adverse events at discharge or death and readmission to hospital. Central coordinating centre staff followed up patients at 6 months and 12 months to measure the primary and secondary outcomes. Data on adverse events were also collected from participants GP's at 6 and 12 months.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Fluoxetine
    Reporting group description
    -

    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: Our trial protocol specifically did not require any Adverse events to be reported unless they were serious, or fullfilled our definition of an outcome
    Serious adverse events
    Placebo Fluoxetine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 1563 (0.58%)
    5 / 1564 (0.32%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    all vascular disorders
         subjects affected / exposed
    1 / 1563 (0.06%)
    0 / 1564 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    All surgical and medical procedures
         subjects affected / exposed
    4 / 1563 (0.26%)
    3 / 1564 (0.19%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    all neoplasms
         subjects affected / exposed
    1 / 1563 (0.06%)
    0 / 1564 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    all social circumstances
         subjects affected / exposed
    1 / 1563 (0.06%)
    0 / 1564 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    All General disorders and administration site conditions
         subjects affected / exposed
    3 / 1563 (0.19%)
    1 / 1564 (0.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Investigations
    all investigations
         subjects affected / exposed
    2 / 1563 (0.13%)
    3 / 1564 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    All cardiac disorders
         subjects affected / exposed
    1 / 1563 (0.06%)
    2 / 1564 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    all blood disorders
         subjects affected / exposed
    1 / 1563 (0.06%)
    0 / 1564 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    all respiratory and mediastinal disorders
         subjects affected / exposed
    1 / 1563 (0.06%)
    0 / 1564 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    All nervous system disorders
         subjects affected / exposed
    2 / 1563 (0.13%)
    3 / 1564 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    All gastrointestinal disorders
         subjects affected / exposed
    4 / 1563 (0.26%)
    0 / 1564 (0.00%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    all renal and urinary disorders
         subjects affected / exposed
    0 / 1563 (0.00%)
    1 / 1564 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    all Hepatobiliary disorders
         subjects affected / exposed
    2 / 1563 (0.13%)
    0 / 1564 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    all musculoskeletal
         subjects affected / exposed
    0 / 1563 (0.00%)
    1 / 1564 (0.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    all metabolism disorders
         subjects affected / exposed
    0 / 1563 (0.00%)
    3 / 1564 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo Fluoxetine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 1563 (0.00%)
    0 / 1564 (0.00%)

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2012
    Description of amendments to V2 of the FOCUS trial protocol Substantial amendment 1: Section 10.3 Removal of the second mailing of patient questionnaires at 1, 6 and 12 months and change to telephone. Substantial amendment 2: Section 12.5.2 Removal of neuroleptic malignant syndrome-like events; anaphylactoid reactions; serotonin Syndrome; pancytopenia, thrombocytopenia or haemolytic anaemia from the list of adverse reactions which will be collected systematically on the discharge form and follow ups. Will be considered as AEs and reported according to our pharmacovigilance procedures which are unchanged. Substantial amendment 3: Timelines (page 47) Change to the expected start date from April 2012 to July 2012 due to delays in receiving the IMP. Substantial amendment 4: Section 14.4 Data Monitoring Committee. Clarification of the arrangements for sharing data with other parallel trials which will be based on the discretion of the Chair of our DMC. Substantial Amendment 5 Traditional PIB for Proxies V1 110512 was reworded to reflect that it is being read by the proxy rather than the patients. Substantial amendment 6 Removal of Protocol Appendix 1 which was replaced by a link.
    01 Sep 2015
    The original CTA was submitted prior to the final supplier of trial IMP being confirmed. Therefore the details of the MA holder which we originally submitted was not the MA holder of the IMP that we are now using (ATC code N06A B03). this amendment provided the correct MA details for the Oxactin 20mg we are using and ensures consistency with the details provided in our annual DSUR reports. Amendments: Change of MA holder and MA number details to reflect the specific IMP used for the trial Change in the response to question D2-2 in the CTA from ‘yes’ to ‘no’ as the same IMP has been used for each patient. Additional clerical amendments made: Section A4: Update to the ISRCTN number (this was not available at the time of the original submission). Section B1: Amendment to sponsor contact Section C1-5: Update to sponsor responsibility for sign off of CTA Section G4: Update to Network name and contact details Section H2-2: Date of ethics submission added as the original CTA was submitted prior to approval given. Section H2-3: Status changed to ‘approved’ and date of ethical approval added as the original CTA was submitted prior to approval given.  Protocol amendments relating to the IMP Section 1.1 Background: Updated the link address to current SmPC Section 9.1 Study Drug: Updated IMP details Section 9.1.1 MA number: Updated MA number Section 9.1.3 MA holder: Updated MA holder details Section 9.4 Storage: Storage temperature updated Section 9.5 Management: Storage temperature updated Notification of change of funder from the 1st October 2014 for the main phase to the NIHR HTA.
    15 Apr 2016
    Change of Chief Investigator.
    21 Nov 2016
    This amendment was required following notification to the sponsor of a revision of the summary of Product characteristics for Oxactin 20mg PL 19611/0017 on 24th July 2015. The SmPC was revised as a result of a variation to the marketing authorisation to update the safety information in line with the Core Safety Profile which was issued following conclusion of Periodic Safety Update Report (PSUR) work sharing procedure FR/H/PSUR/0069/001. In addition, the SmPC was updated to align with the layout and headings in the current Quality Review of Documents (QRD) templates, including the standard statements now required to encourage reporting of suspected adverse reactions. Information included in the latest version of the SmPC contra-indicates the combined use of metoprolol for heart failure and fluoxetine. Following discussion with the trial sponsor it was agreed that immediate action could be implemented to ensure that any patients taking metoprolol for heart failure were excluded with immediate effect. Urgent Safety Measures taken to ensure patient safety: A change was made to the database on 16/11/16 to add metoprolol for hear failure to our current list of excluded medications with immediate effect. All contacts at each site were emailed to inform them of the immediate change to the exclusion criteria and a revised paper randomisation form provided for use with immediate effect. A database report was created for patients randomised who were taking metoprolol at the time of randomisation and who would still be taking the trial medication. Only five patients were affected and each one was checked by the Chief Investigator as to the indication for metoprolol and none were found to be taking the drug for heart failure 17th The MHRA were contacted to advise them of action taken on November and 21st it was confirmed as an urgent safety measure on November 2016. The Data Monitoring Committee and Steering Committee informed. .

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30528472
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