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    Clinical Trial Results:
    BETTER-B (Feasibility) BETter TreatmEnts for Refractory Breathlessness: A feasibility study of the use of mirtazapine for refractory breathlessness

    Summary
    EudraCT number
    		 2015-004064-11
    Trial protocol
    		 GB  
    Global end of trial date
    13 Dec 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    17 Mar 2019
    First version publication date
    11 Jan 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Amendment required to number of patients completing the trial and corresponding minor updates to endpoint tables.

    Trial information

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    Trial identification
    Sponsor protocol code
    BETTER-B (Feasibility)
    Additional study identifiers
    ISRCTN number
    		 ISRCTN32236160
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Professor Irene Higginson, Professor of Palliative Care, King’s College London, Cicely Saunders Institute, Department of Palliative Care, Policy & Rehabilit, +44 207 848 5516, irene.higginson@kcl.ac.uk
    Scientific contact
    Professor Irene Higginson, Professor of Palliative Care, King’s College London, Cicely Saunders Institute, Department of Palliative Care, Policy & Rehabilit, +44 207 848 5516, irene.higginson@kcl.ac.uk
    Sponsor organisation name
    King's College Hospital NHS Foundation Trust
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE5 9RS
    Public contact
    Professor Irene Higginson, Professor of Palliative Care, King’s College London, Cicely Saunders Institute, Department of Palliative Care, Policy & Rehabilit, +44 207 848 5516, irene.higginson@kcl.ac.uk
    Scientific contact
    Professor Irene Higginson, Professor of Palliative Care, King’s College London, Cicely Saunders Institute, Department of Palliative Care, Policy & Rehabilit, +44 207 848 5516, irene.higginson@kcl.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
    13 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine whether a randomised, double-blind, placebo-controlled large-scale trial of mirtazapine for refractory breathlessness is feasible in terms of recruitment, as assessed by the number of patients recruited across 3 hospitals over a 12-month period.
    Protection of trial subjects
    Patients are free to withdraw consent for study treatment and/or consent to participate in the study at any time and without the prejudice to further treatment. Patients who withdraw from study treatment, but are willing to continue to participate in the follow-up visits should be followed according to the procedures outlined in the protocol. The role of the trial steering committee for this trial was to provide independent oversight of ethical and safety aspects of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 Breathlessness is a complex, multifactorial experience and is reported as a subjective measure, and refractory breathlessness is a feature of advanced disease where participants may suffer from adverse events due to their underlying condition(s). Therefore, in order to gain a measure of the benefits and harms of an intervention in a trial, a placebo control is needed.
    Actual start date of recruitment
    01 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    64
    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)
    10
    From 65 to 84 years
    48
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place in three UK centres with each site open for a total of 12 months. King’s College Hospital opened on 17/08/2016, Nottingham opened on 13/10/2016 and Castle Hill Hospital opened on the 24/11/2016. King’s College Hospital had a pause in recruitment between the 12/04/2017 and 03/07/2017 due to short term resource issues.

    Pre-assignment
    Screening details
    		 Male or female aged ≥ 18 years old. Diagnosed with: Cancer, or Chronic obstructive pulmonary disease (COPD), or Interstitial lung disease (ILD), or Chronic heart failure (New York Heart Association (NYHA) class III or IV) Breathlessness severity: Modified MRC dyspnoea scale grade 3 or 4.

    Pre-assignment period milestones
    Number of subjects started
    		 64
    Number of subjects completed
    		 64

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mirtazapine
    Arm description
    		 For participants randomised to receive mirtazapine, the daily dose will be 15mg (one capsule) for the first 14 days; participants will be assessed for possible dose escalation at the trial assessment visit for day 14 and if appropriate, their daily dose will be escalated to 30mg (two capsules) on days 15 through to 28. Where dose escalation is not appropriate, the participant will continue to take a daily dose of 15mg (one capsule) on days 15 through to 28.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mirtazapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg for the first 14 days and either 15 mg or 30 mg from day 15 to day 28 mg milligram(s)

    Arm title
    		 Placebo
    Arm description
    		 For participants randomised to receive placebo the daily dose will be 1 capsule for the first 14 days; participants will be assessed for possible dose escalation on day 14 and if appropriate, their daily dose will be escalated to 2 capsules on days 15 through to 28. Where dose escalation is not appropriate, the participant will continue to take a daily dose of 1 capsule on days 15 through to 28.
    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 for the first 14 days; participants will be assessed for possible dose escalation on day 14 and if appropriate, their daily dose will be escalated to 2 capsules on days 15 through to 28. Where dose escalation is not appropriate, the participant will continue to take a daily dose of 1 capsule on days 15 through to 28.

    Number of subjects in period 1
    		Mirtazapine Placebo
    Started
    30
    34
    Completed
    24
    28
    Not completed
    6
    6
         Adverse event, serious fatal
    1
    -
         Participant Choice
    5
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial period
    Reporting group description
    		 Mirtazapine and placebo

    Reporting group values
    		 Overall trial period Total
    Number of subjects
    		 64 64
    Age categorical
    Mirtazapine
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 10 10
        From 65-84 years
    		 48 48
        85 years and over
    		 6 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.7 ( 8.45 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 47 47

    End points

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    End points reporting groups
    Reporting group title
    Mirtazapine
    Reporting group description
    		 For participants randomised to receive mirtazapine, the daily dose will be 15mg (one capsule) for the first 14 days; participants will be assessed for possible dose escalation at the trial assessment visit for day 14 and if appropriate, their daily dose will be escalated to 30mg (two capsules) on days 15 through to 28. Where dose escalation is not appropriate, the participant will continue to take a daily dose of 15mg (one capsule) on days 15 through to 28.

    Reporting group title
    Placebo
    Reporting group description
    		 For participants randomised to receive placebo the daily dose will be 1 capsule for the first 14 days; participants will be assessed for possible dose escalation on day 14 and if appropriate, their daily dose will be escalated to 2 capsules on days 15 through to 28. Where dose escalation is not appropriate, the participant will continue to take a daily dose of 1 capsule on days 15 through to 28.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    This includes all participants who have received at least one dose of the placebo. Only patients for whom written informed consent was not received and those who recieved Mirtazapine are excluded.

    Primary: Recruitment

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    End point title
    		 Recruitment [1]
    End point description
    Average number of patients recruited per non-calendar month by site
    End point type
    Primary
    End point timeframe
    Length of time sites open to recruitment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary endpoint is the number of patients recruited across 3 hospitals over a 12month period. This has been chosen to determine whether a larger scale trial of the same design is feasible, when expanded to additional centres.
    End point values
    		 Safety Population
    Number of subjects analysed
    64
    Units: Participants
    number (not applicable)
        KCL Average
    1.7
        KCL No. of patients recruited
    20
        KCL No. of months open to recruitment
    12.0
        Nottingham City Average
    1.3
        Nottingham City No. of patients recruited
    13
        Nottingham City No. of months open to recruitment
    10.3
        Castle Hill Average
    2.8
        Castle Hill No. of patients recruited
    31
        Castle Hill No. of months open to recruitment
    11.0
    No statistical analyses for this end point

    Secondary: Screening outcomes

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    End point title
    		 Screening outcomes
    End point description
    Outcomes for patients who were screened
    End point type
    Secondary
    End point timeframe
    Duration sites open to recruitment
    End point values
    		 Safety Population
    Number of subjects analysed
    409 [2]
    Units: Participants
        Randomised
    64
        Not approached due to ineligibility
    142
        Approached, subsequently found to be ineligible
    110
        Consented, subsequently found to be ineligible
    7
        Approached, declined to participate
    83
        Died
    1
        Unable to be contacted
    2
    Notes
    [2] - This is the number of patients screened for eligibility
    No statistical analyses for this end point

    Secondary: Treatment compliance- day 7

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    End point title
    		 Treatment compliance- day 7
    End point description
    Number of participants with at least 1 dose omission or reduction in the timeframe.
    End point type
    Secondary
    End point timeframe
    Day 1- 7
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Participants
    3
    3
    No statistical analyses for this end point

    Secondary: Treatment compliance- day 14

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    End point title
    		 Treatment compliance- day 14
    End point description
    Number of participants with at least 1 dose omission or reduction in the timeframe.
    End point type
    Secondary
    End point timeframe
    Day 8- 14
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    29
    34
    Units: Participants
    5
    6
    No statistical analyses for this end point

    Secondary: Treatment compliance- day 21

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    End point title
    		 Treatment compliance- day 21
    End point description
    Number of participants with at least 1 dose omission or reduction in the timeframe.
    End point type
    Secondary
    End point timeframe
    Day 15- 21
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    29
    31
    Units: Participants
    6
    5
    No statistical analyses for this end point

    Secondary: Treatment compliance- day 28

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    End point title
    		 Treatment compliance- day 28
    End point description
    Number of participants with at least 1 dose omission or reduction in the timeframe.
    End point type
    Secondary
    End point timeframe
    Day 22- 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    29
    30
    Units: Participants
    7
    5
    No statistical analyses for this end point

    Secondary: Blinding

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    End point title
    		 Blinding
    End point description
    All participants and research assessors remained blinded during the trial
    End point type
    Secondary
    End point timeframe
    Duration of trial
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Participants
    30
    34
    No statistical analyses for this end point

    Secondary: Participants remaining on study for 28 days

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    End point title
    		 Participants remaining on study for 28 days
    End point description
    Number of participants who were still on treatment at day 28.
    End point type
    Secondary
    End point timeframe
    Up to day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Participants
    23
    27
    No statistical analyses for this end point

    Secondary: Dose escalation

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    End point title
    		 Dose escalation
    End point description
    Participants who had a dose escalation at day 28
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Participants
        Yes
    10
    11
        No
    13
    15
        N/A participant did not continue treatment
    7
    7
        Missing
    0
    1
    No statistical analyses for this end point

    Secondary: Missing trial outcomes

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    End point title
    		 Missing trial outcomes
    End point description
    There were no participants with missing data for the primary trial outcome (recruitment).
    End point type
    Secondary
    End point timeframe
    Duration sites open to recruitment
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Average breathlessness at day 28

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    End point title
    		 Average breathlessness at day 28
    End point description
    Severity of breathlessness at the assessment visit for day 28 as assessed by the NRS
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29 [3]
    Units: Score
        arithmetic mean (standard deviation)
    4.7 ( 1.96 )
    4.9 ( 1.77 )
    Notes
    [3] - Data for 1 of these participants is missing
    No statistical analyses for this end point

    Secondary: Severity of breathlessness at days 7, 14 and 21

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    End point title
    		 Severity of breathlessness at days 7, 14 and 21
    End point description
    Severity of breathlessness at the assessment visits/calls for days 7, 14 and 21, as assessed by NRS
    End point type
    Secondary
    End point timeframe
    Days 7, 14 and 21
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    29 [4]
    34 [5]
    Units: Score
    arithmetic mean (standard deviation)
        Day 7
    5.0 ( 1.43 )
    5.3 ( 1.66 )
        Day 14
    4.9 ( 1.68 )
    5.2 ( 1.84 )
        Day 21
    5.1 ( 1.97 )
    5.0 ( 1.92 )
    Notes
    [4] - Data is missing for 1 participant on day 7
    [5] - Data is missing for 1 participant on days 7, 14 and 21
    No statistical analyses for this end point

    Secondary: Change in AKPS from baseline at days 14 and 28

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    End point title
    		 Change in AKPS from baseline at days 14 and 28
    End point description
    Change in AKPS from baseline to days 14 and 28. Decreasing numbers indicate a reduced performance status. Note that at day 14 one participant's AKPS is missing in the placebo arm. At day 28 one participant's AKPS is missing in the mirtazapine arm and one participant's AKPS is missing in the placebo arm.
    End point type
    Secondary
    End point timeframe
    Baseline to day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Score
    arithmetic mean (standard deviation)
        Day 14
    -1.0 ( 4.70 )
    -0.6 ( 4.29 )
        Day 28
    -1.1 ( 3.93 )
    -0.7 ( 4.58 )
    No statistical analyses for this end point

    Secondary: mMRC change from baseline at days 14 and 28

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    End point title
    		 mMRC change from baseline at days 14 and 28
    End point description
    Change in mMRC from baseline to days 14 and 28. An increased score indicates increased breathlessness. Note that at day 14 two participant's mMRC is missing in the placebo arm. At day 28 one participant's mMRC is missing in the mirtazapine arm and one participant's mMRC is missing in the placebo arm.
    End point type
    Secondary
    End point timeframe
    From baseline to day 28.
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Score
    arithmetic mean (standard deviation)
        Day 14
    -0.6 ( 0.78 )
    -0.3 ( 0.97 )
        Day 28
    -0.6 ( 0.79 )
    -0.4 ( 1.02 )
    No statistical analyses for this end point

    Secondary: Opioid medication

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    End point title
    		 Opioid medication
    End point description
    Number of patients receiving one or more opioid medications at days 7, 14, 21 and 28. Note that for days 14 and 28 there is one missing value for a participant in the placebo arm.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 21 and 28.
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Participants
        Day 7
    12
    10
        Day 14
    11
    11
        Day 21
    11
    10
        Day 28
    11
    10
    No statistical analyses for this end point

    Secondary: SPPB Change from baseline to day 28

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    End point title
    		 SPPB Change from baseline to day 28
    End point description
    Change in Short Physical Performance Battery (SPPB) from baseline at day 28. For change in score from baseline at day 28 positive scores indicate improvement and negative scores indicate a decline. Note there are 2, 8, 2 and 8 participants' scores missing for chair stand, balance, gait and summary respectively for the mirtazapine arm. Similarly, there are 4, 8, 4 and 8 participants' scores missing for chair stand, balance, gait and summary respectively for the placebo arm.
    End point type
    Secondary
    End point timeframe
    Baseline to day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Score
    arithmetic mean (standard deviation)
        Chair stand score
    0.2 ( 1.10 )
    0.2 ( 1.27 )
        Balance score
    0.1 ( 1.00 )
    0.0 ( 1.17 )
        Gait score
    0.1 ( 0.89 )
    0.2 ( 1.08 )
        Summary score
    0.2 ( 1.83 )
    0.2 ( 1.90 )
    No statistical analyses for this end point

    Secondary: GSES change from baseline at day 28

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    End point title
    		 GSES change from baseline at day 28
    End point description
    Change in GSES scores from baseline at day 28. A decrease in the change from baseline indicates a decrease in the strength of a participants self-efficacy belief. Note that two participants are missing data for this from the placebo arm.
    End point type
    Secondary
    End point timeframe
    Baseline to day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    30
    34
    Units: Score
        arithmetic mean (standard deviation)
    1.5 ( 4.95 )
    0.6 ( 3.15 )
    No statistical analyses for this end point

    Secondary: EQ-5D-5L Mobility

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    End point title
    		 EQ-5D-5L Mobility
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29
    Units: Participants
        I have no problems walking about
    3
    2
        I have slight problems walking about
    6
    7
        I have moderate problems walking about
    13
    10
        I have severe problems walking about
    4
    10
        I am unable to walk about
    2
    0
    No statistical analyses for this end point

    Secondary: EQ-5D-5L Self-care

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    End point title
    		 EQ-5D-5L Self-care
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29
    Units: Participants
        I have no problems washing or dressing myself
    9
    5
        I have slight problems washing or dressing myself
    8
    10
        I have moderate problems washing or dressing
    7
    13
        I have severe problems washing or dressing myself
    3
    1
        I am unable to wash or dress myself
    1
    0
    No statistical analyses for this end point

    Secondary: EQ-5D-5L Usual activities

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    End point title
    		 EQ-5D-5L Usual activities
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29
    Units: Participants
        I have no problems doing my usual activities
    4
    4
        I have slight problems doing my usual activities
    6
    5
        I have moderate problems doing my usual activities
    10
    10
        I have severe problems doing my usual activities
    4
    7
        I am unable to do my usual activities
    4
    2
        Missing
    0
    1
    No statistical analyses for this end point

    Secondary: EQ-5D-5L Pain/Discomfort

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    End point title
    		 EQ-5D-5L Pain/Discomfort
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29
    Units: Participants
        I have no pain or discomfort
    21
    19
        I have slight pain or discomfort
    4
    8
        I have moderate pain or discomfort
    1
    2
        I have severe pain or discomfort
    2
    0
        I have extreme pain or discomfort
    0
    0
    No statistical analyses for this end point

    Secondary: EQ-5D-5L Anxiety/Depression

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    End point title
    		 EQ-5D-5L Anxiety/Depression
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29
    Units: Participants
        I am not anxious or depressed
    19
    17
        I am slightly anxious or depressed
    4
    9
        I am moderately anxious or depressed
    5
    3
        I am severely anxious or depressed
    0
    0
        I am extremely anxious or depressed
    0
    0
    No statistical analyses for this end point

    Secondary: EQ-5D-5L Your health today (score)

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    End point title
    		 EQ-5D-5L Your health today (score)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29
    Units: Score
        arithmetic mean (standard deviation)
    63.4 ( 21.2 )
    60.8 ( 19.0 )
    No statistical analyses for this end point

    Secondary: IPOS Overall total score

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    End point title
    		 IPOS Overall total score
    End point description
    The overall IPOS score is useful in understanding the overall symptoms, concerns, and status of the patient at a specific point in time. A higher score indicates a participant is experiencing a greater severity of symptoms/concerns than a participant with a lower score. The overall IPOS score is the sum of the scores from each of the 17 IPOS questions.
    End point type
    Secondary
    End point timeframe
    Days 14 and 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    29 [6]
    32 [7]
    Units: Score
    arithmetic mean (standard deviation)
        Day 14
    19.2 ( 6.51 )
    20.5 ( 7.88 )
        Day 28
    17.2 ( 8.02 )
    17.8 ( 7.55 )
    Notes
    [6] - At day 28 only 28 participants in the mirtazapine arm were still enrolled on the trial
    [7] - At day 28, 29 participants were still enrolled in the placebo arm of the trial
    No statistical analyses for this end point

    Secondary: HADS anxiety score day 14

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    End point title
    		 HADS anxiety score day 14
    End point description
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    29
    32
    Units: Participants
        Normal
    19
    19
        Mild
    7
    9
        Moderate
    3
    3
        Severe
    0
    1
    No statistical analyses for this end point

    Secondary: HADS anxiety score day 28

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    End point title
    		 HADS anxiety score day 28
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29
    Units: Participants
        Normal
    26
    20
        Mild
    1
    8
        Moderate
    1
    1
        Severe
    0
    0
    No statistical analyses for this end point

    Secondary: HADS depression score day 14

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    End point title
    		 HADS depression score day 14
    End point description
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    29
    32
    Units: Participants
        Normal
    18
    17
        Mild
    10
    7
        Moderate
    1
    8
        Severe
    0
    0
    No statistical analyses for this end point

    Secondary: HADS depression score day 28

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    End point title
    		 HADS depression score day 28
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29
    Units: Participants
        Normal
    17
    17
        Mild
    7
    8
        Moderate
    4
    3
        Severe
    0
    1
    No statistical analyses for this end point

    Secondary: CRQ Day 14

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    End point title
    		 CRQ Day 14
    End point description
    Higher scores represent better participant outcomes. Note that for dyspnoea- patients with all 5 score completed there is data from 6 and 11 participants missing in the mirtazapine and placebo arms respectively. Similarly, for dyspnoea - patients with atleast 50% data there is data from 4 participants missing in each arm.
    End point type
    Secondary
    End point timeframe
    Day 14
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    29
    32
    Units: Score
    arithmetic mean (standard deviation)
        Dyspnoea - Patients with all 5 scores complete
    2.7 ( 1.03 )
    2.6 ( 0.89 )
        Dyspnoea - Patients with atleast 50% data
    2.7 ( 1.06 )
    2.6 ( 0.92 )
        Fatigue
    3.7 ( 1.13 )
    3.5 ( 1.25 )
        Emotional
    5.0 ( 1.16 )
    4.5 ( 1.11 )
        Mastery
    4.8 ( 1.48 )
    4.3 ( 1.41 )
    No statistical analyses for this end point

    Secondary: CRQ Day 28

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    End point title
    		 CRQ Day 28
    End point description
    Higher scores represent better participant outcomes. Note that for dyspnoea- patients with all 5 score completed there is data from 6 and 9 participants missing in the mirtazapine and placebo arms respectively. Similarly, for dyspnoea - patients with atleast 50% data there is data from 4 and 6 participants missing in the mirtazapine and placebo arms respectively.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 Mirtazapine Placebo
    Number of subjects analysed
    28
    29
    Units: Score
    arithmetic mean (standard deviation)
        Dyspnoea - Patients with all 5 scores completed
    3.1 ( 1.11 )
    2.8 ( 0.96 )
        Dyspnoea - Patients with atleast 50% data
    3.1 ( 1.04 )
    2.9 ( 1.04 )
        Fatigue
    3.8 ( 1.26 )
    4.0 ( 1.22 )
        Emotional
    5.0 ( 1.17 )
    4.9 ( 1.25 )
        Mastery
    4.9 ( 1.22 )
    4.9 ( 1.34 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to 7 days post treatment end
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo safety population
    Reporting group description
    		 This includes all participants who have received at least one dose of the placebo. Only patients who received Mirtazapine are excluded.

    Reporting group title
    Mirtazapine safety population
    Reporting group description
    		 This includes all participants who have received at least one dose of Mirtazapine. Only patients who received the placebo are excluded.

    Serious adverse events
    		 Placebo safety population Mirtazapine safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 30 (13.33%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain - cardiac
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal hemorrhage
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchial Infection
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
    Additional description: Participant withdrew from the study prior to death.
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 30 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo safety population Mirtazapine safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 34 (88.24%)
    29 / 30 (96.67%)
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    18 / 34 (52.94%)
    18 / 30 (60.00%)
         occurrences all number
    36
    53
    Irritability
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 30 (10.00%)
         occurrences all number
    8
    5
    Dyspnea
         subjects affected / exposed
    6 / 34 (17.65%)
    6 / 30 (20.00%)
         occurrences all number
    9
    9
    Hypoxia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Productive cough
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 30 (10.00%)
         occurrences all number
    4
    11
    Sore throat
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Anxiety
         subjects affected / exposed
    10 / 34 (29.41%)
    8 / 30 (26.67%)
         occurrences all number
    16
    16
    Confusion
         subjects affected / exposed
    3 / 34 (8.82%)
    5 / 30 (16.67%)
         occurrences all number
    5
    7
    Insomnia
         subjects affected / exposed
    10 / 34 (29.41%)
    4 / 30 (13.33%)
         occurrences all number
    23
    5
    Investigations
    Weight gain
         subjects affected / exposed
    6 / 34 (17.65%)
    5 / 30 (16.67%)
         occurrences all number
    11
    9
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    10 / 34 (29.41%)
    9 / 30 (30.00%)
         occurrences all number
    12
    19
    Dizziness
         subjects affected / exposed
    11 / 34 (32.35%)
    11 / 30 (36.67%)
         occurrences all number
    18
    20
    Headache
         subjects affected / exposed
    6 / 34 (17.65%)
    4 / 30 (13.33%)
         occurrences all number
    8
    4
    Lethargy
         subjects affected / exposed
    11 / 34 (32.35%)
    13 / 30 (43.33%)
         occurrences all number
    26
    29
    Movements involuntary
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    16 / 34 (47.06%)
    21 / 30 (70.00%)
         occurrences all number
    26
    61
    Tremor
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Diarrhea
         subjects affected / exposed
    8 / 34 (23.53%)
    7 / 30 (23.33%)
         occurrences all number
    10
    12
    Dyspepsia
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Dry mouth
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 30 (10.00%)
         occurrences all number
    4
    7
    Dysphagia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Gingival pain
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    6 / 34 (17.65%)
    9 / 30 (30.00%)
         occurrences all number
    7
    14
    Oral pain
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 34 (8.82%)
    4 / 30 (13.33%)
         occurrences all number
    3
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Chest wall pain
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Lung infection
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 30 (10.00%)
         occurrences all number
    6
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 30 (0.00%)
         occurrences all number
    5
    0
    Dehydration
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Other
    Additional description: Increased appetite was a prespecified variable on the CRFs and is not strictly a CTCAE term
         subjects affected / exposed
    11 / 34 (32.35%)
    15 / 30 (50.00%)
         occurrences all number
    24
    39

    More information

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

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

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