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    Clinical Trial Results:
    Morphine for palliative treatment of refractory dyspnea in patients with advanced COPD: benefits and respiratory adverse effects

    Summary
    EudraCT number
    		 2014-004899-35
    Trial protocol
    		 NL  
    Global end of trial date
    03 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jun 2021
    First version publication date
    12 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MORDYC
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02429050
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Maastricht University
    Sponsor organisation address
    Universiteitssingel 40, Maastricht, Netherlands, 6229 ER
    Public contact
    D. Janssen, Centre of expertise for palliative care, Maastricht UMC+, daisy.janssen@mumc.nl
    Scientific contact
    D. Janssen, Centre of expertise for palliative care, Maastricht UMC+, daisy.janssen@mumc.nl
    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
    03 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1.1) to study whether and to what extent oral administration of morphine SR improves health-related quality of life among patients with advanced COPD; 1.2) to explore whether and to what extent oral administration of morphine SR leads to adverse respiratory effects in patients with advanced COPD.
    Protection of trial subjects
    Patients are monitored by a strict schedule with weekly contacts. The burden of side effects is minimized by prescribing laxatives and anti-emetics.
    Background therapy
    		 Patients were optimally treated for COPD, including at least LAMA-LABA therapy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2015
    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
    Netherlands: 111
    Worldwide total number of subjects
    111
    EEA total number of subjects
    111
    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)
    48
    From 65 to 84 years
    62
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period: November 2016 to February 2019 Number of recruited patients: 124 Country of recruitment: Netherlands Setting of recruitment: 1 pulmonary rehabilitation center and 2 general hospitals

    Pre-assignment
    Screening details
    		 Screening criteria: diagnosis of COPD, optimal (non)pharmacological treatment, mMRC grade 2-4, no contra-indication for morphine, no history of substance misuse, no recent exacerbation of COPD. assessed for eligibility: 1380 eligible: 464 (declined to participate due to burden project, fear of adverse effects) randomized: 124

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor
    Blinding implementation details
    Randomization was performed by a web-based random number generator using minimization and stratification for age (<55 years; 55-65 years; 65-75 years; or>75 years) and mMRC grade.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 morphine
    Arm description
    		 morphine treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    dosage: 10 mg administration frequency: 2-3 times a day with 18-2 hours in between.

    Arm title
    		 placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    placebo

    Number of subjects in period 1
    		morphine placebo
    Started
    54
    57
    Completed
    44
    51
    Not completed
    10
    6
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    5
    1
         acute exacerbation of COPD
    2
    3
         Lack of efficacy
    1
    -
         Protocol deviation
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    morphine
    Reporting group description
    		 morphine treatment

    Reporting group title
    placebo
    Reporting group description
    		 -

    Reporting group values
    		 morphine placebo Total
    Number of subjects
    		 54 57 111
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 25 23 48
        From 65-84 years
    		 29 33 62
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.0 ± 8.0 65.7 ± 8.0 -
    Gender categorical
    Units: Subjects
        Female
    		 26 25 51
        Male
    		 28 32 60
    Current smoking
    Units: Subjects
        yes
    		 7 7 14
        no
    		 47 50 97
    mMRC grade
    Units: Subjects
        grade 2
    		 31 31 62
        grade 3
    		 20 19 39
        grade 4
    		 3 7 10
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 27.6 ± 6.6 27.2 ± 5.3 -
    Pack-years
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 40 (29.8 to 51.3) 40 (30 to 50) -
    exacerbations <12 months
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 2 (1 to 4) 2 (0 to 3.5) -
    hospital admissions <12 months
    Units: number
        median (inter-quartile range (Q1-Q3))
    		 0 (0 to 1) 0 (0 to 1) -
    FEV1
    Units: liters
        median (inter-quartile range (Q1-Q3))
    		 0.99 (0.71 to 1.31) 0.95 (0.64 to 1.25) -
    Subject analysis sets

    Subject analysis set title
    subgroup - morphine
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients with mMRC grade 3 or 4 at baseline in the morphine arm

    Subject analysis set title
    subgroup - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients with mMRC grade 3 or 4 at baseline in the placebo arm

    Subject analysis sets values
    		 subgroup - morphine subgroup - placebo
    Number of subjects
    23
    26
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    7
    13
        From 65-84 years
    16
    12
        85 years and over
    0
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.6 ± 8.1
    64.5 ± 9.0
    Gender categorical
    Units: Subjects
        Female
    11
    14
        Male
    12
    12
    Current smoking
    Units: Subjects
        yes
    3
    4
        no
    20
    22
    mMRC grade
    Units: Subjects
        grade 2
    0
    0
        grade 3
    20
    19
        grade 4
    3
    7
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    27.5 ± 6.1
    26.1 ± 6.2
    Pack-years
    Units: years
        median (inter-quartile range (Q1-Q3))
    40 (30 to 50)
    40 (27.8 to 56.3)
    exacerbations <12 months
    Units: number
        median (inter-quartile range (Q1-Q3))
    3 (2 to 4)
    4 (1 to 4)
    hospital admissions <12 months
    Units: number
        median (inter-quartile range (Q1-Q3))
    1 (0 to 1)
    0 (0 to 1)
    FEV1
    Units: liters
        median (inter-quartile range (Q1-Q3))
    0.87 (0.66 to 1.02)
    0.88 (0.58 to 1.18)

    End points

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    End points reporting groups
    Reporting group title
    morphine
    Reporting group description
    		 morphine treatment

    Reporting group title
    placebo
    Reporting group description
    		 -

    Subject analysis set title
    subgroup - morphine
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients with mMRC grade 3 or 4 at baseline in the morphine arm

    Subject analysis set title
    subgroup - placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subgroup of patients with mMRC grade 3 or 4 at baseline in the placebo arm

    Primary: CAT score

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    End point title
    		 CAT score
    End point description
    mean change from baseline
    End point type
    Primary
    End point timeframe
    assessed at 1, 2 and 4 weeks
    End point values
    		 morphine placebo subgroup - morphine subgroup - placebo
    Number of subjects analysed
    54
    57
    23
    26
    Units: score
        arithmetic mean (standard error)
    -3.17 ± 0.73
    -1.00 ± 0.68
    -3.10 ± 1.12
    -1.95 ± 1.03
    Statistical analysis title
    		 total study population
    Comparison groups
    morphine v placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.03
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.14
         upper limit
    		 -0.22
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 subgroup analysis
    Comparison groups
    subgroup - morphine v subgroup - placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.44
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.17
         upper limit
    		 1.84
    Variability estimate
    Standard error of the mean

    Primary: PaCO2

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    End point title
    		 PaCO2
    End point description
    End point type
    Primary
    End point timeframe
    assessed at 4 weeks
    End point values
    		 morphine placebo subgroup - morphine subgroup - placebo
    Number of subjects analysed
    54
    57
    23
    26
    Units: mmHg
        arithmetic mean (standard error)
    1.80 ± 1.43
    0.68 ± 1.35
    3.00 ± 2.40
    1.43 ± 2.18
    Statistical analysis title
    		 total study population
    Comparison groups
    morphine v placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.55
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 5.07
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 subgroup analysis
    Comparison groups
    subgroup - placebo v subgroup - morphine
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.59
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.95
         upper limit
    		 8.64
    Variability estimate
    Standard error of the mean

    Secondary: PaO2

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    End point title
    		 PaO2
    End point description
    End point type
    Secondary
    End point timeframe
    assessed at 4 weeks
    End point values
    		 morphine placebo subgroup - morphine subgroup - placebo
    Number of subjects analysed
    54
    57
    23
    26
    Units: mmHg
        arithmetic mean (standard error)
    -2.48 ± 2.18
    0.98 ± 2.02
    -3.30 ± 3.53
    2.63 ± 3.23
    Statistical analysis title
    		 total study population
    Comparison groups
    placebo v morphine
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.21
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.7
         upper limit
    		 2.12
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 subgroup analysis
    Comparison groups
    subgroup - morphine v subgroup - placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.23
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.73
         upper limit
    		 3.9
    Variability estimate
    Standard error of the mean

    Secondary: respiratory rate

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    End point title
    		 respiratory rate
    End point description
    End point type
    Secondary
    End point timeframe
    assessed at 1, 2 and 4 weeks
    End point values
    		 morphine placebo subgroup - morphine subgroup - placebo
    Number of subjects analysed
    54
    57
    23
    26
    Units: rate
        arithmetic mean (standard error)
    -1.43 ± 0.51
    0.02 ± 0.48
    -1.47 ± 0.77
    -0.73 ± 0.71
    Statistical analysis title
    		 total study population
    Comparison groups
    morphine v placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.04
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.84
         upper limit
    		 -0.09
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 subgroup analysis
    Comparison groups
    subgroup - morphine v subgroup - placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.49
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.79
         upper limit
    		 1.34
    Variability estimate
    Standard error of the mean

    Secondary: Mean breathlessness 24 h

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    End point title
    		 Mean breathlessness 24 h
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at 2 days, 1, 2, 3 and 4 weeks
    End point values
    		 morphine placebo subgroup - morphine subgroup - placebo
    Number of subjects analysed
    54
    57
    23
    26
    Units: Numeric Rating Score
        arithmetic mean (standard error)
    -0.65 ± 0.35
    -0.05 ± 0.33
    -1.13 ± 0.54
    0.17 ± 0.50
    Statistical analysis title
    		 total study population
    Comparison groups
    morphine v placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.21
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.55
         upper limit
    		 0.35
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 subgroup analysis
    Comparison groups
    subgroup - morphine v subgroup - placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.08
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean

    Secondary: Worst breathlessness 24 h

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    End point title
    		 Worst breathlessness 24 h
    End point description
    End point type
    Secondary
    End point timeframe
    Assessed at 2 days, 1, 2, 3 and 4 weeks
    End point values
    		 morphine placebo subgroup - morphine subgroup - placebo
    Number of subjects analysed
    54
    57
    23
    26
    Units: Numeric Rating Score
        arithmetic mean (standard error)
    -0.50 ± 0.31
    0.09 ± 0.30
    -0.85 ± 0.44
    0.46 ± 0.40
    Statistical analysis title
    		 total study population
    Comparison groups
    morphine v placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.19
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.41
         upper limit
    		 0.28
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 subgroup analysis
    Comparison groups
    subgroup - morphine v subgroup - placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.03
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 -0.16
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 November 2016 - 3 June 2019
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    morphine
    Reporting group description
    		 morphine treatment

    Reporting group title
    placebo
    Reporting group description
    		 -

    Serious adverse events
    		 morphine placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 57 (3.51%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 morphine placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 54 (79.63%)
    40 / 57 (70.18%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    27 / 54 (50.00%)
    21 / 57 (36.84%)
         occurrences all number
    27
    21
    General disorders and administration site conditions
    Insomnia
         subjects affected / exposed
    16 / 54 (29.63%)
    23 / 57 (40.35%)
         occurrences all number
    16
    23
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    16 / 54 (29.63%)
    13 / 57 (22.81%)
         occurrences all number
    16
    13
    Vomiting
    Additional description: vomiting and retching
         subjects affected / exposed
    8 / 54 (14.81%)
    10 / 57 (17.54%)
         occurrences all number
    8
    10
    Constipation
         subjects affected / exposed
    25 / 54 (46.30%)
    17 / 57 (29.82%)
         occurrences all number
    25
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Nov 2016
    expansion of inclusion criteria from mMRC grade 3 or 4 to mMRC grade 2, 3 or 4

    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/32804188
    http://www.ncbi.nlm.nih.gov/pubmed/26825021
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