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    Clinical Trial Results:
    Double blind randomised controlled trial of exogenous administration of melatonin in chronic pain (DREAM-CP)

    Summary
    EudraCT number
    		 2018-004048-50
    Trial protocol
    		 GB  
    Global end of trial date
    11 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jan 2025
    First version publication date
    25 Jan 2025
    Other versions
    Summary report(s)
    		 DREAM-CP data summary

    Trial information

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    Trial identification
    Sponsor protocol code
    3-062-18
    Additional study identifiers
    ISRCTN number
    		 ISRCTN12861060
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Aberdeen
    Sponsor organisation address
    Foresterhil, Aberdeen, United Kingdom, AB252ZD
    Public contact
    Professor /Co-investigator, University of Aberdeen, +44 07900603649, h.f.galley@abdn.ac.uk
    Scientific contact
    Professor /Co-investigator, University of Aberdeen, +44 07900603649, h.f.galley@abdn.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
    08 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does melatonin treatment improve sleep disturbance in patients with chronic pain?
    Protection of trial subjects
    All staff working on the trial are GCP trained and have a thorough understanding of anticipated adverse events and the reporting process of these events. The sponsor is notified of any serious adverse event within 24 hours as par protocol. The Data Monitoring Committee (DMC) are assigned to review overall safety data to identify safety issues which may not be apparent on an individual case basis.
    Background therapy
    		 Melatonin will be administered as Circadin (2mg tablets, Flynn Pharmaceuticals Ltd.) which has EMA regulatory approval and is a slow release formulation with a blood concentration profile resembling that of endogenous melatonin
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2019
    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: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    46
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants are recruited from the Pain clinical Aberdeen Royal Infirmary

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 60
    Number of subjects completed
    		 60

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Received Melatonin first then placebo after washout period
    Arm type
    		 melatonin first

    Investigational medicinal product name
    2mg oral Circadin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg Circadin taken 2 hours before planned bedtime

    Arm title
    		 Group B
    Arm description
    		 Received Placebo first then melatonin after washout period
    Arm type
    		 receive placebo before active drug

    Investigational medicinal product name
    2mg oral placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg placebo taken 2 hours before planned bedtime

    Number of subjects in period 1
    		Group A Group B
    Started
    30
    30
    Completed
    30
    28
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    2
    Period 2
    Period 2 title
    Period 1
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Received Melatonin first then placebo after washout period
    Arm type
    		 melatonin first

    Investigational medicinal product name
    2mg oral Circadin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg Circadin taken 2 hours before planned bedtime

    Arm title
    		 Group B
    Arm description
    		 Received Placebo first then melatonin after washout period
    Arm type
    		 receive placebo before active drug

    Investigational medicinal product name
    2mg oral placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg placebo taken 2 hours before planned bedtime

    Number of subjects in period 2
    		Group A Group B
    Started
    30
    28
    Completed
    27
    27
    Not completed
    3
    1
         Consent withdrawn by subject
    3
    1
    Period 3
    Period 3 title
    Washout period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    DREAM-CP is a crossover randomised trial. The washout out period is the crossover period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Received Melatonin first then placebo after washout period
    Arm type
    		 melatonin first

    Investigational medicinal product name
    2mg oral Circadin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg Circadin taken 2 hours before planned bedtime

    Arm title
    		 Group B
    Arm description
    		 Received Placebo first then melatonin after washout period
    Arm type
    		 receive placebo before active drug

    Investigational medicinal product name
    2mg oral placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg placebo taken 2 hours before planned bedtime

    Number of subjects in period 3
    		Group A Group B
    Started
    27
    27
    Completed
    26
    25
    Not completed
    1
    2
         Consent withdrawn by subject
    1
    2
    Period 4
    Period 4 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Received Melatonin first then placebo after washout period
    Arm type
    		 melatonin first

    Investigational medicinal product name
    2mg oral Circadin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg Circadin taken 2 hours before planned bedtime

    Arm title
    		 Group B
    Arm description
    		 Received Placebo first then melatonin after washout period
    Arm type
    		 receive placebo before active drug

    Investigational medicinal product name
    2mg oral placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg placebo taken 2 hours before planned bedtime

    Number of subjects in period 4
    		Group A Group B
    Started
    26
    25
    Completed
    26
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Received Melatonin first then placebo after washout period

    Reporting group title
    Group B
    Reporting group description
    		 Received Placebo first then melatonin after washout period

    Reporting group values
    		 Group A Group B Total
    Number of subjects
    		 30 30 60
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 19 27 46
        From 65-84 years
    		 11 3 14
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.9 ( 14.03 ) 54.61 ( 11.92 ) -
    Gender categorical
    Units: Subjects
        Female
    		 20 16 36
        Male
    		 10 14 24
    Subject analysis sets

    Subject analysis set title
    DREAM Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    DREAM Per protocol

    Subject analysis set title
    DREAM Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    DREAM intention to treat

    Subject analysis sets values
    		 DREAM Per Protocol DREAM Intention-to-treat
    Number of subjects
    51
    58
    Age categorical
    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)
    42
    44
        From 65-84 years
    9
    14
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    33
    36
        Male
    18
    22

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Received Melatonin first then placebo after washout period

    Reporting group title
    Group B
    Reporting group description
    		 Received Placebo first then melatonin after washout period
    Reporting group title
    Group A
    Reporting group description
    		 Received Melatonin first then placebo after washout period

    Reporting group title
    Group B
    Reporting group description
    		 Received Placebo first then melatonin after washout period
    Reporting group title
    Group A
    Reporting group description
    		 Received Melatonin first then placebo after washout period

    Reporting group title
    Group B
    Reporting group description
    		 Received Placebo first then melatonin after washout period
    Reporting group title
    Group A
    Reporting group description
    		 Received Melatonin first then placebo after washout period

    Reporting group title
    Group B
    Reporting group description
    		 Received Placebo first then melatonin after washout period

    Subject analysis set title
    DREAM Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    DREAM Per protocol

    Subject analysis set title
    DREAM Intention-to-treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    DREAM intention to treat

    Primary: Primary outcome

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    End point title
    		 Primary outcome
    End point description
    End point type
    Primary
    End point timeframe
    The primary outcome measure was VSH sleep disturbance after 6 weeks of treatment.
    End point values
    		 Group A Group B
    Number of subjects analysed
    30
    28
    Units: none
        median (full range (min-max))
    481 (67 to 632)
    409 (122 to 673)
    Statistical analysis title
    		 linear mixed model
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 Hours
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 No dictionary used
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Received Melatonin first then placebo after washout period

    Reporting group title
    Group B
    Reporting group description
    		 Received Placebo first then melatonin after washout period

    Serious adverse events
    		 Group A Group B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 28 (7.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Appendicitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 28 (3.57%)
         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: 5%
    Non-serious adverse events
    		 Group A Group B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 30 (76.67%)
    16 / 28 (57.14%)
    General disorders and administration site conditions
    General physical condition abnormal
         subjects affected / exposed
    23 / 30 (76.67%)
    16 / 28 (57.14%)
         occurrences all number
    23
    16

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38355388
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