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    Clinical Trial Results:
    The effect of MElatonin on Depression, Anxiety, CIrcadian and Sleep disturbances in patients after acute myocardial syndrome

    Summary
    EudraCT number
    		 2015-002116-32
    Trial protocol
    		 DK  
    Global end of trial date
    15 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2021
    First version publication date
    04 Mar 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MTM-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02451293
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Center for Surgical Science, Department of Surgery Zealand University Hospital, Køge
    Sponsor organisation address
    Lykkebækvej 1, Køge, Denmark, 4600
    Public contact
    Michael Tvilling Madsen, Zealand University Hospital, +4500 27857247, michael_madsen88@hotmail.com
    Scientific contact
    Michael Tvilling Madsen, Zealand University Hospital, +4500 27857247, michael_madsen88@hotmail.com
    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
    01 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study is to investigate whether prophylactic treatment with melatonin has an effect on depressive symptoms.
    Protection of trial subjects
    Participants were monitored with questionnaires throughout the trial and no harm came to the patient in relation to this outcome assessment beside the time used to fill out the questionnaires. Patients had their blood drawn three times throughout the trial, which was associated with minimal discomfort. Furthermore, non-invasive active monitor so called Actigraph was applied to the patient for a two-week period. The discomfort related to this is equivalent to wearing a wrist worn watch.
    Background therapy
    		 Patients were treated according to the national Danish guidelines for acute coronary syndrom (https://nbv.cardio.dk/aks) and cardiac rehabilitation (https://nbv.cardio.dk/hjerterehabilitering).
    Evidence for comparator
    		 Since there is no usual care for prevention of depression following acute coronary syndrome the comparator was a placebo pill. It is common practice in double-blinded randomized trials to apply placebo pill in the current context.
    Actual start date of recruitment
    18 Jan 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
    Denmark: 252
    Worldwide total number of subjects
    252
    EEA total number of subjects
    252
    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)
    138
    From 65 to 84 years
    110
    85 years and over
    4

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment were performed on 5 clinical departments of cardiology at Zealand, Denmark. Patients were contacted following admission for ACS before discharge and follow-up contact were made during cardiac rehabilitation during the outpatient clinic. First data of were conducted in Februar 2016 and last inclusion was in May 2017.

    Pre-assignment
    Screening details
    		 Screening was performed during weekdays at each department by study investigator. If patients were eligible patients at during primary admissions. Contact information were exchanged for later contact to plan potential inclusion depending on patient consent. . If patient were interest an inclusion interview was planned during outpatient visit.

    Pre-assignment period milestones
    Number of subjects started
    		 252
    Number of subjects completed
    		 252

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The Regional Pharmacy in Region Zealand Denmark handled randomization and allocation concealment. A randomization was produced by applying online software (http://www.randomization.com/) and used a 1:1 allocation in blocks containing six participants (3 melatonin and 3 placebo). To assure allocation concealment during the trial the Regional Pharmacy produced two sets of coded envelopes (an opaque, sealed envelope for each patient, containing the randomization code for each patient).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Melatonin 25 mg
    Arm description
    		 25 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bio-Melatonin
    Investigational medicinal product code
    ATC: NO5CH01
    Other name
    Marketing authorisation number - OGYI-T-8974/01/02/03, CAS 73-31-4
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 12,5 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablet (oral) administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PL1
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 12,5 mg placebo oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks.

    Number of subjects in period 1
    		Melatonin 25 mg Placebo
    Started
    126
    126
    Completed
    126
    126
    Period 2
    Period 2 title
    Day 14
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The Regional Pharmacy in Region Zealand Denmark handled randomization and allocation concealment. A randomization was produced by applying online software (http://www.randomization.com/) and used a 1:1 allocation in blocks containing six participants (3 melatonin and 3 placebo). To assure allocation concealment during the trial the Regional Pharmacy produced two sets of coded envelopes (an opaque, sealed envelope for each patient, containing the randomization code for each patient).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Melatonin 25 mg
    Arm description
    		 25 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bio-Melatonin
    Investigational medicinal product code
    ATC: NO5CH01
    Other name
    Marketing authorisation number - OGYI-T-8974/01/02/03, CAS 73-31-4
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 12,5 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablet (oral) administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PL1
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 12,5 mg placebo oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks.

    Number of subjects in period 2
    		Melatonin 25 mg Placebo
    Started
    126
    126
    Completed
    116
    121
    Not completed
    10
    5
         Consent withdrawn by subject
    5
    3
         Other trial
    1
    -
         Adverse event, non-fatal
    3
    1
         Prolonged hospitalization
    1
    -
         Coronary artery bypass graft
    -
    1
    Period 3
    Period 3 title
    Day 84
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The Regional Pharmacy in Region Zealand Denmark handled randomization and allocation concealment. A randomization was produced by applying online software (http://www.randomization.com/) and used a 1:1 allocation in blocks containing six participants (3 melatonin and 3 placebo). To assure allocation concealment during the trial the Regional Pharmacy produced two sets of coded envelopes (an opaque, sealed envelope for each patient, containing the randomization code for each patient).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Melatonin 25 mg
    Arm description
    		 25 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bio-Melatonin
    Investigational medicinal product code
    ATC: NO5CH01
    Other name
    Marketing authorisation number - OGYI-T-8974/01/02/03, CAS 73-31-4
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 12,5 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablet (oral) administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PL1
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 12,5 mg placebo oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks.

    Number of subjects in period 3
    		Melatonin 25 mg Placebo
    Started
    116
    121
    Completed
    107
    117
    Not completed
    9
    4
         Consent withdrawn by subject
    4
    2
         Adverse event, non-fatal
    1
    1
         Prolonged hospitalization
    1
    -
         Acute myocardial infaction
    2
    -
         Depression
    1
    -
         Acute myocardial infarction
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Melatonin 25 mg
    Reporting group description
    		 25 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet (oral) administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.

    Reporting group values
    		 Melatonin 25 mg Placebo Total
    Number of subjects
    		 126 126 252
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.9 ( 11.32 ) 62.10 ( 10.81 ) -
    Gender categorical
    Units: Subjects
        Female
    		 31 25 56
        Male
    		 95 101 196
    Family history of mental disorder
    Units: Subjects
        Yes
    		 22 25 47
        No
    		 104 101 205
    Cardiac diagnosis
    Type of acute coronary syndrome
    Units: Subjects
        STEMI
    		 53 62 115
        NSTEMI
    		 66 58 124
        UAP
    		 7 6 13
    Percutaneus coronary intervention
    Units: Subjects
        Yes
    		 98 99 197
        No
    		 28 27 55
    NYHA Class
    Units: Subjects
        NYHA I
    		 86 92 178
        NYHA II
    		 34 32 66
        NYHA III
    		 6 2 8
    Medicine compliance day 14
    Medicine compliance above 75% at day 14
    Units: Subjects
        Above 75%
    		 116 121 237
        Below 75%
    		 10 5 15
    Medicine compliance day 84
    Medicine compliance above 75% at day 84
    Units: Subjects
        Below 75%
    		 19 13 32
        Above 75%
    		 107 113 220

    End points

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    End points reporting groups
    Reporting group title
    Melatonin 25 mg
    Reporting group description
    		 25 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet (oral) administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.
    Reporting group title
    Melatonin 25 mg
    Reporting group description
    		 25 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet (oral) administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.
    Reporting group title
    Melatonin 25 mg
    Reporting group description
    		 25 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet (oral) administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.

    Primary: Major Depression Inventory

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    End point title
    		 Major Depression Inventory
    End point description
    The primary outcome of the trial was the Major Depressive Inventory (MDI) and is a self-rating scale consisting of 12 questions covering the ICD-10 criteria of depression. The MDI has a maximum score of 50 points indicating a maximum number of depressive symptoms. Each question supplies between 0 or 5 points; however, for subsets of question 8 and 10 (restlessness/subdued and appetite) only the highest score counts.
    End point type
    Primary
    End point timeframe
    Day 0, Day 14 and Day 84.
    End point values
    		 Melatonin 25 mg Placebo Melatonin 25 mg Placebo Melatonin 25 mg Placebo
    Number of subjects analysed
    126
    126
    116
    121
    107
    117
    Units: Points
        arithmetic mean (confidence interval 95%)
    6.18 (5.32 to 7.05)
    5.98 (5.19 to 6.77)
    5.95 (5.02 to 6.87)
    5.10 (4.30 to 5.80)
    3.54 (2.76 to 4.32)
    4.10 (3.23 to 4.97)
    Statistical analysis title
    		 Students T-test - unpaired
    Statistical analysis description
    intergroups comparison at earch period 1-3.
    Comparison groups
    Melatonin 25 mg v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Primary: Major depression inventory (Depression Yes/No)

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    End point title
    		 Major depression inventory (Depression Yes/No)
    End point description
    Depression (MDI score≥21) during follow-up during the MEDACIS trial on available data
    End point type
    Primary
    End point timeframe
    Day 0, Day 14 and Day 84.
    End point values
    		 Melatonin 25 mg Placebo Melatonin 25 mg Placebo Melatonin 25 mg Placebo
    Number of subjects analysed
    126
    126
    121
    116
    107
    117
    Units: Depression
        Depression
    0
    0
    2
    0
    1
    2
        No depression
    126
    126
    114
    121
    107
    117
    Statistical analysis title
    		 Fischers exact test
    Statistical analysis description
    Fischers exact test at period 1-3
    Comparison groups
    Melatonin 25 mg v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Fisher exact
    Parameter type
    		 number of events
    Confidence interval

    Secondary: Hospital Anxiety and depression scale - Anxiety

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    End point title
    		 Hospital Anxiety and depression scale - Anxiety
    End point description
    The Hospital Anxiety and Depression Scale (HADS) was administered in the current trial three times (at baseline, 2 and 12 weeks) (Zigmond and Snaith, 1983). The HADS was developed as a screening tool for anxiety and depression in a hospital setting and supplies a score of 0–21. A cut-off of 8 points or higher on the HADS-D or HADS-A subscales gives a sensitivity and specificity of 0.8, and this cut-off was applied in the current study.
    End point type
    Secondary
    End point timeframe
    Day 0, Day 14 and Day 84
    End point values
    		 Melatonin 25 mg Placebo Melatonin 25 mg Placebo Melatonin 25 mg Placebo
    Number of subjects analysed
    126
    126
    116
    121
    107
    107
    Units: Points
        arithmetic mean (confidence interval 95%)
    2.98 (2.50 to 3.46)
    2.81 (2.28 to 3.34)
    2.53 (2.01 to 3.06)
    2.39 (1.86 to 2.93)
    1.75 (1.19 to 2.03)
    2.28 (1.68 to 2.87)
    No statistical analyses for this end point

    Secondary: Hospital Anxiety and depression scale - Depression

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    End point title
    		 Hospital Anxiety and depression scale - Depression
    End point description
    The Hospital Anxiety and Depression Scale (HADS) was administered in the current trial three times (at baseline, 2 and 12 weeks) (Zigmond and Snaith, 1983). The HADS was developed as a screening tool for anxiety and depression in a hospital setting and supplies a score of 0–21. A cut-off of 8 points or higher on the HADS-D or HADS-A subscales gives a sensitivity and specificity of 0.8, and this cut-off was applied in the current study.
    End point type
    Secondary
    End point timeframe
    Day 0, Day 14 and Day 84
    End point values
    		 Melatonin 25 mg Placebo Melatonin 25 mg Placebo Melatonin 25 mg Placebo
    Number of subjects analysed
    126
    126
    116
    121
    107
    117
    Units: Point
        arithmetic mean (confidence interval 95%)
    1.68 (1.31 to 2.05)
    1.35 (1.00 to 1.70)
    1.61 (1.19 to 2.03)
    1.11 (0.76 to 1.47)
    1.19 (0.80 to 1.57)
    1.48 (1.09 to 1.88)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported during the conduct of the trial and until 24 hours after intake of last study medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Melatonin 25 mg
    Reporting group description
    		 25 mg melatonin oral tablet administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet (oral) administered approximately 1 hour before bedtime for a duration of 12 weeks following acute coronary syndrome.

    Serious adverse events
    		 Melatonin 25 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 126 (13.49%)
    18 / 126 (14.29%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Cerebral ischaemia
    Additional description: Transitory cerebral ischaemia
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
    Additional description: NSTEMI during the conduct of the trial
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 126 (1.59%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anginal equivalent
    Additional description: Admission of suspected acute myocardial infarction
         subjects affected / exposed
    2 / 126 (1.59%)
    6 / 126 (4.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 126 (0.79%)
    3 / 126 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery bypass
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    3 / 126 (2.38%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    10 / 126 (7.94%)
    15 / 126 (11.90%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (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
    Gout
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Discomfort
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep disorder
         subjects affected / exposed
    11 / 126 (8.73%)
    9 / 126 (7.14%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle discomfort
         subjects affected / exposed
    13 / 126 (10.32%)
    16 / 126 (12.70%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry mouth
         subjects affected / exposed
    12 / 126 (9.52%)
    7 / 126 (5.56%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulitis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    15 / 126 (11.90%)
    12 / 126 (9.52%)
         occurrences causally related to treatment / all
    0 / 27
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    3 / 126 (2.38%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 126 (0.00%)
    3 / 126 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    9 / 126 (7.14%)
    11 / 126 (8.73%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Melatonin 25 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 126 (11.11%)
    18 / 126 (14.29%)
    Cardiac disorders
    Orthostatic hypotension
         subjects affected / exposed
    5 / 126 (3.97%)
    4 / 126 (3.17%)
         occurrences all number
    5
    4
    Nervous system disorders
    Sleep deficit
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 126 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 126 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    6 / 126 (4.76%)
    2 / 126 (1.59%)
         occurrences all number
    6
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Itching scar
         subjects affected / exposed
    1 / 126 (0.79%)
    8 / 126 (6.35%)
         occurrences all number
    1
    8
    Rash
         subjects affected / exposed
    3 / 126 (2.38%)
    2 / 126 (1.59%)
         occurrences all number
    3
    2

    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/31586772
    http://www.ncbi.nlm.nih.gov/pubmed/31355944
    http://www.ncbi.nlm.nih.gov/pubmed/28228148
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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