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    Clinical Trial Results:
    Diabetic retinopathy: Effects of melatonin treatment on visual functions and circadian rhythm.

    Summary
    EudraCT number
    		 2015-003955-23
    Trial protocol
    		 DK  
    Global end of trial date
    07 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2023
    First version publication date
    20 Mar 2023
    Other versions
    Summary report(s)
    		 Trial summary_Eudract no 2015-003955-23

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DR2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03478306
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet
    Sponsor organisation address
    Valdemar Hansens vej 1-13, Glostrup, Denmark, 2600
    Public contact
    Research laboratory section 37, Dept. of Ophthalmology, Rigshospitalet – Glostrup, +45 31614923, shakoor.ba-ali.04@regionh.dk
    Scientific contact
    Research laboratory section 37, Dept. of Ophthalmology, Rigshospitalet – Glostrup, +45 31614923, shakoor.ba-ali.04@regionh.dk
    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
    26 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effects of melatonin treatment on visual functions and circadian rhythm in diabetic patients with or without diabetic retinopathy.
    Protection of trial subjects
    The physical and mental health of each subject was assessed during each visit, i.e. at basline and after treatments. In addition each subject were consulted through phone calls 3 days after the first treatmente date to assess their physical and mental health. Moreover, blood pressure and puls were measured during each visit. Also, blood tests were taken at baseline and at the end of each trial arms to assess red/white blood count, lever and kidney function.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Mar 2018
    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
    Denmark: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    22
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Diabetic subjects with and without non-proliferative diabetic retinopathy were recruited from march 27th 2018 to april 1st 2021 from Steno Diabetes Center Copenhagen or Department of Ophthalmology Rigshospitalet-Glostrup encompassing the capital region in Denmark

    Pre-assignment
    Screening details
    		 Inclusion Criteria: - Diabetic patients - Age range 40-75 years - Participant should be legally competent Exclusion Criteria: - Other known eye disease. - Eye disease manifestation during ocular examination. - Competing neurologic and systemic conditions affecting retina. - Use of any drugs influencing

    Pre-assignment period milestones
    Number of subjects started
    		 31
    Number of subjects completed
    		 31

    Period 1
    Period 1 title
    Baseline 1
    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 subjects were randomized by a central third party, Glostrup pharmacy.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Baseline 1 for melatonin
    Arm description
    		 Baseline for melatonin group 1st period
    Arm type
    		 Experimental

    Investigational medicinal product name
    Melatonin
    Investigational medicinal product code
    SUB11496MIG
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Basline for melatonin group

    Arm title
    		 Baseline 1 for placebo
    Arm description
    		 Baseline for placebo group 1st period
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Baseline for placebo group

    Number of subjects in period 1
    		Baseline 1 for melatonin Baseline 1 for placebo
    Started
    16
    15
    Completed
    15
    14
    Not completed
    1
    1
         Consent withdrawn by subject
    1
    1
    Period 2
    Period 2 title
    Treatment 1
    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 participants were randomized into two treatment arms by an independent party, Glostrup pharmacy A/S, and the lists of the randomization were keep in a closed envelope, which was locked in a box. The melatonin- and placebo tablets were manufactured by the Glostrup Pharmacy A/S and was identical in form, taste and color. The subjects received a bottle with tablets for each treatment arm. Neither the investigator nor the subjects were aware of the active ingredients of the tablets.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Melatonin 1
    Arm description
    		 Subjects recieved 1 tablet melatonin 4 mg every evening 2 hours before bedtime in 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Melatonin
    Investigational medicinal product code
    SUB11496MIG
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet melatonin 4 mg every evening 2 hours before bedtime in 3 weeks.

    Arm title
    		 Placebo 1
    Arm description
    		 Subjects recieved 1 tablet placebo every evening 2 hours before bedtime in 3 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects recieved 1 tablet placebo every evening 2 hours before bedtime in 3 weeks.

    Number of subjects in period 2
    		Melatonin 1 Placebo 1
    Started
    15
    14
    Completed
    15
    14
    Period 3
    Period 3 title
    Baseline 2
    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
    see previous periods

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Baseline 2 for melatonin
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Baseline 2 for placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet placebo 2 hours before bedtime

    Number of subjects in period 3
    		Baseline 2 for melatonin Baseline 2 for placebo
    Started
    14
    15
    Completed
    14
    15
    Period 4
    Period 4 title
    Treatment 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo 2
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet placebo every evening 2 hours prior to bedtime for 3 weeks.

    Arm title
    		 Melatonin 2
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Melatonin
    Investigational medicinal product code
    SUB11496MIG
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet melatonin 4 mg every evening 2 hours prior to bedtime for 3 weeks.

    Number of subjects in period 4
    		Placebo 2 Melatonin 2
    Started
    15
    14
    Completed
    14
    14
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline 1
    Reporting group description
    		 -

    Reporting group values
    		 Baseline 1 Total
    Number of subjects
    		 31 31
    Age categorical
    Units: Subjects
    Age continuous
    age range 40-74
    Units: years
        arithmetic mean (standard deviation)
    		 61 ± 8 -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 21 21
    BMI
    Units: kilogram(s)/square metre
        arithmetic mean (standard deviation)
    		 29 ± 5 -
    blood pressure systolic
    Units: mmHg
        arithmetic mean (standard deviation)
    		 138 ± 20 -
    Blood pressure - diastolic
    Units: mmHg
        arithmetic mean (standard deviation)
    		 77 ± 10 -
    Alcohol concumption
    Units: unit/week
        arithmetic mean (standard deviation)
    		 7 ± 6 -
    HbA1c
    Units: mmol/mol
        arithmetic mean (standard deviation)
    		 60 ± 15 -
    Glucose
    Plasma glucose level at the visiting day.
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 10 ± 4 -
    Hemoglobin
    plasma hemoglobin level during the visit
    Units: mol/L
        arithmetic mean (standard deviation)
    		 11 ± 11 -
    Albumin
    Plasma albumin level prior to treatment start.
    Units: g/dL
        arithmetic mean (standard deviation)
    		 44 ± 3 -
    Bilirubin
    Plasma bilirubin level prior to treatment start.
    Units: μmol/l
        arithmetic mean (standard deviation)
    		 8 ± 3 -
    ALAT
    Plasma alanintransaminase
    Units: U/L
        arithmetic mean (standard deviation)
    		 31 ± 11 -
    Creatinine
    Units: µmol/L
        arithmetic mean (standard deviation)
    		 82 ± 27 -
    Cholesterol, total
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4 ± 1 -
    HDL
    High Density Lipoprotein Cholesterol level prior to treamtent start.
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.5 ± 0.6 -
    LDL
    Low Density Lipoprotein cholesterol measured prior to treatment start
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.8 ± 1.0 -
    VLDL
    Very Low Density Lipoprotein cholesterol measured prior to treatment start
    Units: mmol/
        arithmetic mean (standard deviation)
    		 0.9 ± 0.4 -
    Triclycerides
    Plasma triglycerides measured prior to treatment start
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.4 ± 1.5 -
    Diabetes duration
    Units: year
        arithmetic mean (standard deviation)
    		 31 ± 10 -
    Visual acuity
    Units: ETDRS
        arithmetic mean (standard deviation)
    		 85.1 ± 6.8 -
    Intraocular pressure (IOP)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 14.1 ± 3.0 -

    End points

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    End points reporting groups
    Reporting group title
    Baseline 1 for melatonin
    Reporting group description
    		 Baseline for melatonin group 1st period

    Reporting group title
    Baseline 1 for placebo
    Reporting group description
    		 Baseline for placebo group 1st period
    Reporting group title
    Melatonin 1
    Reporting group description
    		 Subjects recieved 1 tablet melatonin 4 mg every evening 2 hours before bedtime in 3 weeks.

    Reporting group title
    Placebo 1
    Reporting group description
    		 Subjects recieved 1 tablet placebo every evening 2 hours before bedtime in 3 weeks.
    Reporting group title
    Baseline 2 for melatonin
    Reporting group description
    		 -

    Reporting group title
    Baseline 2 for placebo
    Reporting group description
    		 -
    Reporting group title
    Placebo 2
    Reporting group description
    		 -

    Reporting group title
    Melatonin 2
    Reporting group description
    		 -

    Primary: OP1

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    End point title
    		 OP1
    End point description
    Oscillatory potential 1
    End point type
    Primary
    End point timeframe
    Before treatment
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: μV
        arithmetic mean (standard deviation)
    19 ± 14
    12 ± 5
    19 ± 10
    11 ± 7
    16 ± 8
    19 ± 13
    19 ± 7
    15 ± 4
    Statistical analysis title
    		 Wilcoxon signed-rank test
    Comparison groups
    Melatonin 1 v Placebo 1 v Baseline 1 for melatonin v Baseline 1 for placebo v Baseline 2 for melatonin v Baseline 2 for placebo v Placebo 2 v Melatonin 2
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Primary: OP2

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    End point title
    		 OP2
    End point description
    Oscillatory potential amplitude as measure of the amacrines in retina.
    End point type
    Primary
    End point timeframe
    OP1 measured before (baseline) and after treatment
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: μV
        arithmetic mean (standard deviation)
    60 ± 17
    53 ± 26
    55 ± 28
    53 ± 26
    50 ± 18
    71 ± 28
    59 ± 18
    51 ± 25
    Statistical analysis title
    		 Wilcoxon signed-rank test
    Comparison groups
    Melatonin 1 v Placebo 1 v Baseline 1 for melatonin v Baseline 1 for placebo v Baseline 2 for melatonin v Baseline 2 for placebo v Placebo 2 v Melatonin 2
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Primary: OP3

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    End point title
    		 OP3
    End point description
    Oscillatory potential 2, measured with ff-ERG.
    End point type
    Primary
    End point timeframe
    Befor treatment
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: μV
        arithmetic mean (standard deviation)
    19 ± 13
    23 ± 11
    23 ± 16
    20 ± 14
    23 ± 12
    24 ± 21
    20 ± 12
    24 ± 8
    Statistical analysis title
    		 Wilcoxon signed-rank test
    Comparison groups
    Melatonin 1 v Placebo 1 v Baseline 1 for melatonin v Baseline 1 for placebo v Baseline 2 for melatonin v Baseline 2 for placebo v Placebo 2 v Melatonin 2
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Primary: It1

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    End point title
    		 It1
    End point description
    Implicit time of the 1st amplitude in ff-ERG
    End point type
    Primary
    End point timeframe
    Before and after
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: ms
        arithmetic mean (standard deviation)
    20 ± 1
    19 ± 1
    22 ± 5
    19 ± 1
    20 ± 4
    20 ± 2
    20 ± 1
    20 ± 1
    Statistical analysis title
    		 Wilcoxon signed-rank test
    Comparison groups
    Melatonin 1 v Placebo 1 v Baseline 1 for melatonin v Baseline 1 for placebo v Baseline 2 for melatonin v Baseline 2 for placebo v Placebo 2 v Melatonin 2
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (net)
    Confidence interval
    Variability estimate
    Standard deviation

    Primary: It2

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    End point title
    		 It2
    End point description
    Implicit time of the 1st amplitude in ff-ERG
    End point type
    Primary
    End point timeframe
    Before and after
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: ms
        arithmetic mean (standard deviation)
    27 ± 1
    27 ± 1
    29 ± 4
    27 ± 2
    27 ± 2
    28 ± 1
    28 ± 1
    27 ± 1
    Statistical analysis title
    		 Wilcoxon signed-rank test
    Comparison groups
    Melatonin 1 v Placebo 1 v Baseline 1 for melatonin v Baseline 1 for placebo v Baseline 2 for melatonin v Baseline 2 for placebo v Placebo 2 v Melatonin 2
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Primary: It 3

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    End point title
    		 It 3
    End point description
    Implicit time of the 1st amplitude in ff-ERG
    End point type
    Primary
    End point timeframe
    Before and after
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: ms
        arithmetic mean (standard deviation)
    34 ± 2
    33 ± 1
    35 ± 5
    34 ± 3
    34 ± 4
    34 ± 1
    34 ± 1
    33 ± 1
    Statistical analysis title
    		 Wilcoxon signed-rank test
    Comparison groups
    Melatonin 1 v Placebo 1 v Baseline 1 for melatonin v Baseline 1 for placebo v Baseline 2 for melatonin v Baseline 2 for placebo v Placebo 2 v Melatonin 2
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: DA0.01 b-wave amplitude

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    End point title
    		 DA0.01 b-wave amplitude
    End point description
    Dark adapted b-wave amplitdude (rod bipolar cells) measured with ERG.
    End point type
    Secondary
    End point timeframe
    Measured before and after treatment
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: μV
        arithmetic mean (standard deviation)
    138 ± 57
    171 ± 118
    159 ± 74
    192 ± 80
    139 ± 46
    184 ± 92
    163 ± 62
    152 ± 52
    No statistical analyses for this end point

    Secondary: DA0.01 b-wave implicit time

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    End point title
    		 DA0.01 b-wave implicit time
    End point description
    Dark adapted b-wave amplitude (rod bipolar cells) measured with ERG (DA0.01 b-wave implicit time)
    End point type
    Secondary
    End point timeframe
    Measured before and after treatment
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: ms
        arithmetic mean (standard deviation)
    138 ± 57
    94 ± 21
    93 ± 12
    97 ± 8
    99 ± 8
    95 ± 13
    94 ± 10
    93 ± 11
    No statistical analyses for this end point

    Secondary: LA3.0 a-wave amplitude

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    End point title
    		 LA3.0 a-wave amplitude
    End point description
    Light adapted a-wave amplitude (cone bipolar cells) measured with ERG (LA3.0 a-wave amplitude)
    End point type
    Secondary
    End point timeframe
    Measured before and after
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: μV
        arithmetic mean (standard deviation)
    24 ± 12
    20 ± 8
    28 ± 16
    22 ± 8
    20 ± 6
    24 ± 9
    25 ± 8
    20 ± 8
    No statistical analyses for this end point

    Secondary: LA3.0 a-wave implicit time

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    End point title
    		 LA3.0 a-wave implicit time
    End point description
    Light adapted a-wave implicit time measured with ERG.
    End point type
    Secondary
    End point timeframe
    Measured before and after
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: ms
        arithmetic mean (standard deviation)
    15 ± 1
    15 ± 1
    16 ± 1
    15 ± 1
    14 ± 2
    15 ± 1
    15 ± 2
    15 ± 1
    No statistical analyses for this end point

    Secondary: Pupil size

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    End point title
    		 Pupil size
    End point description
    Pupillary size (mm) prior to light stimulation, measured with pupillometry.
    End point type
    Secondary
    End point timeframe
    measured before and after
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: mm
        arithmetic mean (standard deviation)
    5.7 ± 0.8
    5.6 ± 1.0
    5.8 ± 0.9
    5.6 ± 0.9
    6.0 ± 1.0
    5.7 ± 0.8
    5.7 ± 0.9
    5.8 ± 1.2
    No statistical analyses for this end point

    Secondary: Maximal pupillary contraction

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    End point title
    		 Maximal pupillary contraction
    End point description
    Maximal pupillary contraktion in relation to baseline pupillary light size durin glight stimulation. Measured with pupillometer.
    End point type
    Secondary
    End point timeframe
    Measured before and after
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: ratio
        arithmetic mean (standard deviation)
    0.6 ± 0.1
    0.6 ± 0.0
    0.6 ± 0.0
    0.6 ± 0.1
    0.6 ± 0.1
    0.6 ± 0.0
    0.6 ± 0.0
    0.6 ± 0.1
    No statistical analyses for this end point

    Secondary: PIPR_early

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    End point title
    		 PIPR_early
    End point description
    Pupillary contraktion measured 0-10 seconds after termination of blue light stimuli in 20 seconds. Measured with pupillometer.
    End point type
    Secondary
    End point timeframe
    Measured before and after
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: ratio
        arithmetic mean (standard deviation)
    0.5 ± 0.1
    0.4 ± 0.1
    0.5 ± 0.1
    0.4 ± 0.1
    0.4 ± 0.1
    0.5 ± 0.1
    0.4 ± 0.1
    0.4 ± 0.1
    No statistical analyses for this end point

    Secondary: PIPR_late

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    End point title
    		 PIPR_late
    End point description
    Pupillary contraktion measured 10-20 seconds after termination of blue light stimuli in 20 seconds. Measured with pupillometer.
    End point type
    Secondary
    End point timeframe
    Measured before and after treatment
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: ratio
        arithmetic mean (standard deviation)
    0.4 ± 0.1
    0.4 ± 0.1
    0.4 ± 0.1
    0.1 ± 0.1
    0.1 ± 0.1
    0.4 ± 0.1
    0.4 ± 0.1
    0.3 ± 0.1
    No statistical analyses for this end point

    Secondary: PSQI global score

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    End point title
    		 PSQI global score
    End point description
    End point type
    Secondary
    End point timeframe
    Befor and after treatment
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: Global score
        arithmetic mean (standard deviation)
    5.2 ± 3.2
    4.1 ± 3.5
    6.4 ± 3.0
    5.1 ± 3.5
    3.8 ± 2.6
    6.0 ± 3.6
    4.8 ± 3.1
    4.3 ± 3.4
    No statistical analyses for this end point

    Secondary: Melatonin at 04:00 AM

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    End point title
    		 Melatonin at 04:00 AM
    End point description
    Salivary melatonin level measured at 04:00 AM
    End point type
    Secondary
    End point timeframe
    Measured at 04:00 AM befor and after treatment.
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: Pg/mL
        arithmetic mean (standard deviation)
    35.5 ± 43.5
    10.6 ± 14.7
    7.0 ± 12.8
    4.4 ± 4.2
    5.2 ± 7.4
    11.3 ± 14.7
    7.0 ± 12.7
    26.7 ± 18.6
    No statistical analyses for this end point

    Secondary: p-Glucose at 04:00 AM

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    End point title
    		 p-Glucose at 04:00 AM
    End point description
    End point type
    Secondary
    End point timeframe
    Capillary glucose level measured at 04:00 AM
    End point values
    		 Melatonin 1 Placebo 1 Baseline 1 for melatonin Baseline 1 for placebo Baseline 2 for melatonin Baseline 2 for placebo Placebo 2 Melatonin 2
    Number of subjects analysed
    15
    14
    16
    15
    14
    15
    14
    14
    Units: mmol/L
        arithmetic mean (standard deviation)
    7.2 ± 1.9
    8.2 ± 3.7
    7.6 ± 2.5
    8.2 ± 2.2
    9.0 ± 3.9
    7.0 ± 2.4
    7.4 ± 1.5
    9.0 ± 3.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    No serious adverse events (SAE) or Serious Adverse (Drug) Reaction (SAR) were observed
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Annual report
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 1%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non-serious adverse events recorded for these results.

    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? Yes
    Date
    Interruption
    Restart date
    14 Nov 2019
    The recruitment process was interrupted by Danish Medicines Agency due to suspicious laboratory analysis in the process of melatonin production by our external lab-analyse provider. After further investigation the Danish Medicines Agency found that the lab-analysis was conducted properly, and the research was allowed to restart.
    09 Mar 2020

    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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