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    Clinical Trial Results:
    PHASE II CLINICAL TRIAL, SINGLE-BLIND, RANDOMIZED, PLACEBO CONTROLLED TO EXPLORE THE EFFECTIVENESS AND SAFETY OF MELATONIN I.V. IN PATIENTS WITH COVID-19 ENTERED INTO THE ICU (MELCOVID STUDY)

    Summary
    EudraCT number
    2020-001808-42
    Trial protocol
    ES  
    Global end of trial date
    06 Feb 2021

    Results information
    Results version number
    v2(current)
    This version publication date
    03 Dec 2021
    First version publication date
    07 Nov 2021
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    To clarify that the last patient in the study was hospitalized during a long time. It has to be noted that if this last patient is excluded from analysis, the mean total time of hospital admission among survivors was numerically lower in the melatonin group than the placebo group (44.8 vs 59.6 days)

    Trial information

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    Trial identification
    Sponsor protocol code
    PHM-2020-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04568863
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    PHARMAMEL S.L.
    Sponsor organisation address
    Gran Vía 48, 7th floor, Granada, Spain, 18071
    Public contact
    Germaine Escames, PHARMAMEL S.L. (Centro de Transferencia Tecnológica), 34 618 521 646, gescames@ugr.es
    Scientific contact
    Germaine Escames, PHARMAMEL S.L. (Centro de Transferencia Tecnológica), 34 618 521 646, gescames@ugr.es
    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 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate whether intravenous (IV) melatonin treatment reduces mortality in patients with COVID-19 admitted to the Intensive care unit (ICU).
    Protection of trial subjects
    Patients were free to discontinue their participation in the study at any time. Withdrawal from the study did not affect or prejudice the patient’s further treatment. Patients could be withdrawn from study treatment and assessments at any time, if deemed necessary by the Investigator. Patients suspended study therapy and/or withdrew from the same for the following reasons: • Withdrawal of informed consent (decision of the patient to withdraw regardless of the reason). • Unacceptable toxicity • Disease progression which, in the investigator's opinion, did not allow the patient to continue in the study. • The patient did not comply with the protocol, treatment or monitoring requirements. • Any other reason to interrupt the treatment which, in the opinion of the investigator, was the best for the patient. • Any clinical adverse event, test anomaly or breakthrough disease which, in the opinion of the investigator, indicated that continuing treatment with such therapy and with participation in the study was not in the best interest of the patient. • Completion of the study by the research team.
    Background therapy
    All included patients received standard-of-care (SOC) treatment defined by the protocol in force at the centre at the time of study initiation.
    Evidence for comparator
    Not applicable.
    Actual start date of recruitment
    15 Aug 2020
    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
    Spain: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    12
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This was a national study with all patients being included at one Spanish site. Eighteen patients signed the ICF and were assessed for eligibility. There were no screening failures. The included patients (n=18) were randomized 2:1 in the study and received treatment as follows: melatonin (n=12) and placebo (n=6).

    Pre-assignment
    Screening details
    Adults infected by SARS-CoV-2 admitted to the ICU for less than 7 days and without signs of improvement in respiratory failure weere included. Patients were excluded if they were included in another COVID-19 study, had liver transaminases >5 times the ULN, stage IV kidney failure or were on dialysis, pregnancy, terminal illness, autoimmune disease

    Period 1
    Period 1 title
    Study period (overall 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
    Non-study staff prepared the unmasked randomization codes, designed so that patients were assigned proportionally 2:1 to the experimental group or the control group respectively. They also prepared sealed envelopes containing the unmasked randomization code. The research team was provided with a list of masked randomization codes, so that the research staff assigned each eligible patient, in order of inclusion, a masked randomization code.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Melatonin
    Arm description
    This arm included all patients who were randomized to melatonin. The patients included in the study were administered the assigned treatment for up to 7 days, unless any of the following events occurred: discharge of the ICU patient, death of the patient, unacceptable toxicity or ustified treatment interruption according to the researcher's criteria.
    Arm type
    Experimental

    Investigational medicinal product name
    Melatonin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The experimental treatment was melatonin 6 mg/mL solution for injection/infusion. The study medication was administered intravenously by the ICU health personnel in charge of the patient. Melatonin was administered according to the established guideline based on weight: 5 mg/kg current weight/day divided into 4 doses a day (1 dose/6hrs) and with a maximum daily dose of 500 mg. After the first 3 days of treatment, three intensive care physicians in charge of the patient decided whether to extend the treatment until day 6 of the study (total of 7 days of treatment) based on the patient's clinical evaluation.

    Arm title
    Placebo
    Arm description
    This arm included all patients who were randomized to placebo. The patients included in the study were administered the assigned treatment for up to 7 days, unless any of the following events occurred: discharge of the ICU patient, death of the patient, unacceptable toxicity or ustified treatment interruption according to the researcher's criteria.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients included in the placebo group received placebo according to their weight: 5 mg/kg current weight/day divided into 4 doses a day (1 dose/6hrs). The study medication was administered intravenously by the ICU health personnel in charge of the patient. After the first 3 days of treatment, three intensive care physicians in charge of the patient decided whether to extend the treatment until day 6 of the study (total of 7 days of treatment) based on the patient's clinical evaluation.

    Number of subjects in period 1
    Melatonin Placebo
    Started
    12
    6
    Completed
    12
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Melatonin
    Reporting group description
    This arm included all patients who were randomized to melatonin. The patients included in the study were administered the assigned treatment for up to 7 days, unless any of the following events occurred: discharge of the ICU patient, death of the patient, unacceptable toxicity or ustified treatment interruption according to the researcher's criteria.

    Reporting group title
    Placebo
    Reporting group description
    This arm included all patients who were randomized to placebo. The patients included in the study were administered the assigned treatment for up to 7 days, unless any of the following events occurred: discharge of the ICU patient, death of the patient, unacceptable toxicity or ustified treatment interruption according to the researcher's criteria.

    Reporting group values
    Melatonin Placebo Total
    Number of subjects
    12 6 18
    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)
    8 4 12
        From 65-84 years
    4 2 6
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.5 ± 9.73 62.8 ± 11.11 -
    Gender categorical
    Units: Subjects
        Female
    5 2 7
        Male
    7 4 11
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    6 2 8
        Not Hispanic or Latino
    6 4 10
    Race
    Units: Subjects
        White
    12 6 18
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    80.8 ± 17.30 84.7 ± 26.92 -
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    169.3 ± 10.26 169.8 ± 12.89 -
    Body Mass Index (BMI)
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    28.0 ± 4.37 28.9 ± 6.71 -

    End points

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    End points reporting groups
    Reporting group title
    Melatonin
    Reporting group description
    This arm included all patients who were randomized to melatonin. The patients included in the study were administered the assigned treatment for up to 7 days, unless any of the following events occurred: discharge of the ICU patient, death of the patient, unacceptable toxicity or ustified treatment interruption according to the researcher's criteria.

    Reporting group title
    Placebo
    Reporting group description
    This arm included all patients who were randomized to placebo. The patients included in the study were administered the assigned treatment for up to 7 days, unless any of the following events occurred: discharge of the ICU patient, death of the patient, unacceptable toxicity or ustified treatment interruption according to the researcher's criteria.

    Primary: Mortality frequencies

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    End point title
    Mortality frequencies
    End point description
    The absolute and relative frequency of deaths in the study was tabulated by treatment group with the 95%CI of the percentages. There were a total of 6 deaths, 5 deaths in the melatonin group and 1 death in the placebo group. Three of them (2 in the melatonin group and 1 in the placebo group) occurred out of the study period.
    End point type
    Primary
    End point timeframe
    From ICF signature until the end of the study.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12
    6
    Units: Percentage of deaths
    number (confidence interval 95%)
        Number of deaths
    41.7 (15.17 to 72.33)
    16.7 (0.42 to 64.12)
    Statistical analysis title
    Fisher's exact test
    Statistical analysis description
    Fisher's exact test was used to investigate whether there was a difference between treatment groups in the proportion of deaths.
    Comparison groups
    Melatonin v Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.6
    Method
    Fisher exact
    Confidence interval

    Primary: Causes of death

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    End point title
    Causes of death [1]
    End point description
    End point type
    Primary
    End point timeframe
    From ICF signature until the end of the study.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Causes of death were reported by treatment group. No statistical analysis was performed.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    5
    1
    Units: Subjects
        Haemorrhage intracranial
    1
    0
        Multiple organ dysfunction syndrome
    2
    0
        Unknown (deaths occurred out of the study period)
    2
    1
    No statistical analyses for this end point

    Primary: Overall survival

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    End point title
    Overall survival
    End point description
    The Kaplan-Meyer method for overall survival (OS) was performed to test the differences of the experimental treatment over placebo. OS was calculated in days as the time from the day of administration of the first dose of IV melatonin or IV placebo until the date of death due to any cause. For patients alive at the time of the analysis or if lost to follow up, the date of death was censored on the last date the patients were known to be alive.
    End point type
    Primary
    End point timeframe
    From ICF signature until the end of the study.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12
    6
    Units: Percentage of subects
    number (confidence interval 95%)
        0 day
    100.0 (100.0 to 100.0)
    100.0 (100.0 to 100.0)
        10 days
    91.7 (53.9 to 98.8)
    100.0 (100.0 to 100.0)
        20 days
    83.3 (48.2 to 95.6)
    100.0 (100.0 to 100.0)
        30 days
    74.1 (39.1 to 90.9)
    100.0 (100.0 to 100.0)
        40 days
    63.5 (28.9 to 84.7)
    80.0 (20.4 to 96.9)
        50 days
    63.5 (28.9 to 84.7)
    80.0 (20.4 to 96.9)
        60 days
    63.5 (28.9 to 84.7)
    80.0 (20.4 to 96.9)
        70 days
    63.5 (28.9 to 84.7)
    80.0 (20.4 to 96.9)
        80 days
    63.5 (28.9 to 84.7)
    0 (0 to 0)
        90 days
    63.5 (28.9 to 84.7)
    0 (0 to 0)
        100 days
    63.5 (28.9 to 84.7)
    0 (0 to 0)
        110 days
    63.5 (28.9 to 84.7)
    0 (0 to 0)
        120 days
    31.7 (1.7 to 72.5)
    0 (0 to 0)
        130 days
    31.7 (1.7 to 72.5)
    0 (0 to 0)
    Statistical analysis title
    Log-rank test
    Statistical analysis description
    Log rank test was performed to test the differences between the treatment groups.
    Comparison groups
    Melatonin v Placebo
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.427
    Method
    Logrank
    Confidence interval

    Secondary: Length of ICU admission

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    End point title
    Length of ICU admission
    End point description
    ICUBSS= ICU admission time before the study start in days; ICUT=Total ICU admission time in days.
    End point type
    Secondary
    End point timeframe
    ICUBSS, period from date of ICU admission until the date of first treatment study administration; ICUT, from the ICU admission date until the end of the study.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12 [2]
    6 [3]
    Units: day
    arithmetic mean (standard deviation)
        ICUBSS (Death=No)
    6.0 ± 1.15
    5.2 ± 1.79
        ICUBSS (Death=Yes)
    3.2 ± 2.17
    6.0 ± 0
        ICUT (Death=No)
    37.3 ± 32.59
    34.8 ± 23.70
        ICUT (Death=Yes)
    43.4 ± 43.33
    43.0 ± 0
    Notes
    [2] - Death=No (7 subjects); Death=Yes (5 subjects)
    [3] - Death=No (5 subjects); Death=Yes (1 subject)
    No statistical analyses for this end point

    Secondary: Length of Hospital admission

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    End point title
    Length of Hospital admission
    End point description
    THA= Total time of hospital admission in days. It has to be noted that if the last patient is excluded from analysis (i.e., the last patient was hospitalized during a long time), the mean total time of hospital admission among survivors was numerically lower in the melatonin group than the placebo group (44.8 vs 59.6 days).
    End point type
    Secondary
    End point timeframe
    From the calendar day of hospitalization until the date of hospital discharge.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12 [4]
    6 [5]
    Units: day
    arithmetic mean (standard deviation)
        THA (Death=No)
    60.1 ± 45.11
    59.6 ± 25.34
        THA (Death=Yes)
    48.2 ± 44.43
    48.0 ± 0
    Notes
    [4] - Death=No (7 subjects); Death=Yes (5 subjects)
    [5] - Death=No (5 subjects); Death=Yes (1 subject)
    No statistical analyses for this end point

    Secondary: Duration of mechanical ventilation (MV)

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    End point title
    Duration of mechanical ventilation (MV)
    End point description
    TMVBSS = Time with mechanical ventilation before the start of the study in days; TFMV = Time free of mechanical ventilation in days. The total time with MV was tabulated by the type of MV.
    End point type
    Secondary
    End point timeframe
    TMVBSS, from the date with MV before the 1st administration of study drug until the date of 1st administration of study drug. TFMV, cumulative time during study. Total time with MV, start/end dates reported in the ‘Mechanical ventilation’ CRF module.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12 [6]
    6 [7]
    Units: day
    arithmetic mean (standard deviation)
        TMVBSS (Death=No)
    5.7 ± 1.60
    4.8 ± 2.49
        TMVBSS (Death=Yes)
    3.3 ± 1.89
    6.0 ± 0
        TFMV (Death=No)
    40.9 ± 17.93
    24.4 ± 11.08
        TFMV (Death=Yes)
    0.0 ± 0.00
    0.0 ± 0.00
        Duration of invasive MVs (Death=No)
    21.3 ± 19.00
    27.6 ± 20.76
        Duration of invasive MVs (Death=Yes)
    41.2 ± 44.80
    18.0 ± 18.38
        Duration of non-invasive MVs (Death=No)
    16.5 ± 20.51
    9.0 ± 0
        Duration of non-invasive MVs (Death=Yes)
    0 ± 0
    2.0 ± 0
    Attachments
    Mean Days of MV Items (Alive Patients; n=12)
    Notes
    [6] - Death=No (7 subjects); Death=Yes (5 subjects). Missings: n=1 (TMVBSS, Death=Yes).
    [7] - Death=No (5 subjects); Death=Yes (1 subject)
    No statistical analyses for this end point

    Secondary: Change in the score on the SOFA scale

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    End point title
    Change in the score on the SOFA scale
    End point description
    The SOFA scale score numerically quantified the number and severity of failed organs. Final visit performed before day 28 that was recorded in 'Final Visit - Day 28' has been included in the subsequent visit to the last visit performed.
    End point type
    Secondary
    End point timeframe
    Score on the SOFA scale at days 0, 1, 3, 7, 14, 21 and 28.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12 [8]
    6 [9]
    Units: SOFA score (absolute value)
    arithmetic mean (standard deviation)
        Screening - Day 0
    3.8 ± 1.47
    4.8 ± 1.33
        Visit 1 - Day 1
    4.3 ± 2.02
    5.2 ± 1.72
        Visit 2 - Day 3
    4.8 ± 2.09
    5.0 ± 1.67
        Visit 3 - Day 7
    6.3 ± 4.36
    4.3 ± 3.01
        Visit 4 - Day 14
    4.6 ± 2.91
    6.8 ± 2.22
        Visit 5 - Day 21
    5.6 ± 4.27
    6.3 ± 2.06
        Visit Day 28
    4.5 ± 1.29
    4.5 ± 2.38
    Notes
    [8] - Day 0 (n=12), Day 1 (n=12), Day 3 (n=12), Day 7 (n=12), Day 14 (n=10), Day 21 (n=8) and Day 28 (n=4)
    [9] - Day 0 (n=6), Day 1 (n=6), Day 3 (n=6), Day 7 (n=6), Day 14 (n=4), Day 21 (n=4) and Day 28 (n=4)
    No statistical analyses for this end point

    Secondary: Change in the score on the MURRAY scale

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    End point title
    Change in the score on the MURRAY scale
    End point description
    Final visit performed before day 28 that was recorded in 'Final Visit - Day 28' has been included in the subsequent visit to the last visit performed.
    End point type
    Secondary
    End point timeframe
    Score on the MURRAY scale at days 0, 1, 3, 7, 14, 21 and 28.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12 [10]
    6 [11]
    Units: MURRAY score (absolute value)
    arithmetic mean (standard deviation)
        Screening - Day 0
    2.47 ± 0.281
    2.72 ± 0.248
        Visit 1 - Day 1
    2.65 ± 0.582
    2.44 ± 0.364
        Visit 2 - Day 3
    2.47 ± 0.491
    2.15 ± 0.508
        Visit 3 - Day 7
    2.37 ± 0.692
    1.98 ± 1.288
        Visit 4 - Day 14
    2.35 ± 1.019
    2.83 ± 0.236
        Visit 5 - Day 21
    2.49 ± 1.037
    2.46 ± 0.417
        Visit Day 28
    2.68 ± 0.250
    2.16 ± 0.560
    Notes
    [10] - Day 0 (n=12), Day 1 (n=12), Day 3 (n=12), Day 7 (n=12), Day 14 (n=9), Day 21 (n=8) and Day 28 (n=4)
    [11] - Day 0 (n=6), Day 1 (n=6), Day 3 (n=6), Day 7 (n=6), Day 14 (n=4), Day 21 (n=4) and Day 28 (n=4)
    No statistical analyses for this end point

    Secondary: Change in the score on the Glasgow coma scale (GCS)

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    End point title
    Change in the score on the Glasgow coma scale (GCS)
    End point description
    Final visit performed before day 28 that was recorded in 'Final Visit - Day 28' has been included in the subsequent visit to the last visit performed.
    End point type
    Secondary
    End point timeframe
    Score on the GCS at days 0, 1, 3, 7, 14, 21 and 28.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    6 [12]
    6 [13]
    Units: GCS score (absolute value)
    arithmetic mean (standard deviation)
        Screening - Day 0
    15.0 ± 0.00
    0 ± 0
        Visit 1 - Day 1
    15.0 ± 0.00
    10.0 ± 0
        Visit 2 - Day 3
    10.0 ± 0
    11.0 ± 4.24
        Visit 3 - Day 7
    0 ± 0
    11.0 ± 0
        Visit 4 - Day 14
    0 ± 0
    0 ± 0
        Visit 5 - Day 21
    15.0 ± 0
    0 ± 0
        Visit Day 28
    0 ± 0
    14.0 ± 0
    Notes
    [12] - Day 0 (n=2), Day 1 (n=2), Day 3 (n=1), Day 7 (n=0), Day 14 (n=0), Day 21 (n=1) and Day 28 (n=0)
    [13] - Day 0 (n=0), Day 1 (n=1), Day 3 (n=2), Day 7 (n=1), Day 14 (n=0), Day 21 (n=0) and Day 28 (n=1)
    No statistical analyses for this end point

    Secondary: Change in the score on the APACHE II scale

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    End point title
    Change in the score on the APACHE II scale
    End point description
    Too few patients had available assessments, being most of them from the screening visit. Final visit performed before day 28 that was recorded in 'Final Visit - Day 28' has been included in the subsequent visit to the last visit performed.
    End point type
    Secondary
    End point timeframe
    Score on the APACHE II scale at days 0, 1, 3, 7, 14, 21 and 28.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12 [14]
    6 [15]
    Units: APACHE II score (absolute value)
    arithmetic mean (standard deviation)
        Screening - Day 0
    13.8 ± 4.78
    14.7 ± 5.43
        Visit 1 - Day 1
    0 ± 0
    0 ± 0
        Visit 2 - Day 3
    0 ± 0
    13.0 ± 0
        Visit 3 - Day 7
    0 ± 0
    0 ± 0
        Visit 4 - Day 14
    0 ± 0
    0 ± 0
        Visit 5 - Day 21
    0 ± 0
    0 ± 0
        Visit Day 28
    0 ± 0
    0 ± 0
    Notes
    [14] - Day 0 (n=10), Day 1 (n=0), Day 3 (n=0), Day 7 (n=0), Day 14 (n=0), Day 21 (n=0) and Day 28 (n=0)
    [15] - Day 0 (n=6), Day 1 (n=0), Day 3 (n=1), Day 7 (n=0), Day 14 (n=0), Day 21 (n=0) and Day 28 (n=0)
    No statistical analyses for this end point

    Secondary: Thromboembolic processes

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    End point title
    Thromboembolic processes
    End point description
    Number of events, location and severity (affected organ and vascular territory) of thromboembolic events caused by COVID-19. It was not possible to assess whether IV melatonin treatment was associated with a reduction in the frequency and severity of thromboembolic processes caused by COVID-19, as only one single thromboembolic event was observed during the study (Respiratory, thoracic and mediastinal disorders > Pulmonary embolism > Moderate).
    End point type
    Secondary
    End point timeframe
    From ICF signature until the end of the study.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12
    6
    Units: Number of thromboembolic events
        Pulmonary embolism
    1
    0
    No statistical analyses for this end point

    Secondary: Systemic inflammatory response

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    End point title
    Systemic inflammatory response
    End point description
    The systemic inflammatory response was assessed through the change observed from baseline, presented as the percentage value from baseline (calculated as [Visit X value / Screening value]*100), in ferritin, D-dimer, C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) on days 1, 3, 7, 14, 21 and 28. Please see documents attached.
    End point type
    Secondary
    End point timeframe
    Systemic inflammatory parameters on days 0, 1, 3, 7, 14, 21 and 28.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12
    6
    Units: Subjects
        Subjects included in the analysis
    12
    6
    Attachments
    Untitled (Filename: Ferritin.doc)
    Untitled (Filename: D-Dimer.doc)
    Untitled (Filename: C-Reactive Protein.doc)
    Untitled (Filename: Procalcitonin.doc)
    Untitled (Filename: Interleukin-6.doc)
    No statistical analyses for this end point

    Secondary: Change in haematological parameters

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    End point title
    Change in haematological parameters
    End point description
    The change in the haematological parameters was evaluated through the variation from baseline in the levels of erythrocytes, Hb, platelets, fibrinogen, cephalin time, prothrombin time, antithrombin III, ADAMTS13 and Factor Xa (see Table 1 attached). Moreover, levels of basophils, eosinophils, haematocrit, lymphocytes, mean corpuscular haemoglobin concentration (MCHC), mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV), monocytes, neutrophils and leucocytes were also evaluated throughout the study (see Table 2 attached).
    End point type
    Secondary
    End point timeframe
    Haematological parameters on days 0, 1, 3, 7, 14, 21 and 28.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12
    6
    Units: Subjects
        Subjects included in the analysis
    12
    6
    Attachments
    Untitled (Filename: Lymphocytes.doc)
    Untitled (Filename: Neutrophils.doc)
    Table 1
    Table 2
    No statistical analyses for this end point

    Secondary: Change in biochemical parameters

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    End point title
    Change in biochemical parameters
    End point description
    The change in the biochemical parameters was evaluated through the variation from baseline in the levels of creatine kinase (CK), lactate dehydrogenase (LDH), glutamate-oxalacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), bilirubin, vitamin D and 1,25-OH-Vit D (calcitriol), calcium, albumin, blood urea nitrogen (BUN), creatinine and troponin on days 1, 3, 7, 14, 21 and 28. Please see documents attached.
    End point type
    Secondary
    End point timeframe
    Biochemical parameters on days 0, 1, 3, 7, 14, 21 and 28.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12
    6
    Units: Subjects
        Subjects included in the analysis
    12
    6
    Attachments
    Bilirubin
    Biochemical parameters
    No statistical analyses for this end point

    Secondary: Change in arterial blood gas parameters and electrolytes

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    End point title
    Change in arterial blood gas parameters and electrolytes
    End point description
    The change in the arterial blood gas parameters and electrolytes was evaluated through the variation from baseline in pH, SaO2, PaCO2, PO2, HCO3, glucose, Na, K, chlorine, lactate, anion gap and PaO2/FiO2 on days 1, 3, 7, 14, 21 and 28. Please see document attached.
    End point type
    Secondary
    End point timeframe
    Arterial blood gas parameters and electrolytes on days 0, 1, 3, 7, 14, 21 and 28.
    End point values
    Melatonin Placebo
    Number of subjects analysed
    12
    6
    Units: Subjects
        Subjects included in the analysis
    12
    6
    Attachments
    Arterial blood gas parameters and electrolytes
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The collection of information on AEs should start on the basis of obtaining informed consent. All serious AEs must be reported to the sponsor within 24 hours of investigator’s awareness, regardless of their relationship to the experimental drug.
    Adverse event reporting additional description
    All identified AEs should be noted and described in the patient's medical history. The following information must be collected for all AEs: date of onset , intensity, causal relationship with the study drug in the opinion of the investigator, treatment required for the AE, serious criteria of the AE and information on its resolution or outcome.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Melatonin
    Reporting group description
    This arm included all patients who were randomized to melatonin. The patients included in the study were administered the assigned treatment for up to 7 days, unless any of the following events occurred: discharge of the ICU patient, death of the patient, unacceptable toxicity or ustified treatment interruption according to the researcher's criteria.

    Reporting group title
    Placebo
    Reporting group description
    This arm included all patients who were randomized to placebo. The patients included in the study were administered the assigned treatment for up to 7 days, unless any of the following events occurred: discharge of the ICU patient, death of the patient, unacceptable toxicity or ustified treatment interruption according to the researcher's criteria.

    Serious adverse events
    Melatonin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    5
    1
         number of deaths resulting from adverse events
    3
    0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Melatonin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    5 / 6 (83.33%)
    Vascular disorders
    Haemodynamic instability
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Hypertension
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Hypotension
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Shock haemorrhagic
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Oedema
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Procedural failure
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Penile oedema
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Scrotal oedema
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 6 (33.33%)
         occurrences all number
    1
    2
    Bradycardia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 12 (41.67%)
    1 / 6 (16.67%)
         occurrences all number
    6
    1
    Hypersplenism
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Leucocytosis
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Lymphopenia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Neutrophilia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Thrombocytosis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Bronchospasm
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hypoxia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pneumothorax
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Duodenal ulcer
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Faecal vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Haematochezia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Intestinal obstruction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Haematuria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Oliguria
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    2
    3
    Polyuria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Renal failure
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    Hyperuricaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Hypophosphataemia
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Candida infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Enterobacter infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Enterobacter tracheobronchitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 6 (33.33%)
         occurrences all number
    1
    2
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal candidiasis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Haemophilus infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Klebsiella infection
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Peritonitis bacterial
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Pneumonia pseudomonal
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Pseudomonas infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Septic shock
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Staphylococcal bacteraemia
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Tracheobronchitis bacterial
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    2
    3
    Urinary tract infection bacterial
         subjects affected / exposed
    4 / 12 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    4
    1
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection fungal
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0

    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.
    The interpretation of current results is limited by the short-term 7-days treatment period and the size of the population (n=18). The treatment of melatonin up to 7 days is not enough to reveal its anti-inflammatory and antioxidant effects in full.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/32758298
    http://www.ncbi.nlm.nih.gov/pubmed/32770854
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