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    Clinical Trial Results:
    Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: a randomised, placebo-controlled, blinded trial (the SMART trial)

    Summary
    EudraCT number
    		 2010-024065-46
    Trial protocol
    		 DK  
    Global end of trial date
    09 Jun 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jan 2020
    First version publication date
    31 Jan 2020
    Other versions
    Summary report(s)
    		 Summary of results, main paper

    Trial information

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    Trial identification
    Sponsor protocol code
    2010-379
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01431092
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Psykiatrisk Center Glostrup
    Sponsor organisation address
    Nordstjernevej 41, Glostrup, Denmark, 2600
    Public contact
    Psykiatrisk Center Glostrup, Center for Neuropsykiatrisk Skizofreniforskning, 0045 3864 0840, lone.baandrup@regionh.dk
    Scientific contact
    Psykiatrisk Center Glostrup, Center for Neuropsykiatrisk Skizofreniforskning, 0045 3864 0840, lone.baandrup@regionh.dk
    Sponsor organisation name
    Mental Health Center Glostrup
    Sponsor organisation address
    Ndr. Ringvej 29-67, Glostrup, Denmark, 2600
    Public contact
    Lone Baandrup, Center for Neuropsychiatric Research, Mental Health Center Glostrup, Ndr. Ringvej 29-67, DK-2600, 20363304 20363304, lone.baandrup@regionh.dk
    Scientific contact
    Center for Neuropsychiatric Research, Mental Health Center Glostrup, Ndr. Ringvej 29-67, DK-2600, Center for Neuropsychiatric Research, Mental Health Center Glostrup, Ndr. Ringvej 29-67, DK-2600, 20363304 20363304, lone.baandrup@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
    03 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    We assessed if prolonged-release melatonin can facilitate withdrawal of long-term benzodiazepine usage in patients with schizophrenia or bipolar disorder.
    Protection of trial subjects
    Frequent follow-up visits and telephone contacts
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 2011
    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: 86
    Worldwide total number of subjects
    86
    EEA total number of subjects
    86
    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)
    86
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects referred from outpatient mental health care settings

    Pre-assignment
    Screening details
    		 Out of 155 patients screened, 86 were randomised: 42 to PRM versus 44 to placebo. The mean age of the 69 excluded patients was 50.9 years and 40.6% were men. Figure 1 illustrates the flow of participants through the trial (CONSORT diagram). Only one patient was switched to a long-acting benzodiazepine (diazepam) before tapering began.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prolonged-release melatonin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    melatonin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule (2 mg) 2 hours before bedtime

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule (2 mg) 2 hours before bedtime

    Number of subjects in period 1
    		Prolonged-release melatonin Placebo
    Started
    42
    44
    Completed
    30
    32
    Not completed
    12
    12
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    2
    1
         Protocol deviation
    10
    7
         Lack of efficacy
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prolonged-release melatonin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Prolonged-release melatonin Placebo Total
    Number of subjects
    		 42 44 86
    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)
    		 42 44 86
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.9 ± 8.7 49.4 ± 12.3 -
    Gender categorical
    Units: Subjects
        Female
    		 19 19 38
        Male
    		 23 25 48

    End points

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    End points reporting groups
    Reporting group title
    Prolonged-release melatonin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: mean daily dosage of benzodiazepines (including benzodiazepine relateddrugs) at 24 week follow-up

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    End point title
    		 mean daily dosage of benzodiazepines (including benzodiazepine relateddrugs) at 24 week follow-up
    End point description
    End point type
    Primary
    End point timeframe
    24 weeks follow-up
    End point values
    		 Prolonged-release melatonin Placebo
    Number of subjects analysed
    42 [1]
    44
    Units: mg diazepam equivalents
    42
    44
    Notes
    [1] - Primary outcome was available for all included subjects
    Statistical analysis title
    		 univariate general linear model
    Statistical analysis description
    All analyses were adjusted by the protocol specified stratification variable (baseline diazepam equivalents > 15 mg, yes/no) and the baseline value of the dependent outcome variable. All analyses were intention to treat. Two-sided 5% significance tests were used. We analysed the primary outcome using the univariate general linear model.
    Comparison groups
    Prolonged-release melatonin v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Regression, Linear
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Prolonged-release melatonin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Prolonged-release melatonin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 42 (28.57%)
    10 / 44 (22.73%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    Psychiatric disorders
    Suicidal ideation
    Additional description: All reported AEs in the suicidal ideation category were associated with hospitalisation (mostly of brief duration) and were therefore categorised as SAEs.
         subjects affected / exposed
    9 / 42 (21.43%)
    4 / 44 (9.09%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatremia
    Additional description: Acute severe hyponatremia with confusion and seizures
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Prolonged-release melatonin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 42 (61.90%)
    28 / 44 (63.64%)
    Vascular disorders
    unspecified
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 44 (9.09%)
         occurrences all number
    26
    28
    Nervous system disorders
    Mood altered
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 44 (2.27%)
         occurrences all number
    26
    28
    Immune system disorders
    Influenza like illness
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 44 (0.00%)
         occurrences all number
    26
    28
    Gastrointestinal disorders
    Unspecified
         subjects affected / exposed
    8 / 42 (19.05%)
    4 / 44 (9.09%)
         occurrences all number
    26
    28
    Psychiatric disorders
    somnolence
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 44 (4.55%)
         occurrences all number
    26
    28
    Musculoskeletal and connective tissue disorders
    Unspecified
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 44 (6.82%)
         occurrences all number
    26
    28

    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 (see link)

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26086792
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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