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    Clinical Trial Results:
    Chronotherapeutic lifestyle intervention for diabetes and obesity to reset the circadian rhythm and improve cardiometabolic risk in the European population

    Summary
    EudraCT number
    2012-005255-17
    Trial protocol
    GB  
    Global end of trial date
    01 Nov 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Jan 2020
    First version publication date
    03 Jan 2020
    Other versions
    Summary report(s)
    Eurythdia Final Report

    Trial information

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    Trial identification
    Sponsor protocol code
    ED14/11124
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Leeds
    Sponsor organisation address
    Worsley Building, Leeds, United Kingdom, LS2 9LN
    Public contact
    Clare Skinner, University of Leeds, 0113 3434897, c.e.skinner@leeds.ac.uk
    Scientific contact
    Clare Skinner, University of Leeds, 0113 3434897, c.e.skinner@leeds.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    to investigate the effectiveness of 6 months of randomization to melatonin therapy or placebo as a chronotherapeutic intervention for individuals at high risk of development of T2DM. This will be carried out by analysing the influence of these interventions on glucose regulation, insulin resistance, cardiometabolic function and markers of central and peripheral circadian rhythms, in particular CLOCK mRNA, in healthy first degree relatives of patients with T2DM
    Protection of trial subjects
    All information collected during the course of the trial will be kept strictly confidential. Information will be held securely on paper and electronically at the LIGHT Laboratories, University of Leeds for the duration of the study. Data collection will be performed on paper at each individual participants visit and transcribed to electronic CRFs. The paper copies containing visit data will act as source data. The investigators will comply with all aspects of the Data Protection Act 1998. All data obtained in this study should be entered within 7 days of patient contact in the appropriate case report form (eCRF). The investigator should ensure the accuracy, completeness, legibility and timeliness of the data reported in the CRFs and in all required reports. Data reported on the CRF should be consistent with the source documents or the discrepancies should be explained. Paper documentation will be completed in black ink ballpoint pen. Errors must be corrected by drawing a single line through the incorrect entry and writing in the new value/ data positioned as close to the original as possible. Any change or correction to should not obscure or eliminate the original entry (“correction fluid” should not be used) and should be dated, initialled and explained (if necessary) by the person making the correction. The investigator has to date and sign off the completed paper documentation including copies of blood results and any other reports. Corrections made after the investigators review and signature of the completed CRF have to be signed and dated by the investigator. If an investigation was not performed, this needs to be indicated with “n.d.” (not done). Prior to start and during the study, when applicable, the investigator will list on the form “Delegation of Tasks” all person to whom he/ she delegated significant trial-related duties.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jul 2014
    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
    United Kingdom: 71
    Worldwide total number of subjects
    71
    EEA total number of subjects
    71
    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)
    63
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 4000 patients were screened and 340 relatives of patients could be contacted. A total of 75 patients willing to participate were subsequently randomized in a 1:1 random allocation held by the Leeds Teaching Hospitals Trust pharmacy to either 6 months melatonin therapy or placebo

    Pre-assignment
    Screening details
    Inclusion Criteria: Age 18-75,Males, females of non-child bearing potential (post-menopausal or 6 weeks post-sterilisation), females of child-bearing potential,)One or more first degree relative with an established diagnosis of T2DM,Absence of clinical symptoms and signs of infection,Absence of systemic disease.

    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
    Investigator, Subject
    Blinding implementation details
    Subjects were assigned to a specified treatment according to a random list, which was generated before the beginning of the study. Labelling for the study and blinding according to randomization list will be performed at the UMC-Hamburg Hospital pharmacy; study medication will be shipped from Hamburg to the hospital pharmacy in Leeds for dispensing to study participants.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Melatonin Treatment
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Oral Melatonin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neurim Pharmaceuticals (Zug, Switzerland swissinfo@neurim.com) will provide 2 mg prolonged-release melatonin tablet: Circadin® 2 mg tablets. Placebo tablets have been developed to match the Circadin® 2 mg tablets in blind clinical studies. They contain the same excipients than those used in the composition of Circadin® 2 mg tablets (Ammonio Methacrylate Copolymer, Type B [Eudragit RSPO®], Calcium Hydrogen Phosphate Dihydrate, Lactose Monohydrate, Silica, Colloidal Anhydrous [Aerosil®], Talcum, Magnesium Stearate), except the ethanol used to dissolve the drug substance and spray it in the dry excipient blend for a partial wet granulation. The tablets (active/placebo) are then obtained by dry-mixing and direct compression. Since the residual ethanol has to be less than 5000 ppm in the final formulation of Circadin® 2 mg tablets, the placebo formulation without ethanol can be considered as equivalent to the Circadin® tablet formulation, except the absence of the drug substance.

    Arm title
    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
    Placebo tablets have been developed to match the Circadin® 2 mg tablets in blind clinical studies. They contain the same excipients than those used in the composition of Circadin® 2 mg tablets (Ammonio Methacrylate Copolymer, Type B [Eudragit RSPO®], Calcium Hydrogen Phosphate Dihydrate, Lactose Monohydrate, Silica, Colloidal Anhydrous [Aerosil®], Talcum, Magnesium Stearate), except the ethanol used to dissolve the drug substance and spray it in the dry excipient blend for a partial wet granulation.

    Number of subjects in period 1
    Melatonin Treatment Placebo
    Started
    36
    35
    Completed
    30
    30
    Not completed
    6
    5
         Consent withdrawn by subject
    6
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Melatonin Treatment
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    Melatonin Treatment Placebo Total
    Number of subjects
    36 35 71
    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)
    32 31 63
        From 65-84 years
    4 4 8
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    31 28 59
        Male
    5 7 12

    End points

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    End points reporting groups
    Reporting group title
    Melatonin Treatment
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: The differences in indices of glucose regulation (HbA1c, OGTT, insulin AUC) between intervention and control groups.

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    End point title
    The differences in indices of glucose regulation (HbA1c, OGTT, insulin AUC) between intervention and control groups. [1]
    End point description
    End point type
    Primary
    End point timeframe
    total study duration will be 26 months, with trial recruitment anticipated to be 12 months. This would leave 14 months for end point analysis.
    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: Please see results paper which has been uploaded and contains details of the statistical analysis.
    End point values
    Melatonin Treatment Placebo
    Number of subjects analysed
    36
    35
    Units: mmol/mol
        HbA1c
    3497
    3709
    Attachments
    Primary and Secondary outcome tables
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    AEs will be collected for all participants and will be evaluated according to the NCRI Common Toxicity Criteria. AEs will be collected for all participants from date of randomisation until 30 days after the last dose of treatment
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Melatonin Treatment
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    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: No Non-Serious adverts were reported as this was a healthy volunteers trial.
    Serious adverse events
    Melatonin Treatment Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 35 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Elective Cholecystectomy
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Appendicitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bilateral Cellulitis
    Additional description: Cellulitis in both feet. Treated by GP with oral antibiotics and with IV antibiotics in hospital.
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 35 (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 Treatment Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 35 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2014
    Protocol and PIS amended to v3.0 & v2.0
    19 Jun 2015
    Participant Information Sheet V4, ,Informed Consent Form V3 Supplementary Protocol added to study
    22 Jun 2015
    GP cover letter version 1 dated 22/06/15 Additional info for attaching to letter above, version 1 dated 22nd june 2015
    23 Jun 2015
    Protocol updated to version 4.0, dated 18th June 2015

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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