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    Clinical Trial Results:
    A randomized, double-blind, parallel group, placebo-controlled trial of metformin in tuberous sclerosis complex.

    Summary
    EudraCT number
    2011-001319-30
    Trial protocol
    GB  
    Global end of trial date
    28 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Sep 2018
    First version publication date
    27 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CH/2011/3670
    Additional study identifiers
    ISRCTN number
    ISRCTN92545532
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University Hospitals Bristol NHS Foundation Trust
    Sponsor organisation address
    Upper Maudlin street, Bristol , Bristol, United Kingdom, BS28AE
    Public contact
    Jessica Bisset Research operational Manager University Hospitals Bristol NHS Foundation Trust , University Hospitals Bristol NHS Foundation Trust , 0117 3420233, r&dsponsorship@uhbristol.nhs.uk
    Scientific contact
    University Hospitals Bristol NHS Foundation Trust , University Hospitals Bristol NHS Foundation Trust , 0117 3420204, sam.amin.14@ucl.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
    27 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does the drug metformin reduce the size of kidney tumours in people with Tuberous Sclerosis Complex?
    Protection of trial subjects
    regular follow up and contact with patients to ensure safety local GPs are informed about this trial so that they are aware and protect patients
    Background therapy
    The drug metformin works on the part of the body's cells that controls growth, and might provide an alternative way to control cell growth. If it does, then treatment with metformin could slow down, stop or even reverse the growth of tumours in TSC. Metformin has been shown to reduce the growth of some tumours growing in test-tubes and in mice, and is associated with a lower risk of development of cancerous tumours in some patients. This study is testing the idea that metformin is effective in reducing the size of kidney tumours in people with TSC. It is a randomised double-blind placebo controlled trial. Half will take metformin and half will take a sugar-pill (placebo) for 12 months. All will have regular checks for side effects. All will have scans at the start, 6, 12 and 18 months to monitor tumour size. At the same times they will have evaluations of their facial and nail tumours and epilepsy severity. At the start of the study and at 12 months they will have evaluations of their cognitive abilities and their quality of life.
    Evidence for comparator
    Rapamycin and Everolimus are drugs that are known to inhibit mTOR and studies have shown that they can reduce TSC-related kidney and brain tumour size. They can cause significant side effects and their long term effect is unknown. In addition, they are very expensive drugs. Metformin is a drug that potentially offers the benefit of mTOR inhibition without the side effect profile of rapamycin. It is used by millions of people with type 2 diabetes and has a very benign side effect profile. It does not lower blood sugar in non-diabetic people unless given in overdose. It has recently been shown to inhibit mTOR and has been used to inhibit the growth of cancerous cells (breast cancer and squamous cell carcinoma cells) in vitro via this mTOR inhibition. It has been shown to kill human breast cancer cells in a mouse model and was used in this mouse model at concentrations lower than typically used for the treatment of diabetes. It is hypothesised that metformin will reduce TSCrelated tumour size via inhibition of mTOR
    Actual start date of recruitment
    13 Nov 2012
    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
    United Kingdom: 55
    Worldwide total number of subjects
    55
    EEA total number of subjects
    55
    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)
    2
    Adolescents (12-17 years)
    9
    Adults (18-64 years)
    44
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were recruited from three specialist TSC clinics in Bath, Bristol and London in the United Kingdom. Prior to their standard clinic appointment, all clinic patients were sent a letter introducing the study (including participant information sheets and study team contact details).

    Pre-assignment
    Screening details
    72 patients assessed for eligibility 1 declined due to placebo 5 declined – no reason 9 not eligible 2 unwell 55 enrolled and randomly assigned 4 did not start treatment: Mother changed mind Decided to take part in another study Busy life style change One did not start due to social reason

    Period 1
    Period 1 title
    treatment 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
    Patients were randomly allocated (1:1) to placebo or metformin for 12 months. The randomisation was stratified by centre and minimised by age-group (10 to <20; 20 to <30; 30 to <40; and 40 to <65) and by the presence or absence of learning disabilities. The randomisation was concealed. The investigators randomised patients online, and wrote randomisation number and treatment pack number on the study prescription form

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Metformin arm
    Arm description
    Patients received metformin for 12 months
    Arm type
    Experimental

    Investigational medicinal product name
    metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For adult patients, the starting dose was 500mg twice a day orally. At 6 months, the dose was escalated to 500mg three times a day as long as the patient was tolerating the treatment. For children aged 10-16 years, the drug dosing started at 500mg once a day. After two weeks at this dose, it was escalated to 500mg twice a day. At 6 months the dose was escalated to 500mg three times a day as long as the patient was tolerating treatment well.

    Arm title
    placebo
    Arm description
    patients received placebo
    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
    For adult patients, the starting dose was 500mg twice a day orally. At 6 months, the dose was escalated to 500mg three times a day as long as the patient was tolerating the treatment. For children aged 10-16 years, the drug dosing started at 500mg once a day. After two weeks at this dose, it was escalated to 500mg twice a day. At 6 months the dose was escalated to 500mg three times a day as long as the patient was tolerating treatment well.

    Number of subjects in period 1
    Metformin arm placebo
    Started
    28
    27
    Completed
    27
    24
    Not completed
    1
    3
         Consent withdrawn by subject
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    treatment period
    Reporting group description
    -

    Reporting group values
    treatment period Total
    Number of subjects
    55 55
    Age categorical
    The randomisation was stratified by centre and minimised by age-group (10 to <20; 20 to <30; 30 to <40; and 40 to <65)
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    2 2
        Adolescents (12-17 years)
    8 8
        Adults (18-64 years)
    45 45
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    29 29
        Male
    26 26
    Subject analysis sets

    Subject analysis set title
    primary and secondary outcomes
    Subject analysis set type
    Full analysis
    Subject analysis set description
    full analysis performed

    Subject analysis sets values
    primary and secondary outcomes
    Number of subjects
    51
    Age categorical
    The randomisation was stratified by centre and minimised by age-group (10 to <20; 20 to <30; 30 to <40; and 40 to <65)
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    2
        Adolescents (12-17 years)
    7
        Adults (18-64 years)
    42
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    25
        Male
    26

    End points

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    End points reporting groups
    Reporting group title
    Metformin arm
    Reporting group description
    Patients received metformin for 12 months

    Reporting group title
    placebo
    Reporting group description
    patients received placebo

    Subject analysis set title
    primary and secondary outcomes
    Subject analysis set type
    Full analysis
    Subject analysis set description
    full analysis performed

    Primary: primary end point

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    End point title
    primary end point
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    Metformin arm placebo primary and secondary outcomes
    Number of subjects analysed
    27
    24
    51 [1]
    Units: 9 to 41
        number (confidence interval 95%)
    27 (9 to 41)
    24 (9 to 41)
    0 (0 to 0)
    Notes
    [1] - this is for AML volume
    Statistical analysis title
    Two-tailed t-tests
    Statistical analysis description
    Analysis was by intention to treat. 
The primary analysis of effectiveness was a comparison of the percentage volume change of renal AMLs in the metformin and placebo arms. Two-tailed t-tests were used to compare the mean percentage change in each group. The secondary outcome variables were analysed as the primary outcomes.
    Comparison groups
    placebo v Metformin arm v primary and secondary outcomes
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.221
    Method
    t-test, 2-sided
    Parameter type
    Median difference (net)
    Point estimate
    15.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9
         upper limit
    41
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 months during the trial and 6 month post trial
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    Not used
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Metformin
    Reporting group description
    -

    Reporting group title
    placebo
    Reporting group description
    -

    Serious adverse events
    Metformin placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 27 (11.11%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    kidney bleeding
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Metformin placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 27 (29.63%)
    3 / 24 (12.50%)
    Injury, poisoning and procedural complications
    fall
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    Nervous system disorders
    seizure
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    Headache
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    gastric upset
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    food poisoning
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    dental infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2014
    Chief Investigator - change of employer; change of Principal Investigator at site; addition of a new site

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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