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    Clinical Trial Results:
    Effects of Metformin on portal hypertension in patients with cirrhosis.

    Summary
    EudraCT number
    		 2017-001132-19
    Trial protocol
    		 DK  
    Global end of trial date
    12 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Sep 2021
    First version publication date
    09 Sep 2021
    Other versions
    Summary report(s)
    		 DOI to manuscripts

    Trial information

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    Trial identification
    Sponsor protocol code
    1-10-72-67-17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University
    Sponsor organisation address
    Hedeager 3, 2nd floor, Aarhus N, Denmark, 8200
    Public contact
    Steno Diabetes Center Aarhus, Aarhus University Hospital , 0045 61714731, nikolaj.rittig@clin.au.dk
    Scientific contact
    Steno Diabetes Center Aarhus, Aarhus University Hospital , 0045 61714731, nikolaj.rittig@clin.au.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
    12 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objective of the study is to investigate if Metformin lowers portal blood pressure in patients with cirrhosis.
    Protection of trial subjects
    No specific measures were put in place. Trial subjects were investigated during planned clinical procedures and received standard clinical care and treatment.
    Background therapy
    		 All trial subjects had catheters placed in the hepatic vein (n=32) or portal vein (n=9) + in the femoral artery (n=32) or hand vein (n=9). Catheters were used to measure pressure + obtain blood.
    Evidence for comparator
    		 Animal studies indicate that portal pressure declines and lactate levels increases following metformin consumption - thus a clinical relevant dose of metformin was tested against placebo treatment to investigate whether these effects translates into humans.
    Actual start date of recruitment
    01 Jan 2018
    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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    29
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was carried out during the period January 2018 until September 2020, at the Department of Hepatology & Gastroenterology, Aarhus University Hospital, 8200 Aarhus N, DK. Trial subjects were recruited trough the outpatient clinic when referred to liver vein catheterization (LVC) or transjugular intrahepatic portosystemic shunt (TIPS).

    Pre-assignment
    Screening details
    		 Inclusion: 18 years, cirrhosis, informed consent, clinical indication for liver vein catherization (LVC) or transjugular intrahepatic portosystemic shunt (TIPS) Exclusion: Child pugh class >12, pregnancy/nursing, incapable to understand/read Danish, known allergies/side effects to metformin, eGFR<30 ml

    Pre-assignment period milestones
    Number of subjects started
    		 40
    Number of subjects completed
    		 40

    Period 1
    Period 1 title
    Entire study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Two GCP-experienced personal without any other relation to the study placed either a 1000 mg pill of metformin Activas (Teva pharmaceuticals Industries, US) or placebo (Glostrup Pharmacy, Denmark) in sealed opaque envelopes marked with a unique identification number. Block randomized, metformin and placebo (2:2). A nurse without any other relation to the study blindly drew an envelope and crushed the pill inside before diluting it in approximately 50 ml of tap water and serving it.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LVC - metformin
    Arm description
    		 1000 mg metformin
    Arm type
    		 Active comparator

    Investigational medicinal product name
    metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg metformin crushed and dissolved in 50 ml tap water.

    Arm title
    		 LVC- placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    A placebo tablet dissolved in 50 ml tap water.

    Arm title
    		 TIPS - portal vein
    Arm description
    		 All trial subjects (TIPS) received a single dose metformin
    Arm type
    		 Experimental

    Investigational medicinal product name
    metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg metformin was dissolved in 50 ml tap water and served for the trial subjects.

    Arm title
    		 TIPS - arterialized blood
    Arm description
    		 Systemic blood
    Arm type
    		 Other sampling site

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		LVC - metformin LVC- placebo TIPS - portal vein TIPS - arterialized blood
    Started
    16
    16
    4
    4
    Completed
    16
    16
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Entire study
    Reporting group description
    		 -

    Reporting group values
    		 Entire study Total
    Number of subjects
    		 40 40
    Age categorical
    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)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 29 29
        From 65-84 years
    		 11 11
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 23 23
    Subject analysis sets

    Subject analysis set title
    LVC
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The patients tested during LVC.

    Subject analysis set title
    TIPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The trial subjects with TIPS.

    Subject analysis sets values
    		 LVC TIPS
    Number of subjects
    32
    8
    Age categorical
    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)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    24
    5
        From 65-84 years
    8
    4
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    15
    1
        Male
    17
    3

    End points

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    End points reporting groups
    Reporting group title
    LVC - metformin
    Reporting group description
    		 1000 mg metformin

    Reporting group title
    LVC- placebo
    Reporting group description
    		 Placebo

    Reporting group title
    TIPS - portal vein
    Reporting group description
    		 All trial subjects (TIPS) received a single dose metformin

    Reporting group title
    TIPS - arterialized blood
    Reporting group description
    		 Systemic blood

    Subject analysis set title
    LVC
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The patients tested during LVC.

    Subject analysis set title
    TIPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The trial subjects with TIPS.

    Primary: HVPG

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    End point title
    		 HVPG
    End point description
    End point type
    Primary
    End point timeframe
    difference between baseline and 90 min value
    End point values
    		 LVC - metformin LVC- placebo TIPS - portal vein TIPS - arterialized blood
    Number of subjects analysed
    16
    15
    4 [1]
    4 [2]
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    -2.9 (-5.1 to -0.7)
    0.9 (-1 to 2.7)
    1 (1 to 1)
    1 (1 to 1)
    Attachments
    		 fig 1
    fig 2
    Untitled (Filename: Figures_LVK3600600.tiff_new.jpg)
    fig 4
    Untitled (Filename: tables_LVK.docx)
    Notes
    [1] - N/A
    [2] - N/A
    Statistical analysis title
    		 Two-way RM ANOVA
    Comparison groups
    LVC - metformin v LVC- placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Lactate

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    End point title
    		 Lactate
    End point description
    End point type
    Primary
    End point timeframe
    baseline - 90 min
    End point values
    		 LVC - metformin LVC- placebo TIPS - portal vein TIPS - arterialized blood TIPS
    Number of subjects analysed
    16 [3]
    16 [4]
    4 [5]
    4
    8
    Units: procent
        arithmetic mean (confidence interval 95%)
    1 (1 to 1)
    1 (1 to 1)
    1 (1 to 1)
    1.23 (1.06 to 1.4)
    23 (6 to 40)
    Attachments
    		 fig1
    fig2
    fig3
    Notes
    [3] - N/A
    [4] - N/A
    [5] - 8 individuals - there own "control". Portal vs arterialized blood
    Statistical analysis title
    		 2-way RM ANOVA and posthoc t-test
    Comparison groups
    TIPS - portal vein v TIPS - arterialized blood
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 post hoc t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6
         upper limit
    		 40
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 hours
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Total
    Reporting group description
    		 -

    Serious adverse events
    		 Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 40 (12.50%)
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2019
    Invitation to the TIPS project by letter (chronic TIPS inclusion) and prolonged the period to include patients.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34165199
    http://www.ncbi.nlm.nih.gov/pubmed/34331316
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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
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