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    Clinical Trial Results:
    Renal and cardiac effects of terlipressin and dobutamin in cirrhosis and ascites. A randomised study.

    Summary
    EudraCT number
    		 2012-002275-33
    Trial protocol
    		 DK  
    Global end of trial date
    24 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2021
    First version publication date
    24 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0805-2012-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Center for Leverforskning Odense
    Sponsor organisation address
    Kløvervænget 12, Odense, Denmark, 2100
    Public contact
    Aleksander Krag, Dept. Gastroenterology, Universityhospital Odense, 0045 29647719, mads.egerod.israelsen@rsyd.dk
    Scientific contact
    Aleksander Krag, Dept. Gastroenterology, Universityhospital Odense, 20681060 29647719, mads.egerod.israelsen@rsyd.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
    01 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Many patients with cirrhosis will die of renal failure - the hepatorenal syndrome, which has a median survival of less than 1 month. Hepatorenal syndrome is treated with terlipressin, which increases blood pressure and improves renal function. However, terlipressin also causes a decline in cardiac function, which is unfortunate, since the renal function relies on a sufficient cardiac output. This may explain why only half of the patients respond to this treatment. We aim to investigate if renal function in patients with cirrhosis and ascites can be improved by combining terlipressin with dobutamin - a drug that increases cardiac function. Dobutamin increases cardiac output primarily by increasing heart rate.
    Protection of trial subjects
    This study was performed according to International Council for Harmonisation: Good Clinical Practice (ICH-GCP) and the Declaration of Helsinki and approved by the Committee of Health Research Ethics in the Region of Southern Denmark. External monitoring was performed by Good Clinical Practice Unit at Odense University Hospital.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2013
    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: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    25
    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)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From June 2014 to May 2018 we screened patients with cirrhosis and ascites in the outpatient clinic at Odense University Hospital, 46 of which were eligible for the study.

    Pre-assignment
    Screening details
    		 We screened 245 patients with cirrhosis and ascites in the outpatient clinic at Odense University Hospital, 46 of which were eligible for the study. Twenty-seven agreed to participate and were included and randomised. Two participants experienced an adverse event between inclusion and the investigation, and they did not receive any study drugs

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dobutamine + Terlipressin
    Arm description
    		 Dobutamine followed by terlipressin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dobutamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Dobutamine was infused continuously starting at 10 µg/kg body weight/min and increased every 3 minutes by 10 µg/kg body weight/min until reaching the targeted heart rate or a max dose of 40 µg/kg body weight/min. Target heart rate was a 50% increase of resting heart rate or a maximum heart rate of 120 beats per minute.

    Arm title
    		 Terlipressin + Dobutamin
    Arm description
    		 terlipressin followed by dobutamine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Terlipressin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Terlipressin 2 mg in 10 mL (9 mg/mL) NaCl solution was administrated as a bolus injection over 2 min. Dobutamine was infused continuously starting at 10 µg/kg body weight/min and increased every 3 minutes by 10 µg/kg body weight/min until reaching the targeted heart rate or a max dose of 40 µg/kg body weight/min. Target heart rate was a 50% increase of resting heart rate or a maximum heart rate of 120 beats per minute.

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Experimental

    Investigational medicinal product name
    Terlipressin + Dobutamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous bolus use , Intravenous drip use
    Dosage and administration details
    Terlipressin 2 mg in 10 mL (9 mg/mL) NaCl solution was administrated as a bolus injection over 2 min. Dobutamine was infused continuously starting at 10 µg/kg body weight/min and increased every 3 minutes by 10 µg/kg body weight/min until reaching the targeted heart rate or a max dose of 40 µg/kg body weight/min. Target heart rate was a 50% increase of resting heart rate or a maximum heart rate of 120 beats per minute.

    Number of subjects in period 1
    		Dobutamine + Terlipressin Terlipressin + Dobutamin Placebo
    Started
    10
    10
    5
    Completed
    10
    10
    5

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 25 25
    Age categorical
    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)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    58.8 (9.9)
    Units: years
        arithmetic mean (standard deviation)
    		 59 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 17 17

    End points

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    End points reporting groups
    Reporting group title
    Dobutamine + Terlipressin
    Reporting group description
    		 Dobutamine followed by terlipressin

    Reporting group title
    Terlipressin + Dobutamin
    Reporting group description
    		 terlipressin followed by dobutamine

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Subject analysis set title
    Glomerular filtration rate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cr-EDTA measurement

    Primary: Glomerular filtration rate

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    End point title
    		 Glomerular filtration rate
    End point description
    End point type
    Primary
    End point timeframe
    240 minutes
    End point values
    		 Dobutamine + Terlipressin Terlipressin + Dobutamin Placebo Glomerular filtration rate
    Number of subjects analysed
    10
    10
    5
    25 [1]
    Units: ml
        arithmetic mean (confidence interval 95%)
    -10.4 (-25.5 to 4.8)
    18.8 (5.7 to 32.0)
    9.0 (-11.1 to 29.2)
    0.0 (-1.0 to 1.0)
    Attachments
    		 Untitled (Filename: Screenshot 2021-02-06 at 02.27.54.png)
    Notes
    [1] - --
    Statistical analysis title
    		 mixed model
    Comparison groups
    Dobutamine + Terlipressin v Terlipressin + Dobutamin v Placebo v Glomerular filtration rate
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 day
    Adverse event reporting additional description
    We observed two SAEs that developed after signing the informed consent but in both cases the participants were excluded before receiving the study drugs. These are not included in following report
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Dobutamine
    Reporting group description
    		 -

    Reporting group title
    Terlipressin
    Reporting group description
    		 -

    Reporting group title
    Terlipressin and Dobutamine
    Reporting group description
    		 -

    Serious adverse events
    		 Dobutamine Terlipressin Terlipressin and Dobutamine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dobutamine Terlipressin Terlipressin and Dobutamine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    15 / 20 (75.00%)
    7 / 10 (70.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    hypotension
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Palpitations
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Cardiac disorders
    Dyspnoea
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Head discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    15 / 20 (75.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    15
    0
    Nausea
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 20 (25.00%)
    5 / 10 (50.00%)
         occurrences all number
    1
    5
    5
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 20 (10.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    2

    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 treatment duration was relative short compared with treatment of AKI-HRS in clinical practice. Based on the results from present study, we cannot conclude that changes in vasoactive substances and their subsequent effects on renal perfusion were

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31841026
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