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    Clinical Trial Results:
    Serelaxin To Lower Portal Pressure in Patients with Cirrhosis and Portal Hypertension (STOPP)

    Summary
    EudraCT number
    2015-004031-12
    Trial protocol
    GB  
    Global end of trial date
    31 Aug 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jan 2020
    First version publication date
    26 Jan 2020
    Other versions
    Summary report(s)
    Clinical Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    AC15007
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02669875
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    ACCORD (Academic and Clinical Central Office for Research and Development for NHS Lothian/University of Edinburgh)
    Sponsor organisation address
    Queen's Medical Research Institute, Edinburgh BioQuarter, 47 Little France Crescent, Edinburgh, United Kingdom, EH16 4TJ
    Public contact
    Professor Jonathan Fallowfield, University of Edinburgh, 44 01312426589, Jonathan.Fallowfield@ed.ac.uk
    Scientific contact
    Professor Jonathan Fallowfield, University of Edinburgh, 44 01312426589, Jonathan.Fallowfield@ed.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
    31 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To demonstrate that 2 hours treatment with serelaxin through a drip reduces the portal pressure in patients with liver cirrhosis and high blood pressure in the portal vein.
    Protection of trial subjects
    We offered participants the option of a small dose of sedative (midazolam) prior to insertion of the femoral venous catheter. Fluoroscopic (x-ray) screening was kept to an absolute minimum (catheter positioning only). We used a non-invasive method to measure cardiac output so did not need to pass a catheter into the heart, thus obviating the risk of cardiac arrhythmias associated with right atrial pressure measurement.
    Background therapy
    -
    Evidence for comparator
    The small placebo control arm was included to allow double-blindness (not as a comparison group) and to help generate valuable information for designing a future larger randomised controlled trial.
    Actual start date of recruitment
    19 Oct 2017
    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: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    15
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This was a single-site study, undertaken at the Royal Infirmary of Edinburgh (Edinburgh, UK) between 19th October 2017 and 31st August 2018.

    Pre-assignment
    Screening details
    A total of 17 participants were screened. Of these, 2 had a screening failure and did not proceed to randomisation. Fifteen patients were randomised and 11 completed the trial (n=9 serelaxin, n=2 placebo). Reasons for withdrawal were baseline HVPG <10 mmHg (n=2) and technical failure (n=2).

    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
    Both treatments were prepared to be similar in appearance, colour, and organoleptic properties. The procedures for emergency unblinding complied with the European Clinical Trials Directive 2001/20/EC (EUCTD).

    Arms
    Arm title
    Serelaxin
    Arm description
    Recombinant human relaxin-2 (serelaxin (Novartis Pharmaceuticals, UK)) administered via peripheral i.v. infusion.
    Arm type
    Experimental

    Investigational medicinal product name
    Serelaxin
    Investigational medicinal product code
    RLX030
    Other name
    recombinant human relaxin-2
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min. This was achieved by a single infusion bag with a change in the administration rate.

    Number of subjects in period 1 [1]
    Serelaxin
    Started
    11
    Completed
    9
    Not completed
    2
         Stop/go if HVPG < 10mmHg
    1
         Technical failure with HVPG
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The primary outcome relates to the change at 2 hours in the treated group; the placebo group was included only to help maintain the blind (investigators could not be confident that a treatment had been received) and to provide a background rate of adverse events

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Serelaxin
    Reporting group description
    Recombinant human relaxin-2 (serelaxin (Novartis Pharmaceuticals, UK)) administered via peripheral i.v. infusion.

    Reporting group values
    Serelaxin Total
    Number of subjects
    11 11
    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
    Male or female adult subjects over 18 years of age
    Units: years
        arithmetic mean (standard deviation)
    56 ± 7.8 -
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    8 8
    MELD score
    Units: interger
        arithmetic mean (full range (min-max))
    10 (6 to 14) -

    End points

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    End points reporting groups
    Reporting group title
    Serelaxin
    Reporting group description
    Recombinant human relaxin-2 (serelaxin (Novartis Pharmaceuticals, UK)) administered via peripheral i.v. infusion.

    Subject analysis set title
    Baseline HVPG
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The primary endpoint was the change from baseline in fasting hepatic venous pressure gradient (HVPG) after 2 hr serelaxin infusion. No formal comparison will be made between treatment and placebo.

    Subject analysis set title
    2h HVPG following serelaxin
    Subject analysis set type
    Per protocol
    Subject analysis set description
    value at 2 hours

    Primary: HVPG

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    End point title
    HVPG
    End point description
    End point type
    Primary
    End point timeframe
    The primary outcome is to examine if the baseline to 2 hr change in fasting hepatic venous pressure gradient (HVPG) is a clinically significant one.
    End point values
    Serelaxin Baseline HVPG 2h HVPG following serelaxin
    Number of subjects analysed
    9 [1]
    9
    9
    Units: mmHg
        arithmetic mean (standard deviation)
    15.6 ± 4.3
    15.9 ± 3.3
    15.6 ± 4.3
    Attachments
    Untitled (Filename: Figure2HVPG.pdf)
    Notes
    [1] - data for end of trial reported here
    Statistical analysis title
    paired t-test
    Comparison groups
    Baseline HVPG v 2h HVPG following serelaxin
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.76
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    3.1
    Variability estimate
    Standard deviation
    Dispersion value
    3.5

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall trial
    Adverse event reporting additional description
    Safety assessments included collection of adverse events (AE), clinical examination, vital signs, laboratory tests and electrocardiograms (ECGs). Both the severity of AEs and relation to study medication treatment was collected.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Serelaxin
    Reporting group description
    Recombinant human relaxin-2 (serelaxin (Novartis Pharmaceuticals, UK)) administered via peripheral i.v. infusion.

    Reporting group title
    Placebo
    Reporting group description
    Placebo for serelaxin

    Serious adverse events
    Serelaxin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Serelaxin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 9 (77.78%)
    1 / 2 (50.00%)
    Vascular disorders
    Arterial puncture
    Additional description: mild bruising; no serious sequelae
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Syncope
    Additional description: Syncopal episode on inserting venflons or catheters
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 2 (0.00%)
         occurrences all number
    5
    0
    Hypotension
    Additional description: diastolic - transient, asymptomatic, resolved spontaneously
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Conduction disorder
    Additional description: Prolonged QTc - transient, asymptomatic, resolved spontaneously
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Non infectious, no bloody, spontaneously resolved
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    Abdominal discomfort
    Additional description: mild right upper quadrant ache - resolved spontaneously
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Liver function test increased
    Additional description: bilirubin - mild, spontaneously resolved
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Abscess
    Additional description: dental
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Oct 2016
    The amendment related to a protocol update. The PIS and consent were updated in-line with the changes. There was also the addition of new documents (Female Partner Information Sheet and Consent plus the GP letter).

    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 study was terminated before the recruitment target was met due to a global drug supply issue (Novartis stopped manufacturing serelaxin and there was none available with a shelf-life beyond 31st August 2018). Therefore, the study was underpowered.
    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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