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    Clinical Trial Results:
    The Effect of Sildenafil (REVATIO®) on Post Cardiac Surgery Acute Kidney Injury: A Randomised, Placebo-controlled Phase IIb Clinical Trial: The REVAKI-2 Trial

    Summary
    EudraCT number
    		 2015-003259-24
    Trial protocol
    		 GB  
    Global end of trial date
    20 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Oct 2019
    First version publication date
    26 Oct 2019
    Other versions
    Summary report(s)
    		 Study Manuscript (proof)

    Trial information

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    Trial identification
    Sponsor protocol code
    0360
    Additional study identifiers
    ISRCTN number
    		 ISRCTN18386427
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Leicester
    Sponsor organisation address
    University Road, Leicester, United Kingdom,
    Public contact
    Research Manager, Mrs Tracy Kumar, 44 01162583039, tk98@le.ac.uk
    Scientific contact
    Research Manager, Mrs Tracy Kumar, 44 01162583039, tk98@le.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
    18 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The REVAKI-2 Trial proposes to test the hypothesis that postoperative acute kidney injury (AKI) will be less in cardiac surgery patients identified as being at increased risk of developing AKI preoperatively, by the administration of sildenafil, a PDE-5 inhibitor
    Protection of trial subjects
    Exclusion criteria applied regarding contra-indication for the investigation product. Research bloods attempted to be taken at the same time as routine clinical blood tests to minimise risk of pain, bruising, blood clots, and infections.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 129
    Worldwide total number of subjects
    129
    EEA total number of subjects
    129
    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)
    0
    From 65 to 84 years
    125
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 There were 129 patients recruited and randomised between September 2015 and September 2018 which made up the analysis population, 60 of whom were allocated to Sildenafil and 69 to Placebo.

    Pre-assignment
    Screening details
    		 Potential research participants were identified by qualified study staff from clinical and theatre lists and hospital medical notes and referrals from other trusts.

    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
    		 Subject, Investigator
    Blinding implementation details
    The active drug or placebo according to randomisation will be prepared by the unblinded researchers. This will be prepared in a clinical area whereby the unblinded researchers are the only team members aware of the allocated treatment. The blinded team will not handle the supply or returns of the investigational medicinal product. Both active drug (bolus and infusion) and placebo (bolus and infusion) will be clearly labelled as REVAKI-2 sildenafil/placebo and are identical in appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sildenafil
    Arm description
    		 Sildenafil citrate 12.5mg in 65mls of 5% dextrose solution was administered intravenously over 150 minutes starting at the time of skin incision.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sildenafil Citrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sildenafil citrate 12.5mg in 65mls of 5% dextrose solution was administered intravenously over 150 minutes starting at the time of skin incision.

    Arm title
    		 Placebo
    Arm description
    		 . In the Placebo group, a 5% dextrose solution was administered to the same volume and timing as the intervention (Sildenafil citrate 12.5mg in 65mls of 5% dextrose solution was administered intravenously over 150 minutes starting at the time of skin incision).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dextrose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    . In the Placebo group, a 5% dextrose solution was administered to the same volume and timing as the intervention (Sildenafil citrate 12.5mg in 65mls of 5% dextrose solution was administered intravenously over 150 minutes starting at the time of skin incision.)

    Number of subjects in period 1
    		Sildenafil Placebo
    Started
    60
    69
    Completed
    55
    62
    Not completed
    5
    7
         Adverse event, serious fatal
    1
    3
         Lost to follow-up
    4
    4

    Baseline characteristics

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

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 129 129
    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
    Units: years
        arithmetic mean (full range (min-max))
    		 72 (52 to 88) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24
        Male
    		 105 105

    End points

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    End points reporting groups
    Reporting group title
    Sildenafil
    Reporting group description
    		 Sildenafil citrate 12.5mg in 65mls of 5% dextrose solution was administered intravenously over 150 minutes starting at the time of skin incision.

    Reporting group title
    Placebo
    Reporting group description
    		 . In the Placebo group, a 5% dextrose solution was administered to the same volume and timing as the intervention (Sildenafil citrate 12.5mg in 65mls of 5% dextrose solution was administered intravenously over 150 minutes starting at the time of skin incision).

    Primary: Serum Creatinine

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    End point title
    		 Serum Creatinine [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    pre-operation to 96 hours post-surgery
    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 manuscript attachment
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Please see manuscript attachment
    End point values
    		 Sildenafil
    Number of subjects analysed
    60
    Units: µmol.L-1
        number (confidence interval 95%)
    0.88 (-5.82 to 7.59)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    consent to 3 month follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14
    Frequency threshold for reporting non-serious adverse events: 0%
    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: Please see manuscript attachment

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Sep 2016
    List of expected adverse events was updated. Concomitant medication timing was updated
    13 Jun 2017
    The AKI risk score used in the inclusion criteria was amended. The blood volumes to be collected were updated.

    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
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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