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    Summary
    EudraCT Number:2015-003259-24
    Sponsor's Protocol Code Number:0360
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-10-23
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-003259-24
    A.3Full title of the trial
    The Effect of Sildenafil (REVATIO®) on Post Cardiac Surgery Acute Kidney Injury: A Randomised, Placebo-controlled Phase IIb Clinical Trial: The REVAKI-2 Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The Effect of Sildenafil (Revatio®) on Post Cardiac Surgery Acute Kidney Injury (AKI): A Randomised, Placebo-controlled Clinical Trial: "REVAKI 2 Trial"
    A.3.2Name or abbreviated title of the trial where available
    REVAKI-2
    A.4.1Sponsor's protocol code number0360
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN18386427
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Leicester
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBritish Heart Foundation
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMrs Tracy Kumar
    B.5.2Functional name of contact pointResearch Manager
    B.5.3 Address:
    B.5.3.1Street AddressClinical Sciences Wing, Glenfield Hospital
    B.5.3.2Town/ cityLeicester
    B.5.3.3Post codeLE3 9QP
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01162583039
    B.5.6E-mailtk98@le.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Revatio (Sildenafil)
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSildenafil
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSildenafil citrate
    D.3.9.1CAS number 139755-83-2
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.05 to 0.667
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Post cardiac surgery acute kidney injury
    E.1.1.1Medical condition in easily understood language
    Kidney damage following cardiac surgery
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10069339
    E.1.2Term Acute kidney injury
    E.1.2System Organ Class 10038359 - Renal and urinary disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary objectives of the trial
    1. Estimate differences in the frequency of AKI (defined as a rise in serum creatinine of >26µmol.l-1 within 48 hours or a doubling of the serum creatinine within 7 days as defined by the KDIGO criteria [20]), between patients allocated to receive sildenafil compared to participants allocated to placebo.
    2. Estimate differences in biomarkers of postoperative renal injury, and myocardial injury, between participants allocated to sildenafil compared to participants allocated to placebo.
    3. Estimate differences in the frequency of sepsis, low cardiac output, acute lung, brain, or gut injury or death between patients allocated to receive sildenafil compared to patients participants allocated to placebo. These outcomes, along with the primary outcome will also be considered as a composite endpoint.
    4. Estimate differences in Multiple Organ Dysfunction Scores between patients allocated to sildenafil versus patients allocated to placebo.
    5. Estimate differences in the frequency of other
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult cardiac surgery patients (>18 years) and above undergoing cardiac surgery with cardiopulmonary bypass and cardioplegic arrest.
    2. Identified as representing a high risk group for AKI using a modified AKI risk score equal or greater than 22%.
    3. Female subjects of childbearing potential are not to be pregnant (to be confirmed by urine human chorionic gonadotropin pregnancy test prior to dosing). Women are considered not to be of childbearing potential if they have been surgically sterilised (eg, tubal ligation, oophorectomy or hysterectomy) or are postmenopausal in the absence of hormone replacement therapy and complete absence of menses for at least 24 consecutive months.
    4. Able, in the opinion of the investigator, and willing to give informed consent.
    E.4Principal exclusion criteria
    1.Cardiac surgery patients (<18 years) undergoing cardiac surgery with cardiopulmonary bypass and cardioplegic arrest.
    2. Emergency or salvage procedure
    3.Ejection fraction <20%
    4.CKD Stage 5, defined as eGFR<15ml/min or renal replacement therapy. (as per the Modified diet in Renal Disease formula ) or renal replacement therapy
    5.Patients with a pre-existing sepsis or organ injury defined as documented sepsis, AKI, acute lung injury, myocardial infarction, low cardiac output, liver injury, stroke or pancreatitis within 5 days of surgery.
    6.Administration of potent CYP 3A4 inhibitors within 1 month prior to study participation (e.g. HIV protease inhibitors, imidazole antifungals and erythromycin, please see Appendix 1 for a full list of prohibited medications).
    7.Administration of nitrate medicines (e.g. glyceryl trinitrate within 24 hours of surgery.
    8.Patients allergic to any other PDE-5 Inhibitor.
    9.Any ongoing malignancy or prior malignancy that currently requires treatment.
    10.Patients who are participating in another interventional clinical study.
    11.Patients who have loss of vision in one eye due to non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether it is connected to previous PDE5 inhibitor exposure.
    12.Risk of pregnancy
    13. Unable, in the opinion of the investigator, or unwilling to give informed consent
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome for the trial is serum creatinine measured daily from baseline for up to 7 days post-surgery or discharge if earlier.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Serum creatinine measured at daily for up to 7 days post-surgery or discharge if earlier.
    E.5.2Secondary end point(s)
    1. AKI defined according to the Kidney Diseases Improving Global Outcomes (KIDIGO) serum creatinine criteria.
    2. Changes in biochemical markers of renal injury and dysfunction (urine neutrophil gelatinase-associated lipocalin (NGAL)), and myocardial injury (serum troponin), measured at baseline and at 24 hours post-surgery.
    3. Acute lung injury, low cardiac output, acute brain injury, acute liver or gut injury, sepsis syndrome, death.
    4. Multiple Organ Dysfunction (MOD) Score at ICU admission, 24, 48, 72 and 96 hours.
    5. Organ injury, sepsis or death: A composite of sepsis syndrome, acute kidney injury, acute lung injury, acute brain injury, low cardiac output syndrome, gut or liver injury, or death.
    6. Length of ICU and hospital stay.
    7. Vital sign measurements and vasopressor use during and after drug administration.
    8. Postoperative blood loss, transfusion of RBC and non RBC allogenic blood components.
    9. Expected adverse events other than those included in the primary endpoint.
    10. Endothelial function as measured by the reactive hyperemia peripheral arterial tonometry (RH-PAT) index.
    11. Laboratory measures of platelet, leucocyte and endothelial cell activation from blood samples and tracheal aspirates.
    E.5.2.1Timepoint(s) of evaluation of this end point
    please see above
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    For an individual participant, the end of the trial is defined as completion of the 3-month postal follow-up assessment (3 months post surgery). The definition of the end of the trial as a whole is the date when all participants have completed the 3-month postal follow-up or have been lost to follow-up.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 66
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state126
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 126
    F.4.2.2In the whole clinical trial 126
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    As per normal clinical practice. Sildenafil will not be provided to patients after the trial.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-11-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-09-20
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