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    Summary
    EudraCT Number:2015-004424-65
    Sponsor's Protocol Code Number:15085MS-AS
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2016-03-29
    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 number2015-004424-65
    A.3Full title of the trial
    Prevention of post-operative complications by using HMG-CoA Reductase Inhibitor in patients undergoing oesophagectomy - A multicentre, randomised, double blind, placebo controlled trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Prevention of heart and lung complications by using simvastatin in patients undergoing surgery for removal of food pipe
    A.3.2Name or abbreviated title of the trial where available
    Simvastatin to prevent complications after oesophagectomy v1.0
    A.4.1Sponsor's protocol code number15085MS-AS
    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 SponsorBelfast Health and Social Care Trust
    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 supportPublic Health Agency
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Queen's University of Belfast
    B.5.2Functional name of contact pointDr Murali Shyamsundar
    B.5.3 Address:
    B.5.3.1Street AddressRoom N2019, Centre for Infection and Immunity, The Wellcome-Wolfson Building, Lisburn Road
    B.5.3.2Town/ cityBelfast
    B.5.3.3Post codeBT9 6BL
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02890976381
    B.5.6E-mailmurali.shyamsundar@qub.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 Information not present in EudraCT
    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 nameSimvastatin
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPEnteral use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSimvastatin
    D.3.9.1CAS number 79902-63-9
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 placeboTablet
    D.8.4Route of administration of the placeboEnteral use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Post-operative complications - Post-operative Pulmonary complication, Acute Respiratory Distress Syndrome and Myocardial Infarction
    E.1.1.1Medical condition in easily understood language
    Post surgical complications - Complications of lungs, severe lung injury (ARDS) and heart attack
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The principal research question is whether treatment with simvastatin when compared to a placebo (dummy pill) reduces complications related to the heart and lungs after oesophagectomy (surgery to remove the food pipe).

    Patients who undergo oesophagectomy receive ventilation (breathing support) to one lung while the other lung is allowed to collapse down. This will allow access to the foodpipe and this is a major surgery. The ventilation of one lung can lead to stretch of one lung while the other lung will be collapsed down. Both stretch and collapse can lead to inflammation and these patients have a high incidence of lung related complications such as pneumonia and in a more severe situation a condition called acute respiratory distress syndrome (ARDS). They also have a significant stress on the heart which can cause heart attacks (myocardial ischaemia).

    Various smaller studies have shown that patients who are on the group of medications called statins (to which the study drug si
    E.2.2Secondary objectives of the trial
    The secondary research questions will look at the following:
    1. Chances of complications such as post surgical lung complications and heart attacks up to 28 days post surgery or hospital discharge whichever is earlier
    2. Abnormal heart rhythm by day 28 or hospital discharge whichever is earlier
    3. Clots in deep veins by day 28 or hospital discharge whichever is earlier
    4. Surgical complications by day 28 or hospital discharge whichever is earlier
    5. Duration for which breathing support was used after surgery
    6. Safety of the study drug as measured by liver, kidney function and muscle enzyme
    7. Health related quality of life (HRQoL)
    8. Length of ICU stay (level 3 care)
    9. Length of HDU stay (level 2 care)
    10. Length of hospital stay
    11. Health service contacts up to 90 days post surgery
    12. Cost effectiveness of the study drug
    13. Hospital mortality and 90 day mortality
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Adult patients ≥18 years of age undergoing elective oesophagectomy
    2.Female subjects must be surgically sterile, or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 30 days after completion of treatment. A pregnancy test, measured by urine HCG in females with child bearing potential, will be performed at pre-operative assessment clinic
    E.4Principal exclusion criteria
    1.Age < 18 years
    2.Creatinine Kinase (CK) > 5 times upper limit normal range in the local laboratory
    3.Known active liver disease (Child’s Pugh score > 11) or abnormal liver function tests i.e. transaminases (AST or ALT) > 3 times upper limit normal range in the local laboratory
    4.Renal impairment (calculated creatinine clearance less than 30mL/minute)
    5.Inability to take oral medication pre-operatively
    6.Subject reported lactose intolerance
    7.Participation in other intervention trials within 30 days.
    8.Current treatment with statins
    9.Known hypersensitivity to the study medication
    10.Previous adverse reaction to statins
    11.Concomitant use of fibrates or other lipid-lowering therapy
    12.Concomitant use of itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprivir, telaprevir, nefazodone, cyclosporine, danazol, amiodarone, amlodipine, verapamil or diltiazem, fusidic acid
    13.Patients must be able to understand and give signed and dated informed consent indicating that they understand all the pertinent aspects of the trial prior to enrolment
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure is a composite endpoint of the incidence of ARDS defined according to the Berlin definition, post-operative pulmonary complications (PPC) as defined by Melbourne group scale and myocardial infarction as defined by ischaemic chest pain, ECG changes and a raise in plasma troponin and also by myocardial ischaemia post non-cardiac surgery (MINS) criteria during the first seven days post operatively.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The patient undergoing oesophagectomy will be followed up post-operatively to evaluate the primary outcome for the first seven days after surgery. The outcome is a composite primary endpoint of the occurrence of PPC, ARDS and MI. PPC will be evaluated everyday against an eight point criteria called the Melbourne Group Scale(MGS) where the presence of four or more criteria defines a PPC. ARDS will be evaluated using the Berlin definition. MI will be evaluated using the classical definition of raised cardiac enzyme, cardiac ischaemic chest pain, typical ECG changes as well as by the myocardial injury in non-cardiac surgery (MINS) criteria which is evaluated by measuring blood troponin levels on the first three days after surgery.
    E.5.2Secondary end point(s)
    Secondary outcomes include clinical outcomes, safety and data for the economic evaluation.
    Clinical Outcomes
    1. Mortality at day 28 and day 90
    2. Ventilator free days (VFDs) and are defined as the number of days in the first 28 days following surgery that a patient is free from ventilator assistance, for greater than 48 hrs.
    3. ARDS, PPC and MI within 28 days of surgery or hospital discharge if earlier
    4. Atrial fibrillation within 28 days of surgery or hospital discharge if earlier
    5. Venous thromboembolism within 28 days of surgery or hospital discharge if earlier
    6. Incidence and nature of any surgical complications will be recorded

    Safety
    1. CK >10 times the upper limit of normal (day 0, day 3 and day 7 post-surgery)
    2. ALT/AST >5 times the upper limit of normal (day 0, day 3 and day 7 post-surgery)
    3. Serious adverse events (SAEs), adverse events(AEs) and occurrence of suspected unexpected serious adverse reactions (SUSARs)

    Health Economic Outcomes
    1. Health related quality of life (HRQoL):
    • EQ-5D-5L at randomisation and at 90 days post-surgery.

    2. Health and Social Care Service Use:
    • Length of ICU stay (level 3 care)
    • Length of HDU stay (level 2 care)
    • Length of hospital stay
    • Health service contacts up to 90 days post-surgery

    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will be followed up after their oesophagectomy for the evaluation of their secondary endpoints

    1. Clinical secondary endpoints will be evaluated till day 28 post surgery or till hospital discharge whichever is earlier

    2. Data for health economic evaluation will be collected by administration of the health related quality of life questionnaire (EQ-5D-5L) at baseline and at 90 days after surgery. Health resource utilisation data will be collected at day 90 post surgery. We will also collect data regarding their use of level 3, level 2 care and also the hospital length of stay as part of healthcare utilisation data.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    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 Yes
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned15
    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 No
    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
    Last visit last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days9
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days9
    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: 252
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 state452
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 452
    F.4.2.2In the whole clinical trial 452
    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)
    This intervention is a peri-operative intervention and is planned for only a maximum of 7 days post surgery. Patients will be treated as per routine standard of care after the duration of study drug administration.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NICRN
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-24
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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