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    Summary
    EudraCT Number:2015-003050-41
    Sponsor's Protocol Code Number:HJE-PHARMA-001
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-07-20
    Trial 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 ConcernedDenmark - DHMA
    A.2EudraCT number2015-003050-41
    A.3Full title of the trial
    Efficacy of GLP-1 agonists and restrictive vs. liberal FiO2 in patients undergoing coronary artery bypass grafting or aortic valve replacement – a 2-by-2 factorial designed, randomized clinical study
    GLP-1- og Iltbehandling til Organbeskyttelse ved hjerteoperation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    GLP-1 and hyperoxia for organ protection in heart surgery
    GLP-1- og Iltbehandling til Organbeskyttelse ved hjerteoperation
    A.3.2Name or abbreviated title of the trial where available
    GLP-1 and hyperoxia in CABG/AVR surgery patients
    A.4.1Sponsor's protocol code numberHJE-PHARMA-001
    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 SponsorRigshospitalet
    B.1.3.4CountryDenmark
    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 supportNone
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRigshospitalet
    B.5.2Functional name of contact pointHjertemedicinsk Klinik
    B.5.3 Address:
    B.5.3.1Street AddressBlegdams Vej 9
    B.5.3.2Town/ cityCopenhagen E
    B.5.3.3Post code2100
    B.5.3.4CountryDenmark
    B.5.6E-maillars.koeber@regionh.dk
    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 Byetta
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb / AstraZeneca EEIG
    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 nameByetta
    D.3.2Product code EU/1/06/362/001-2
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    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.IMP: 2
    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 No
    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 nameOxygen
    D.3.2Product code None
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPEndotracheopulmonary use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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 Yes
    D.3.11.13.1Other medicinal product typeOxygen administred at either 50% FiO2 or 100% FiO2.
    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 infusion
    D.8.4Route of administration of the placeboIntravenous drip use (Noncurrent)
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboMedicinal gas, compressed
    D.8.4Route of administration of the placeboEndotracheopulmonary use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    We investigate the efficacy of commercially available GLP-1 analog for reducing organ damage in patients undergoing heart surgery (i.e. coronary artery bypass grafting and/or aortic valve replacement).
    In addition we investigate the efficacy of restrictive versus liberal oxygenation (i.e. FiO2 50% versus FiO2 100%) for reducing organ damage during weaning after heart surgery. The study is a two-by-two factorial designed randomized clinical trial.
    E.1.1.1Medical condition in easily understood language
    Patients undergoing heart surgery are vulnerable to organ damage occurring during the operation. GLP-1 infusion and/or restrictive oxygenation could possibly decrease this damage.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10008937
    E.1.2Term Chronic ischemic heart disease, unspecified
    E.1.2System Organ Class 100000011627
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To reduce the degree of post-operative organ damage following coronary artery bypass grafting and/or aortic valve replacement, defined as the composite end point of time to death from any cause, renal dysfunction requiring dialysis, stroke or hospital admission/prolongation with worsening/new onset heart failure (HF). The methods GLP-1 versus placebo peri-operatively and restrictive (FiO2 50%) versus liberal (FiO2 100%) oxygenation during weaning will be tested in a 2-by-2 design.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to determine the efficacy of a GLP-1 agonist compared to placebo on the individual components of the primary endpoint. Similar analyses are planned for the comparison of restrictive vs. liberal administration of oxygen during weaning from circulatory bypass.
    Minor manifestations of organ damage will be investigated by comparing the effect of a GLP-1 agonist in pre-defined sub-studies with that of placebo on changes in neuropsychological scores, left ventricular ejection fraction, plasma creatinine and calculated creatinine clearance.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    There will be three sub-studies focusing on one organ-system each:
    1) Heart
    2) Brain
    3) Kidneys
    Each sub-study will investigate the secondary endpoints related to their organ-system.
    The intervention will be administered exactly as dictated by the main trial. Therefor participation in a sub-study will have no impact on the IMP-use.
    E.3Principal inclusion criteria
    1) Before any study-specific procedure, including assessments for screening, the appropriate written informed consent must be obtained
    2) ≥ 18 years of age at the time of signing informed consent
    3) IHD requiring CABG (multi-vessel coronary artery disease or coronary anatomy not suitable for percutaneous coronary intervention) and/or Aortic Valve Disease scheduled for AVR, irrespective of other concomitant valve surgery.
    E.4Principal exclusion criteria
    1) Obstructive hypertrophic cardiomyopathy, active myocarditis, constrictive pericarditis, untreated hypothyroidism or hyperthyroidism or history of or active acute pancreatitis.
    2) Acute (i.e. off hours, within hours surgery), Sub-acute surgery (i.e. the following days are eligible).
    3) Known allergy towards Exenatide/Byetta or albumin (vehicle).
    4) On the urgent waiting list for a heart transplant (UNOS category 1A or 1B, or equivalent). Patients on the non-urgent waiting list for a heart transplant (UNOS category 2 or 7, or equivalent) are eligible for inclusion in the study.
    5) Recipient of any major organ transplant (e.g. lung, liver, heart)
    6) Receiving or has received cytotoxic or cytostatic chemotherapy and/or radiation therapy for treatment of a malignancy within 6 month before randomization or clinical evidence of current malignancy, with the following exceptions: basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, prostate cancer (if stable localized disease, with a life expectancy of > 2.5 years in the opinion of the investigator)
    7) Currently enrolled in, or at least 30 days not yet elapsed since ending participation in other investigational drug trial(s) for the treatment of Diabetes or malignant Obesity investigating the use of GLP-1 agonists or receiving other investigational agent(s). Concomitant participation in other non-pharmacological trials is not an exclusion criterion.
    8) Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on self-report.
    9) Pregnant, based on investigator evaluation (e.g., positive human chorionic gonadotropin test) or currently breast feeding.
    10) Any condition (e.g., psychiatric illness) or situation that, in the investigator’s opinion, could put the subject at significant risk, confound the study results, or interfere significantly with the subject’s participation in the study.
    E.5 End points
    E.5.1Primary end point(s)
    1) Time to death from any cause or
    2) Time to any of the following events
    a) renal failure requiring any type of renal replacement therapy
    b) stroke defined as persisting (>24 hours) of any neurological sign or symptom of neurological dysfunction as determined by the treating physician based on available
    i) clinical information and/or
    ii) CT scan.
    MRI performed as part of a substudy will not be used for the definition of stroke and/or
    c) new onset/worsening heart failure defined as
    i) need for mechanical circulatory support at the ICU,
    ii) inability to close the sternotomy due post-surgical hemodynamic instability and/or
    iii) persistent (>48 hours from initiation of first surgical procedure after randomization) need for inotropic hemodynamic support
    iv) Admission for heart failure during follow-up following discharge from the index admission.
    E.5.1.1Timepoint(s) of evaluation of this end point
    A 12-month follow-up for the primary endpoint is planned.
    E.5.2Secondary end point(s)
    Efficacy:
    • Time to death from any cause
    • Time to death or stroke (as defined above)
    • Time to death or renal dysfunction requiring dialysis (as defined above)
    • Time to death or new hospitalization for heart failure during follow-up following discharge from the index admission
    • Time to death or new onset/worsening in-hospital heart failure (as defined above)
    • Change from baseline in patient-reported outcome (PRO), focusing on CPC and mRS scales as well as ‘two simple questions’ at 6 months follow up
    • In-hospital death from any cause or hospital prolongation with renal failure requiring dialysis, stroke or new onset/worsening heart failure.
    E.5.2.1Timepoint(s) of evaluation of this end point
    A 12-month follow-up for the secondary endpoint is planned.
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.1.7.1Other trial design description
    The GLP-1-analog vs placebo arm will be double blind, the FiO2 50% vs FiO2 100% will be single blind
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    The control for restrictive vs liberal oxygenation will be FiO2 100%
    E.8.2.4Number of treatment arms in the trial4
    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.8.5The 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
    The trial is event driven and power calculations show that to be able to show a 25% risk reduction we will need 323 primary events to have a power of 80% or more. With an expected annual event rate of 16% we expect to include approximately 1400 patients in the trial. As treatment is given immediately prior to open heart surgery no drop-outs are expected.
    Last contact to the subject will be 12 months +/- 2 weeks after last randomization.
    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 months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 500
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 900
    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 state1400
    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)
    No trial-specific treatment will take place after the subject has ended participation. The subjects will undergo normal clinical follow-up as occurring normally.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-10-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-10
    P. End of Trial
    P.End of Trial StatusOngoing
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