Coronary DiseaseGLORIOUSNCT02673931
GLP-1 and Hyperoxia for Organ Protection in Heart Surgery
A study testing Byetta (Lilly, Exenatide), Conoxia (AGA, oxygen) and 20% Human Albumin in people with Coronary Disease and Shock, Cardiogenic, run by Copenhagen University Hospital, Rigshospitalet at 1 site in Denmark.
Trial summary
Patients undergoing open heart surgery are at risk of suffering damage to the heart, brain and kidneys. This study is designed as a 2-by-2 randomized clinical trial with the purpose of investigating the organ protective effects of the glucagon-like-peptide-1 (GLP-1) agonist Exenatide versus placebo and restrictive… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Coronary Disease, Shock, Cardiogenic, Renal Failure
- What is being tested?
- Byetta (Lilly, Exenatide), Conoxia (AGA, oxygen) and 20% Human Albumin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,400 participants
- Where
- 1 siteDenmark
- Study dates
- Feb 2016to Sep 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Before any study-specific procedure, including assessments for screening, the appropriate written informed consent must be obtained.
- ≥ 18 years of age at the time of signing informed consent.
- Ischemic heart disease requiring coronary artery bypass grafting (multi-vessel coronary artery disease or coronary anatomy not suitable for percutaneous coronary intervention) and/or aortic valve disease scheduled for aortic valve replacement, irrespective of other concomitant valve surgery.
Who cannot join
- Active treatment with GLP-1 agonists
- Obstructive hypertrophic cardiomyopathy, active myocarditis, constrictive pericarditis, untreated hypothyroidism or hyperthyroidism or history of or active acute pancreatitis.
- Acute (i.e. off hours, within hours surgery), Sub-acute surgery (i.e. the following days) are eligible.
- Known allergy towards Exenatide/Byetta or albumin (vehicle).
- 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.
- Recipient of any major organ transplant (e.g. lung, liver, heart)
Show all 12Show fewer
- 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)
- 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.
- Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on self-report.
- Pregnant, based on investigator evaluation (e.g., positive human chorionic gonadotropin test) or currently breast feeding.
- 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.
- Previous participation in the trial.
Trial locations and contacts
1 site in 1 country.
Denmark1 site
Rigshospitalet - Copenhagen University Hospital
Copenhagen, 2100
About this study
Official title: Efficacy of a Glucagon-like-peptide-1 Agonist and Restrictive vs. Liberal Oxygen Supply in Patients Undergoing Coronary Artery Bypass Grafting or Aortic Valve Replacement - a 2-by-2 Factorial Designed, Randomized Clinical Study
Patients undergoing open heart surgery are at risk of suffering damage to the heart, brain and kidneys.
This study is designed as a 2-by-2 randomized clinical trial with the purpose of investigating the organ protective effects of the glucagon-like-peptide-1 (GLP-1) agonist Exenatide versus placebo and restrictive versus liberal oxygenation during weaning from cardio-pulmonary bypass.
Read the detailed description
Patients with coronary artery disease (CAD) have associated atherosclerotic renal and cerebral disease making these organs especially vulnerable to ischemia during open heart surgery. At the Heart Center at Rigshospitalet in Copenhagen the investigators perform more than 1000 open heart surgery operations yearly. The primary indication is CAD with or without associated valvular disease.
Surgical treatment of patients with CAD is performed as coronary artery bypass grafting (CABG) or off- pump coronary artery bypass grafting (OPCAB). CABG requires the use of extracorporeal circulation, while this is not the case for OPCAB.
During extracorporeal circulation the heart is arrested and anticoagulated. Blood is exposed to artificial surfaces and mechanical stress potentially resulting in increased risk of a systemic inflammatory response syndrome (SIRS), arterial emboli and organ hypoperfusion with the potential for multi organ failure.
The 30-day mortality following elective CABG is 1-2%, increasing to 7% if associated with valve surgery. The elderly patients with reduced renal function and more concomitant disease have a 30-day mortality as high as 20%. Patients dying following open heart surgery often have severe heart failure including cardiogenic shock, occlusion of grafts or native coronary arteries, renal failure, stroke/transient ischemic attack and severe inflammation prior to death.
The incidence of renal failure requiring dialysis is dependent on renal function prior to surgery. With more elderly patients having surgery this incidence is increasing. Renal failure is often seen in conjunction with progression of heart failure or development of new onset heart failure. Factors associated with brain involvement in cardiac surgery are macro embolism, systemic hypotension, systemic venous hypertension and maldistribution of cerebral blood flow. The incidence of postoperative cognitive deficits are above 50% depending on when this is measured. After 12 months the figure is approximately 30%. Known factors associated with cognitive deficits are age and duration of bypass, however type of surgery (valve insertion), temperature, equipment (oxygenators, filters) and techniques of de-airing may be important. For the neuropsychological deficits micro embolism, altered brain flow and a systemic inflammatory response are probably involved. The incidence of these complications during OPCAB is unknown, but expected to be slightly lower.
Many pharmacological interventions have been tested in order to protect the brain during surgery with varying degree of success (Ketamine vs. Remifentanil, Glucose, insulin, potassium solution; Platelet activate factor antagonist; Piracetam; Lidocaine; Ramacemide; Clomethiozole. None of these has made it into clinical practice.
Glucagon-like-peptide-1 agonist - Background Exenatide has been proven effective in reducing infarct size in a model of acute myocardial infarcts and reperfusion in swine. Several animal studies and some clinical studies have been published demonstrating a beneficial effect of glucagon-like-peptide-1 (GLP-1) analogs in the treatment of various degenerative neurological diseases. The fact that type-2 diabetes has been shown to be associated with the development of the development of Alzheimer's disease and Parkinson's disease has lead to the hypothesis that insulin signaling impairment could be involved in the disease process. By the introduction of incretins such as GLP-1 analogs as treatments options in type-2 diabetes, increased awareness of potential role in the amelioration of symptoms associated with neurodegenerative diseases have emerged. In fact GLP-1 analogs have beneficial effects on memory formation and on synaptic plasticity in the brain in animal models, and prevent detrimental effects of β-amyloid in a rat model. Clinical studies have yet to prove these associations in humans. In addition it is well known that GLP-1 and analogs crosses the blood-brain barrier. Regarding ischemic injury in stroke models GLP-1 analogs have also drawn some attention. Exenatide (also known as exentide-4) infused after focal brain ischemia has been shown to reduce infarct volume in mice.
In clinical testing in humans a recent randomized clinical study investigated the effect of Exendin-4 (Exenatide) on final infarct size in myocardial infarction. Patients receiving Exenatide tended to have a lower final infarct size and a larger salvage index evaluated by cardiac magnetic resonance 3 months following index event. These findings have been confirmed in later trials. Importantly the investigational drug was administered in acutely ill patients, receiving acute revascularization for acute myocardial infarction, with no increased risk of adverse events, and no excess adverse events including hypoglycemia or pancreatitis were reported.
Restrictive vs. liberal oxygen administration during weaning from circulatory by-pass - Background Weaning from cardiopulmonary bypass is a process completing the cardiac surgery procedure, during which, the heart has been stopped, and the function of the heart and lungs has been substituted by an extracorporeal blood pump and oxygenator. After completion of the surgical procedure the heart is allowed to start beating, and will gradually take over the function of the extracorporeal by-pass. Also the patient ventilated. During this process is standard procedure to administer 100% FiO2 during the weaning process to ensure sufficient oxygen supply to the heart and other organs. The FiO2 is often reduced according to the patients needs during transfer to the intensive care unit.
This study hypothesize that a FiO2 of 50% is superior to the standard FiO2 of 100% in reducing the incidence of the primary and secondary endpoints as described below, based on the following background data.
Preclinical data suggest that hyperoxia increase cerebral damage and neurological dysfunction following brain ischemia. Most data originates from cardiac arrest models in which a no-flow state is induced and cerebral injury or neurological dysfunction is assessed. Fairly small randomized controlled trials (RCT's) in humans have found increased levels of neuron-specific enolase (NSE) but not S-100B in patients randomized to FiO2=100% compared to FiO2=30%.
Hyperoxia during and after ischemia has been investigated in several settings, and a final consensus of its benefits and hazards has yet to be established. In the following the term hyperoxia is used in situations where the FiO2 is increased to levels above 50% for simplicity.
Hyperoxia may increase the risk of developing lung injury (hyperoxia-induced lung injury - HALI), which carries a high morbidity and mortality. However, this condition seems to require several days of extremely high FiO2 to be significant and various ventilation modes may have a significant impact as well. The risk of HALI associated with shorter periods of hyperoxia seems small.
Ischemia reperfusion injury has been investigated in smaller studies only in relation to circulatory bypass with no significant impact on magnitude of increase in biomarkers related to cardiac injury according to a review by. Oxygen administration during transport for primary percutaneous coronary intervention (PCI) in patients with ST segment myocardial infarction has recently been associated with increased release of creatinine kinasis and larger final infarcts size on cardiac Magnetic Resonance Imaging (MRI). The impact of shorter courses of oxygen supplement during weaning from circulatory bypass has yet to be investigated. A direct influence of hyperoxia with an increase in systemic vascular resistance has also been suggested, and hyperoxia may not be associated with improved tissue oxygenation, while the clinical effects of this finding remain to be understood.
A recent systematic review and metaanalysis suggested that the risk of surgical site infections may be reduced with hyperoxia. However, a larger RCT in abdominal surgery found an increased mortality with hyperoxia, in particular in patients undergoing surgery for malignancies.
In summary, hyperoxia may reduce risks associated with surgery with regards to surgical site infections and possibly reperfusion injury, whereas the effects on overall benefit in term of mortality may be detrimental. Further research is needed, and for the time being an equipoise with regards to the benefits of hyperoxia when weaning patients from circulatory bypass exits. Most patients will require some degree of oxygen supplement when lungs are ventilated after apnea during circulatory bypass, hence this study pragmatically studies a restrictive (FiO2=50%) vs. a liberal oxygenation strategy (FiO2=100%)
Following open heart surgery damage to brain, kidneys and the myocardium is frequently seen due to organ ischemia. Animal experiments as well as small human studies suggest that a GLP-1 agonist may be able to reduce ischemic damage. Currently, there is no protective treatment available.
A GLP-1 agonist has the potential to protect the brain, the kidneys and the heart during open heart surgery. The treatment can easily be administered for a short time to a large population at risk. Thus, a large scale randomized study testing the efficacy of a GLP-1 agonist against placebo can conclusively determine if patients will benefit from this treatment given pre-operatively.
Restrictive vs. liberal oxygenation during weaning from circulatory bypass has not been tested in clinical trails and as seen above an equipoise for assessing the net clinical benefit of these strategies exists.
Clinical Hypothesis
- A GLP-1 agonist started pre-operatively to patients undergoing coronary artery bypass grafting will reduce mortality and morbidity due to damage to the heart, brain and kidneys.
- Restrictive oxygenation (FiO2=50%) during cardiopulmonary bypass and weaning thereof will reduce mortality and morbidity due to damage to the heart, brain and kidneys as well as reduce significant surgical site infection (requiring surgical debridement and/or prolonging hospitalization) compared to liberal oxygenation (FiO2=100%).
- Conditions
- Coronary Disease, Shock, Cardiogenic, Renal Failure, Stroke, Brain Injury, Aortic Valve Disease
- Being tested
- Byetta (Lilly, Exenatide), Conoxia (AGA, oxygen), 20% Human Albumin
- Keywords
- Open Heart Surgery, Organ protection
- Medical subject headings
- Coronary Disease, Shock, Cardiogenic, Renal Insufficiency, Stroke, Brain Injuries, Aortic Valve Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Byetta (Lilly, Exenatide)Drug
Also called GLP-1 agonist
See description of arms
Conoxia (AGA, oxygen)Drug
Also called Oxygen
See description arms
20% Human AlbuminDrug
Also called Albumin
| Study group | Role | What they receive |
|---|---|---|
| GLP-1 | Experimental | 700 patients will be randomized to GLP-1, that will be administered as follows:
248.5 mL of isotonic sodium chloride added 1.5 mL of 20% human albumin added 25 microg Byetta (Lilly, Exenatide).
The study drug infusion is initiated immediately before open heart surgery and ended after 6 hours and 15 minutes. A set dose of 17.4 microg will be given. Receives: Drug: Byetta (Lilly, Exenatide) |
| Placebo | Placebo comparator | 20% Human Albumin is given as placebo. 700 patients will be randomized to placebo, that will be administered as follows:
248.5 mL of isotonic sodium chloride added 1.5 mL of 20% human albumin.
The placebo infusion is initiated immediately before open heart surgery and ended after 6 hours and 15 minutes at the same rate as the study drug. Receives: Drug: 20% Human Albumin |
| Restrictive Oxygenation | Experimental | The intervention is FiO2 of 50%, given as 'Conoxia (AGA, oxygen)'. 700 patients will be randomized to a FiO2 of 50% as long as the arterial O2 saturation (Sa02) remains above 91% during cardiopulmonary bypass, when weaning from and the following hour after weaning from cardiopulmonary bypass. The oxygenation strategy is discontinued and the patient is treated at the discretion of the attending physician after
1. a maximum of 1 hours of intervention or
2. the patient is slid from the operating table to a hospital bed for transfer to the intensive care unit, whichever comes first. Receives: Drug: Conoxia (AGA, oxygen) |
| Liberal Oxygenation | Active comparator | The intervention is a FiO2 of 100%, given as 'Conoxia (AGA, oxygen)'. 700 patients will be randomized to a FiO2 of 100% during cardiopulmonary bypass, when weaning from and the following hour after weaning from cardiopulmonary bypass. The oxygenation strategy is discontinued and the patient is treated at the discretion of the attending physician after
1. a maximum of 1 hours of intervention or
2. the patient is slid from the operating table to a hospital bed for transfer to the intensive care unit, whichever comes first. Receives: Drug: Conoxia (AGA, oxygen) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time in days to the first occurring of the following co-primary end-points throughout the follow-up period
- Death from any cause or
- Any of the following adverse events
- Renal failure requiring any type of renal replacement therapy
- Stroke, defined as persisting (>24 hours) of any neurological sign or symptom of neurological dysfunction as determined by the treating physician based on available clinical information or CT-scan
- New onset/worsening heart failure defined as need for mechanical circulatory support at the ICU, inability to close the sternotomy due to post-surgical hemodynamic instability and/or persistent (> 48 hours from initiation of first surgical procedure after randomization) need for inotropic hemodynamic support. In addition admission for heart failure during follow-up following discharge from the index admission.
Measured: Minimum 12 months
Secondary outcomes (2)
Time in days to the occurrence of individual end-points throughout the follow-up period
- Time to death from any cause, or
- Time to death or stroke, or
- Time to death or renal dysfunction requiring dialysis, or
- Time to death or new hospitalization for heart failure during follow-up following discharge from the index admission, or
- Time to death or new onset/worsening in-hospital heart failure.
Measured: Minimum 12 months
Incidence of serious adverse events
- Surgical site infections with need for antibiotics for more than 48 hours (excluding routine use of antibiotics for open sternum, surgical intervention, and/or endocarditis within 6 months of surgery, or
- Doubling of S-creatinine or urine output below 0.5 mL/kg/hour for 12 hours or more at any time point during index admission, or
- Hypoglycemia, defined as blood glucose < 3 mmol/L, during index admission, or
- Pancreatitis, defined as s-amylase > 3 times upper normal limit, during index admission, or
- A relative reduction of LVEF of 50% compared to baseline at any time point during index admission, or
- Re-operation for bleeding during index admission, or
- Re-operation for any cause during index admission, or
- Post-surgery MI (Type 5 MI[41]) during index admission, or
- Re-admission for cardiovascular causes within 12 months
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Feb 2016 (estimated)
- Study startFeb 2016
- Primary completionSep 2024 (estimated)
- Study completionSep 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Coronary DiseaseStudies of the same condition, open and under way.
- More trials run by Copenhagen University Hospital, RigshospitaletThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1,400 participants (actual)
Sponsor and investigators
- Lead sponsor
- Copenhagen University Hospital, Rigshospitalet
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Lars Kober, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Peter Skov Olsen, MD, DMSc, Study director, Copenhagen University Hospital, RigshospitaletJens Christian Nilsson, MD, PhD, Principal investigator, Copenhagen University Hospital, RigshospitaletLars Køber, MD, DMSc, Study chair, Copenhagen University Hospital, Rigshospitalet
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02673931
- Sponsor's protocol ID
- HJE-PHARMA-001
- Acronym
- GLORIOUS
- Status last verified
- Aug 2024
- First submitted
- 6 Dec 2015
- Last updated
- 28 Aug 2024
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Wiberg S, Moller CH, Kjaergaard J, Mikkelsen AD, Sorensen HM, Kunkel JB, Olsen PS, Hofsten DE, Ravn J, Ravn H, Boesgaard S, Hassager C, Kober L, Nilsson JC. Restrictive versus liberal oxygenation in patients undergoing cardiopulmonary bypass-assisted heart surgery: a randomised controlled trial. Br J Anaesth. 2025 Dec;135(6):1618-1625. doi: 10.1016/j.bja.2025.08.005. Epub 2025 Sep 19.
PubMed 40975689Kjaergaard J, Moller CH, Wiberg S, Mikkelsen AD, Moller-Sorensen H, Ravn HB, Ravn J, Olsen PS, Hofsten DE, Boesgaard S, Kober L, Nilsson JC, Hassager C. Efficacy of the Glucagon-Like Peptide-1 Agonist Exenatide in Patients Undergoing CABG or Aortic Valve Replacement: A Randomized Double-Blind Clinical Trial. Circ Cardiovasc Interv. 2025 May;18(5):e014961. doi: 10.1161/CIRCINTERVENTIONS.124.014961. Epub 2025 Apr 23.
PubMed 40265262Wiberg S, Kjaergaard J, Mogelvang R, Moller CH, Kandler K, Ravn H, Hassager C, Kober L, Nilsson JC. Efficacy of a glucagon-like peptide-1 agonist and restrictive versus liberal oxygen supply in patients undergoing coronary artery bypass grafting or aortic valve replacement: study protocol for a 2-by-2 factorial designed, randomised clinical trial. BMJ Open. 2021 Nov 5;11(11):e052340. doi: 10.1136/bmjopen-2021-052340.
PubMed 34740932
Study at a glance
From the registry record, last updated by the sponsor on 28 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy of a Glucagon-like-peptide-1 Agonist and Restrictive vs. Liberal Oxygen Supply in Patients Undergoing Coronary Artery Bypass Grafting or Aortic Valve Replacement - a 2-by-2 Factorial Designed, Randomized Clinical Study
- ClinicalTrials.gov ID
- NCT02673931
- Acronym / sponsor ID
- GLORIOUS / HJE-PHARMA-001
- Conditions
- Coronary Disease, Shock, Cardiogenic, Renal Failure, Stroke, Brain Injury, Aortic Valve Disease
- Keywords
- Open Heart Surgery, Organ protection
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 1,400 participants (actual)
- Lead sponsor
- Copenhagen University Hospital, RigshospitaletUniversity, hospital or other
- Study start
- Feb 2016 (actual)
- Primary completion
- Sep 2024 (estimated)
- Study completion
- Sep 2024 (estimated)
- First posted
- 4 Feb 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Patients undergoing open heart surgery are at risk of suffering damage to the heart, brain and kidneys.
This study is designed as a 2-by-2 randomized clinical trial with the purpose of investigating the organ protective effects of the glucagon-like-peptide-1 (GLP-1) agonist Exenatide versus placebo and restrictive versus liberal oxygenation during weaning from cardio-pulmonary bypass.
Detailed description
Patients with coronary artery disease (CAD) have associated atherosclerotic renal and cerebral disease making these organs especially vulnerable to ischemia during open heart surgery. At the Heart Center at Rigshospitalet in Copenhagen the investigators perform more than 1000 open heart surgery operations yearly. The primary indication is CAD with or without associated valvular disease.
Surgical treatment of patients with CAD is performed as coronary artery bypass grafting (CABG) or off- pump coronary artery bypass grafting (OPCAB). CABG requires the use of extracorporeal circulation, while this is not the case for OPCAB.
During extracorporeal circulation the heart is arrested and anticoagulated. Blood is exposed to artificial surfaces and mechanical stress potentially resulting in increased risk of a systemic inflammatory response syndrome (SIRS), arterial emboli and organ hypoperfusion with the potential for multi organ failure.
The 30-day mortality following elective CABG is 1-2%, increasing to 7% if associated with valve surgery. The elderly patients with reduced renal function and more concomitant disease have a 30-day mortality as high as 20%. Patients dying following open heart surgery often have severe heart failure including cardiogenic shock, occlusion of grafts or native coronary arteries, renal failure, stroke/transient ischemic attack and severe inflammation prior to death.
The incidence of renal failure requiring dialysis is dependent on renal function prior to surgery. With more elderly patients having surgery this incidence is increasing. Renal failure is often seen in conjunction with progression of heart failure or development of new onset heart failure. Factors associated with brain involvement in cardiac surgery are macro embolism, systemic hypotension, systemic venous hypertension and maldistribution of cerebral blood flow. The incidence of postoperative cognitive deficits are above 50% depending on when this is measured. After 12 months the figure is approximately 30%. Known factors associated with cognitive deficits are age and duration of bypass, however type of surgery (valve insertion), temperature, equipment (oxygenators, filters) and techniques of de-airing may be important. For the neuropsychological deficits micro embolism, altered brain flow and a systemic inflammatory response are probably involved. The incidence of these complications during OPCAB is unknown, but expected to be slightly lower.
Many pharmacological interventions have been tested in order to protect the brain during surgery with varying degree of success (Ketamine vs. Remifentanil, Glucose, insulin, potassium solution; Platelet activate factor antagonist; Piracetam; Lidocaine; Ramacemide; Clomethiozole. None of these has made it into clinical practice.
Glucagon-like-peptide-1 agonist - Background Exenatide has been proven effective in reducing infarct size in a model of acute myocardial infarcts and reperfusion in swine. Several animal studies and some clinical studies have been published demonstrating a beneficial effect of glucagon-like-peptide-1 (GLP-1) analogs in the treatment of various degenerative neurological diseases. The fact that type-2 diabetes has been shown to be associated with the development of the development of Alzheimer's disease and Parkinson's disease has lead to the hypothesis that insulin signaling impairment could be involved in the disease process. By the introduction of incretins such as GLP-1 analogs as treatments options in type-2 diabetes, increased awareness of potential role in the amelioration of symptoms associated with neurodegenerative diseases have emerged. In fact GLP-1 analogs have beneficial effects on memory formation and on synaptic plasticity in the brain in animal models, and prevent detrimental effects of β-amyloid in a rat model. Clinical studies have yet to prove these associations in humans. In addition it is well known that GLP-1 and analogs crosses the blood-brain barrier. Regarding ischemic injury in stroke models GLP-1 analogs have also drawn some attention. Exenatide (also known as exentide-4) infused after focal brain ischemia has been shown to reduce infarct volume in mice.
In clinical testing in humans a recent randomized clinical study investigated the effect of Exendin-4 (Exenatide) on final infarct size in myocardial infarction. Patients receiving Exenatide tended to have a lower final infarct size and a larger salvage index evaluated by cardiac magnetic resonance 3 months following index event. These findings have been confirmed in later trials. Importantly the investigational drug was administered in acutely ill patients, receiving acute revascularization for acute myocardial infarction, with no increased risk of adverse events, and no excess adverse events including hypoglycemia or pancreatitis were reported.
Restrictive vs. liberal oxygen administration during weaning from circulatory by-pass - Background Weaning from cardiopulmonary bypass is a process completing the cardiac surgery procedure, during which, the heart has been stopped, and the function of the heart and lungs has been substituted by an extracorporeal blood pump and oxygenator. After completion of the surgical procedure the heart is allowed to start beating, and will gradually take over the function of the extracorporeal by-pass. Also the patient ventilated. During this process is standard procedure to administer 100% FiO2 during the weaning process to ensure sufficient oxygen supply to the heart and other organs. The FiO2 is often reduced according to the patients needs during transfer to the intensive care unit.
This study hypothesize that a FiO2 of 50% is superior to the standard FiO2 of 100% in reducing the incidence of the primary and secondary endpoints as described below, based on the following background data.
Preclinical data suggest that hyperoxia increase cerebral damage and neurological dysfunction following brain ischemia. Most data originates from cardiac arrest models in which a no-flow state is induced and cerebral injury or neurological dysfunction is assessed. Fairly small randomized controlled trials (RCT's) in humans have found increased levels of neuron-specific enolase (NSE) but not S-100B in patients randomized to FiO2=100% compared to FiO2=30%.
Hyperoxia during and after ischemia has been investigated in several settings, and a final consensus of its benefits and hazards has yet to be established. In the following the term hyperoxia is used in situations where the FiO2 is increased to levels above 50% for simplicity.
Hyperoxia may increase the risk of developing lung injury (hyperoxia-induced lung injury - HALI), which carries a high morbidity and mortality. However, this condition seems to require several days of extremely high FiO2 to be significant and various ventilation modes may have a significant impact as well. The risk of HALI associated with shorter periods of hyperoxia seems small.
Ischemia reperfusion injury has been investigated in smaller studies only in relation to circulatory bypass with no significant impact on magnitude of increase in biomarkers related to cardiac injury according to a review by. Oxygen administration during transport for primary percutaneous coronary intervention (PCI) in patients with ST segment myocardial infarction has recently been associated with increased release of creatinine kinasis and larger final infarcts size on cardiac Magnetic Resonance Imaging (MRI). The impact of shorter courses of oxygen supplement during weaning from circulatory bypass has yet to be investigated. A direct influence of hyperoxia with an increase in systemic vascular resistance has also been suggested, and hyperoxia may not be associated with improved tissue oxygenation, while the clinical effects of this finding remain to be understood.
A recent systematic review and metaanalysis suggested that the risk of surgical site infections may be reduced with hyperoxia. However, a larger RCT in abdominal surgery found an increased mortality with hyperoxia, in particular in patients undergoing surgery for malignancies.
In summary, hyperoxia may reduce risks associated with surgery with regards to surgical site infections and possibly reperfusion injury, whereas the effects on overall benefit in term of mortality may be detrimental. Further research is needed, and for the time being an equipoise with regards to the benefits of hyperoxia when weaning patients from circulatory bypass exits. Most patients will require some degree of oxygen supplement when lungs are ventilated after apnea during circulatory bypass, hence this study pragmatically studies a restrictive (FiO2=50%) vs. a liberal oxygenation strategy (FiO2=100%)
Following open heart surgery damage to brain, kidneys and the myocardium is frequently seen due to organ ischemia. Animal experiments as well as small human studies suggest that a GLP-1 agonist may be able to reduce ischemic damage. Currently, there is no protective treatment available.
A GLP-1 agonist has the potential to protect the brain, the kidneys and the heart during open heart surgery. The treatment can easily be administered for a short time to a large population at risk. Thus, a large scale randomized study testing the efficacy of a GLP-1 agonist against placebo can conclusively determine if patients will benefit from this treatment given pre-operatively.
Restrictive vs. liberal oxygenation during weaning from circulatory bypass has not been tested in clinical trails and as seen above an equipoise for assessing the net clinical benefit of these strategies exists.
Clinical Hypothesis
- A GLP-1 agonist started pre-operatively to patients undergoing coronary artery bypass grafting will reduce mortality and morbidity due to damage to the heart, brain and kidneys.
- Restrictive oxygenation (FiO2=50%) during cardiopulmonary bypass and weaning thereof will reduce mortality and morbidity due to damage to the heart, brain and kidneys as well as reduce significant surgical site infection (requiring surgical debridement and/or prolonging hospitalization) compared to liberal oxygenation (FiO2=100%).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| GLP-1 | Experimental | Drug: Byetta (Lilly, Exenatide)700 patients will be randomized to GLP-1, that will be administered as follows: 248.5 mL of isotonic sodium chloride added 1.5 mL of 20% human albumin added 25 microg Byetta (Lilly, Exenatide). The study drug infusion is initiated immediately before open heart surgery and ended after 6 hours and 15 minutes. A set dose of 17.4 microg will be given. |
| Placebo | Placebo comparator | Drug: 20% Human Albumin20% Human Albumin is given as placebo. 700 patients will be randomized to placebo, that will be administered as follows: 248.5 mL of isotonic sodium chloride added 1.5 mL of 20% human albumin. The placebo infusion is initiated immediately before open heart surgery and ended after 6 hours and 15 minutes at the same rate as the study drug. |
| Restrictive Oxygenation | Experimental | Drug: Conoxia (AGA, oxygen)The intervention is FiO2 of 50%, given as 'Conoxia (AGA, oxygen)'. 700 patients will be randomized to a FiO2 of 50% as long as the arterial O2 saturation (Sa02) remains above 91% during cardiopulmonary bypass, when weaning from and the following hour after weaning from cardiopulmonary bypass. The oxygenation strategy is discontinued and the patient is treated at the discretion of the attending physician after 1. a maximum of 1 hours of intervention or 2. the patient is slid from the operating table to a hospital bed for transfer to the intensive care unit, whichever comes first. |
| Liberal Oxygenation | Active comparator | Drug: Conoxia (AGA, oxygen)The intervention is a FiO2 of 100%, given as 'Conoxia (AGA, oxygen)'. 700 patients will be randomized to a FiO2 of 100% during cardiopulmonary bypass, when weaning from and the following hour after weaning from cardiopulmonary bypass. The oxygenation strategy is discontinued and the patient is treated at the discretion of the attending physician after 1. a maximum of 1 hours of intervention or 2. the patient is slid from the operating table to a hospital bed for transfer to the intensive care unit, whichever comes first. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Before any study-specific procedure, including assessments for screening, the appropriate written informed consent must be obtained.
- ≥ 18 years of age at the time of signing informed consent.
- Ischemic heart disease requiring coronary artery bypass grafting (multi-vessel coronary artery disease or coronary anatomy not suitable for percutaneous coronary intervention) and/or aortic valve disease scheduled for aortic valve replacement, irrespective of other concomitant valve surgery.
Key exclusion criteria (12 listed)
- Active treatment with GLP-1 agonists
- Obstructive hypertrophic cardiomyopathy, active myocarditis, constrictive pericarditis, untreated hypothyroidism or hyperthyroidism or history of or active acute pancreatitis.
- Acute (i.e. off hours, within hours surgery), Sub-acute surgery (i.e. the following days) are eligible.
- Known allergy towards Exenatide/Byetta or albumin (vehicle).
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Byetta (Lilly, Exenatide)Also: GLP-1 agonistSee description of arms | Drug | GLP-1 |
| Conoxia (AGA, oxygen)Also: OxygenSee description arms | Drug | Liberal Oxygenation, Restrictive Oxygenation |
| 20% Human AlbuminAlso: Albumin | Drug | Placebo |
Primary outcome
Time in days to the first occurring of the following co-primary end-points throughout the follow-up period
Time frame: Minimum 12 months
1. Death from any cause or 2. Any of the following adverse events 1. Renal failure requiring any type of renal replacement therapy 2. Stroke, defined as persisting (>24 hours) of any neurological sign or symptom of neurological dysfunction as determined by the treating physician based on available clinical information or CT-scan 3. New onset/worsening heart failure defined as need for mechanical circulatory support at the ICU, inability to close the sternotomy due to post-surgical hemodynamic instability and/or persistent (> 48 hours from initiation of first surgical procedure after randomization) need for inotropic hemodynamic support. In addition admission for heart failure during follow-up following discharge from the index admission.
2 secondary outcomes
Time in days to the occurrence of individual end-points throughout the follow-up period
Time frame: Minimum 12 months
Incidence of serious adverse events
Time frame: 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Aug 2024.
- Derived from this study: PubMed 40975689Wiberg S, Moller CH, Kjaergaard J, Mikkelsen AD, Sorensen HM, Kunkel JB, Olsen PS, Hofsten DE, Ravn J, Ravn H, Boesgaard S, Hassager C, Kober L, Nilsson JC. Restrictive versus liberal oxygenation in patients undergoing cardiopulmonary bypass-assisted heart surgery: a randomised controlled trial. Br J Anaesth. 2025 Dec;135(6):1618-1625. doi: 10.1016/j.bja.2025.08.005. Epub 2025 Sep 19.
- Derived from this study: PubMed 40265262Kjaergaard J, Moller CH, Wiberg S, Mikkelsen AD, Moller-Sorensen H, Ravn HB, Ravn J, Olsen PS, Hofsten DE, Boesgaard S, Kober L, Nilsson JC, Hassager C. Efficacy of the Glucagon-Like Peptide-1 Agonist Exenatide in Patients Undergoing CABG or Aortic Valve Replacement: A Randomized Double-Blind Clinical Trial. Circ Cardiovasc Interv. 2025 May;18(5):e014961. doi: 10.1161/CIRCINTERVENTIONS.124.014961. Epub 2025 Apr 23.
- Derived from this study: PubMed 34740932Wiberg S, Kjaergaard J, Mogelvang R, Moller CH, Kandler K, Ravn H, Hassager C, Kober L, Nilsson JC. Efficacy of a glucagon-like peptide-1 agonist and restrictive versus liberal oxygen supply in patients undergoing coronary artery bypass grafting or aortic valve replacement: study protocol for a 2-by-2 factorial designed, randomised clinical trial. BMJ Open. 2021 Nov 5;11(11):e052340. doi: 10.1136/bmjopen-2021-052340.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Skov Olsen, MD, DMSc study director
Copenhagen University Hospital, Rigshospitalet
Jens Christian Nilsson, MD, PhD principal investigator
Copenhagen University Hospital, Rigshospitalet
Lars Køber, MD, DMSc study chair
Copenhagen University Hospital, Rigshospitalet
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Byetta (Lilly, Exenatide), Conoxia (AGA, oxygen) and 20% Human Albumin in people with Coronary Disease and Shock, Cardiogenic, run by Copenhagen University Hospital, Rigshospitalet at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 28 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time in days to the first occurring of the following co-primary end-points throughout the follow-up period (time frame: Minimum 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02673931, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Aug 2024.