GLP-1 Analogs for Neuroprotection After Cardiac Arrest (GLIP1)

GLP-1 Analogs for Neuroprotection After Out-of-hospital Cardiac Arrest, a Randomized Clinical Trail

Experimental studies and previous clinical trials suggest neuroprotective effects of GLP-1 analogs in various degenerative neurological diseases, and in hypoxic brain injuries in experimental designs. This study is designed as a safety and feasibility study with patients randomized 1:1 to receive GLP-1 analogs immediately after hospital admission after out of hospital cardiac arrest.

Study Overview

• Status: Completed
• Conditions: Cardiac Arrest; Coma
• Intervention / Treatment: Drug: Byetta (Lilly, Exenatide); Other: 20% Human Albumin

Detailed Description

In comatose patients resuscitated from out of hospital cardiac arrest, neurological injuries remain the leading cause of death. The in-hospital mortality is reported at 30-50%, and the total mortality, although improved substantially over the last decade, remain to be significant, in most countries up to 90%. The brain of a patient resuscitated after cardiac arrest (CA) may have suffered ischemia and when the spontaneous circulation is re-established, the subsequent reperfusion may cause further damage. Brain ischemia and the reperfusion injury lead to tissue degeneration and loss of neurological function, the extent dependent on duration and density of the insult. Temperature control and mild induced hypothermia (MIH) (33-36°C) mitigate this damage in the experimental setting and clinical trials have shown promising results in improving neurological function and survival. Recent large scale clinical trials however have investigated milder degree of hypothermia in this setting, which suggest a role for active neuroprotection outside of temperature management. Also recently, increased attention to the possible role of Glucagon-Like Peptide-1 (GLP-1) in neuroprotection has been raised, both in the context of ameliorating degenerative disease and in reducing inflammation on ischemic cerebral stroke.

Several experimental studies have shown that GLP-1 analogs has a beneficial effect in the treatment of various degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease. GLP-1 analogs have been shown to reduce brain infarct size in mice after focal brain ischemia as well as to reduce heart infarct size in swine in a model of myocardial infarction.

Recent clinical testing in humans have demonstrated a benefit of GLP-1 infusion on myocardial infarct size and a larger salvage index in patients with myocardial infarction. The GLP-1 analogs were infused in acutely ill patients in many ways similar to cardiac arrest patients with no increased risk of adverse events.

This study is a double blinded randomized study seeking to evaluate the potential neuroprotective effects of GLP-1 analogs infused in comatose patients after out of hospital cardiac arrest.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Kardiologisk Afdeling, Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Out of hospital cardiac arrest (OHCA) of presumed cardiac cause
• Sustained return of spontaneous circulation (ROSC)
• Unconsciousness (GCS <8 (Glasgow coma scale)) (patients not able to obey verbal commands)
• Sustained ROSC (Sustained ROSC: Sustained ROSC is when chest compressions have been not required for 20 consecutive minutes and signs of circulation persist)

Exclusion Criteria:

• Conscious patients (obeying verbal commands)
• Females of childbearing potential (unless a negative pregnancy test can rule out pregnancy within the inclusion window)
• In-hospital cardiac arrest (IHCA)
• OHCA of presumed non-cardiac cause, e.g. after trauma or dissection/rupture of major artery OR Cardiac arrest caused by initial hypoxia (i.e. drowning, suffocation, hanging).
• Known bleeding diathesis (medically induced coagulopathy (e.g. warfarin, clopidogrel) does not exclude the patient).
• Suspected or confirmed acute intracranial bleeding
• Suspected or confirmed acute stroke
• Unwitnessed asystole
• Known limitations in therapy and Do Not Resuscitate-order
• Known disease making 180 days survival unlikely
• Known pre-arrest cerebral performance category 3 or 4
• >4 hours (240 minutes) from ROSC to screening
• Systolic blood pressure <80 mm Hg in spite of fluid loading/vasopressor and/or inotropic medication/intra aortic balloon pump/axial flow device*
• Temperature on admission <30°C.
• Known allergy to GLP-1 analogs, including Exenatide
• Known pancreatitis
• Diabetic ketoacidosis,

• Uncorrected blood glucose at admission < 2.5 mmol/l.

  • If the systolic blood pressure (SBP) is recovering during the inclusion window (220 minutes) the patient can be included.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GLP-1; Half of the participants will receive the study drug, that will be given as follows: 250 mL isotonic sodium chloride added 1.5 mL of 20% Human Albumin added 25 microg Byetta (Lilly, Exenatide). The study drug infusion is initiated as soon as possible at rate of 72ml/hour (0.12 μg/min) for 15 min (set volume at 18 ml), followed by 26ml/hour (0.043 μg/min) to be continued for 6 hours (set volume at 156 ml). This concludes the pharmacological intervention.	Drug: Byetta (Lilly, Exenatide); See description of Arms; Other Names: Byetta; Other: 20% Human Albumin; See description of Arms
Placebo Comparator: Placebo; Half of the participants will receive placebo, that will be given as follows: 250 mL isotonic sodium chloride added 1.5 mL of 20% Human Albumin. The placebo infusion is administered exactly the same way as the study drug infusion.	Other: 20% Human Albumin; See description of Arms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Feasibility: Over 90% initiation of study drug infusion	4 hours from return of spontaneous circulation
Efficacy assessed by Area under the Neuron-specific Enolase curve	72 hours from admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurological prognostication	Blinded neurological evaluation by neurologist on "VAS-scale"	Day 5
Area under Neuron-specific Enolase curves (NSE)	Daily measurements of NSE values	48 hours
All cause mortality	Vital status by end of study by registry based follow-up	180 days
Cerebral status	Telephone based assessment of Cerebral Performance Category and modified Rankin Scale.	30 days, 90 days and 180 days
Safety: Cumulated incidence of serious adverse events related to study drug: death, need for mechanical hemodynamic support, hypoglycaemia < 3.0 mmol/l, pancreatitis (S-amylase > 3 UNL), need for renal replacement therapy in the first 3 days.		180 days
Area under S100b curve	Daily measurements of S100b	48 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular Ejection Fraction (LVEF)	LVEF on last in-hospital echocardiogram.	Day 5 or later
EEG findings	Presence of EEG findings associated with poor prognosis.	Day 3 to 5

Collaborators and Investigators

• Sponsor: Jesper Kjaergaard
• Investigators: Principal Investigator: Jesper Kjaergaard, MD., DMSc., Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Wiberg S, Hassager C, Schmidt H, Thomsen JH, Frydland M, Lindholm MG, Hofsten DE, Engstrom T, Kober L, Moller JE, Kjaergaard J. Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial. Circulation. 2016 Dec 20;134(25):2115-2124. doi: 10.1161/CIRCULATIONAHA.116.024088. Epub 2016 Nov 12.
• Toftgaard Pedersen A, Kjaergaard J, Hassager C, Frydland M, Hartvig Thomsen J, Klein A, Schmidt H, Moller JE, Wiberg S. Association between inflammatory markers and survival in comatose, resuscitated out-of-hospital cardiac arrest patients. Scand Cardiovasc J. 2022 Dec;56(1):85-90. doi: 10.1080/14017431.2022.2074093.
• Wiberg S, Kjaergaard J, Schmidt H, Thomsen JH, Frydland M, Winther-Jensen M, Lindholm MG, Hofsten DE, Engstrom T, Kober L, Moller JE, Hassager C. The Glucagon-Like Peptide-1 Analog Exenatide Increases Blood Glucose Clearance, Lactate Clearance, and Heart Rate in Comatose Patients After Out-of-Hospital Cardiac Arrest. Crit Care Med. 2018 Feb;46(2):e118-e125. doi: 10.1097/CCM.0000000000002814.
• Wiberg S, Hassager C, Thomsen JH, Frydland M, Hofsten DE, Engstrom T, Kober L, Schmidt H, Moller JE, Kjaergaard J. GLP-1 analogues for neuroprotection after out-of-hospital cardiac arrest: study protocol for a randomized controlled trial. Trials. 2016 Jun 30;17(1):304. doi: 10.1186/s13063-016-1421-2.

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: January 25, 2015
• First Submitted That Met QC Criteria: May 10, 2015
• First Posted (Estimate): May 13, 2015

Study Record Updates

• Last Update Posted (Actual): September 28, 2017
• Last Update Submitted That Met QC Criteria: September 26, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: GLP-1; Cardiac arrest; Neuroprotection
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Arrest; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Exenatide
• Other Study ID Numbers: 2013-TTMPharma-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No