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Background  Attenuating the neurological damage occurring after out-of-hospital cardiac arrest is an ongoing research effort. This dual-centre study investigates the neuroprotective effects of the glucagon-like-peptide-1 analogue Exenatide administered within 4 hours from the return of spontaneous circulation to comatose patients resuscitated from out-of-hospital cardiac arrest.    Methods/design  This pilot study will randomize a total of 120 unconscious patients with sustained return of spontaneous circulation after out-of-hospital cardiac arrest undergoing targeted temperature management in a blinded one-to-one fashion to a 6-hour and 15-minute infusion of either Exenatide or placebo. Patients are eligible for inclusion if resuscitated from cardiac arrest with randomization from 20 minutes to 240 minutes after return of spontaneous circulation. The co-primary endpoint is feasibility, defined as the initiation of treatment within the inclusion window in more than 90 % of participants, and efficacy, defined as the area under the neuron-specific enolase curve from 0 to 72 hours after admission. Secondary endpoints include all-cause mortality at 30 days and Cerebral Performance Category as well as a modified Rankin Score at 180 days. The study has been approved by the Danish National Board of Health and the local Ethics Committee and is monitored by Good Clinical Practice units. The study is currently enrolling.    Discussion  This paper presents the methods and planned statistical analyses used in the GLP-1 trial and aims to minimize bias and data-driven reporting of results.    Trial registration  1) Danish National Board of Health, EudraCT 2013-004311-45. Registered on 25 March 2014.  2) Videnskabsetisk komité C, Region Hovedstaden, No. 45728. Registered on 29 January 2014.  3) Clinicaltrial.gov,  NCT02442791 . Registered on 25 of January 2015.    Electronic supplementary material  The online version of this article (doi:10.1186/s13063-016-1421-2) contains supplementary material, which is available to authorized users.

GLP-1 analogues for neuroprotection after out-of-hospital cardiac arrest: study protocol for a randomized controlled trial