The effect of GLP-1RA exenatide on Idiopathic Intracranial Hypertension: Randomised Clinical Trial

Therapeutics to reduce intracranial pressure are an unmet need. Pre-clinical data has demonstrated a novel strategy to lower intracranial pressure using glucagon-like peptide-1 receptor signaling. Here, we translate these findings into patients by conducting a randomized, placebo controlled, double-blind trial to assess the effect of exenatide, a glucagon-like peptide-1 receptor agonist, on intracranial pressure in idiopathic intracranial hypertension. Telemetric intracranial pressure catheters enabled long-term intracranial pressure monitoring. The trial enrolled adult women with active idiopathic intracranial hypertension (intracranial pressure >25 cmCSF and papilloedema) who receive subcutaneous exenatide or placebo. The three primary outcome measures were intracranial pressure at 2.5 hours, 24 hours and 12 weeks and alpha set a priori at less than 0.1. Among the 16 women recruited, 15 completed the study (mean age 28 ± 9, body mass index 38.1 ± 6.2 kg/m2, intracranial pressure 30.6 ± 5.1 cmCSF). Exenatide significantly and meaningfully lowered intracranial pressure at 2.5 hours -5.7 ± 2.9 cmCSF ( p=0 . 048 ); 24 hours of -6.4 ± 2.9 cmCSF ( p=0 . 030 ); and 12 weeks -5.6 ± 3.0 cmCSF ( p=0 . 058 ). No serious safety signals were noted. This data provides confidence to proceed to a phase 3 trial in idiopathic intracranial hypertension and highlights the potential to utilise glucagon-like peptide-1 receptor agonist in other conditions characterised by raised intracranial pressure. ### Competing Interest Statement JLM was funded by the UK Ministry of Defence for the duration of the study. OG reports scientific consultancy fees from Invex therapeutics (2020). AY reports receiving speaker fees from Teva, UK, outside the submitted work. KB works for UCB. Professor Mollan reports other Invex Therapeutics, other Heidelberg engineering during the conduct of the study; other from Chugai-Roche Ltd, other from Janssen, other from Allergan, other from Santen, other from Roche, other from Neurodiem, outside the submitted work. Professor Sinclair reports personal fees from Invex therapeutics in her role as Director with stock holdings, during the conduct of the study (since 28.06.2019); other from Allergan, Novartis, Cheisi and Amgen outside the submitted work. All other authors declare no competing interests. ### Clinical Trial ISTCRN12678718 ### Funding Statement This study was funded by Enterprising Birmingham, University of Birmingham, UK, from 1st August 2016. Further funding was sought and from 1st August 2019 an investigator led grant was obtained from Invex therapeutics. JLM was funded by the Ministry of Defence for the duration of the study. AY was funded by an Association of British Neurologists and Guarantors of the Brain fellowship. OG was funded by Brain research UK. YL and NHG are supported by the Intramural Research Program, National Institute on Aging, NIH (AG000333). AJS was funded by a National Institute for Health Research (NIHR) clinician scientist fellowship (NIHR-CS-011-028) and the Medical Research Council, UK (MR/K015184/1) for the duration of the study. AJS is funded by a Sir Jules Thorn Award for Biomedical Science. The view expressed are those of the authors and not necessarily those of the UK National Health Service, MoD, NIHR, or the UK department of Health and Social Care. Role of Funder/Sponsor: The MoD, NIHR, MRC and Invex Therapeutics had no role in the design or conduct of the study; no role in collection, management or interpretation of the data; writing of the manuscript; and no role in the decision to submit the manuscript for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Solihull Research Ethics Committee, West midlands, UK (17/WM/0179) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors * ADA= : anti-drug antibodies; A/G ratio= : andro-gynoid ratio; BMI= : body mass index; DEXA= : dual energy x-ray absorptiometry; DPP-4= : dipeptidyl-peptidase 4; GLP-1= : glucagon-like peptide 1; HbA1C,= : glycated haemoglobin; HCG= : human choroid gonadotrophin; HIT-6= : headache impact test 6; HOMA2-IR= : Homeostasis model assessment of insulin resistance; HVF= : Humphrey visual field; ICP= : intracranial pressure; IIH= : idiopathic intracranial hypertension; logMAR= : logarithm of the minimum angle of resolution, LP= : lumbar puncture; MCS= : mental component score; MHD= : monthly headache days; NRS= : numerical rating sale; OCT= : optical coherence tomography; PCS= : physical component score; PIS= : patient information sheet; PMD= : perimetric mean deviation; PK= : pharmacokinetics; RNFL= : retinal nerve fibre layer; SF-36= : short form 36; VA= : visual acuity, VRS= : verbal rating scale.