The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction
Authors: VanDusen Keith W. , Eleswarpu Sarada , Moretti Eugene W. , Devinney Michael J. , Crabtree Donna M. , Laskowitz Daniel T. , Woldorff Marty G. , Roberts Kenneth C. , Whittle John , Browndyke Jeffrey N. , Cooter Mary , Rockhold Frank W. , Anakwenze Oke , Bolognesi Michael P. , Easley Mark E. , Ferrandino Michael N. , Jiranek William A. , Berger Miles ,   MARBLE Study Investigators, Adams Samuel B. , Amundsen Cindy L. , Avasarala Pallavi , Barber Matthew D. , Berchuck Andrew , Blazer III Daniel G. , Brassard Rachele , Brigman Brian E. , Cai Victor , Christensen Soren K. , Cox Mitchel W. , Davidson Brittany A. , DeOrio James K. , Erdmann Detlev , Erickson Melissa M. , Funk Bonita L. , Gadsden Jeffrey , Gage Mark J. , Gingrich Jeff R. , Greenup Rachel A. , Ha Christine , Habib Ashraf , Abi Hachem Ralph , Hall Ashley E. , Hartwig Matthew G. , Havrilesky Laura J. , Heflin Mitchell T. , Holland Courtney , Hollenbeck Scott T. , Hopkins Thomas J. , Inman Brant A. , Jang David W. , Kahmke Russel R. , Karikari Isaac , Kawasaki Amie , Klapper Jacob A. , Klifto Christopher S. , Klinger Rebecca , Knechtle Stuart J. , Lagoo-Deenadayalan Sandhya A. , Lee Walter T. , Levinson Howard , Lewis Brian D. , Lidsky Michael E. , Lipkin Michael E. , Mantyh Christopher R. , McDonald Shelley R. , Migaly John , Miller Timothy E. , Mithani Suhail K. , Mosca Paul J. , Moul Judd W. , Novick Thomas L. , Olson Steven A. , Pappas Theodore N. , Park John J. , Peterson Andrew C. , Phillips Brett T. , Polascik Thomas J. , Potash Peter , Preminger Glenn M. , Previs Rebecca A. , Robertson Cary N. , Scales Jr Charles D. , Shah Kevin N. , Scheri Randall P. , Siddiqui Nazema Y. , Smani Shayan , Southerland Kevin W. , Stang Michael T. , Syed Ayesha , Szydlowska Alicja , Thacker Julie K.M. , Terrando Niccolò , Toulgoat-DuBois Yanne , Visco Anthony G. , Weidner Alison C. , Yanamadala Mamata , Zani Jr Sabino 
Published: May 2020

Background: Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer’s disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. Objective: MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. Methods: 201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive placebo or drug before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. Conclusion: MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.