The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction

Article type: Research Article

Authors: VanDusen, Keith W.^a | Eleswarpu, Sarada^a | Moretti, Eugene W.^a | Devinney, Michael J.^a | Crabtree, Donna M.^b | Laskowitz, Daniel T.^c | Woldorff, Marty G.^{d; e} | Roberts, Kenneth C.^f | Whittle, John^a | Browndyke, Jeffrey N.^d | Cooter, Mary^a | Rockhold, Frank W.^g | Anakwenze, Oke^h | Bolognesi, Michael P.^h | Easley, Mark E.^h | Ferrandino, Michael N.ⁱ | Jiranek, William A.ⁱ | Berger, Miles^{a; f; j; *} | MARBLE Study Investigators

Collaborators: Adams, Samuel B.^h | Amundsen, Cindy L.^j | Avasarala, Pallavi^a | Barber, Matthew D.^j | Berchuck, Andrew^j | Blazer III, Daniel G.ⁱ | Brassard, Rachele^a | Brigman, Brian E.^h | Cai, Victor^a | Christensen, Soren K.^a | Cox, Mitchel W.ⁱ | Davidson, Brittany A.^j | DeOrio, James K.^h | Erdmann, Detlevⁱ | Erickson, Melissa M.^h | Funk, Bonita L.^a | Gadsden, Jeffrey^a | Gage, Mark J.^h | Gingrich, Jeff R.ⁱ | Greenup, Rachel A.ⁱ | Ha, Christine^a | Habib, Ashraf^a | Abi Hachem, Ralph^{i; k} | Hall, Ashley E.^a | Hartwig, Matthew G.ⁱ | Havrilesky, Laura J.^j | Heflin, Mitchell T.^{j; l} | Holland, Courtney^a | Hollenbeck, Scott T.ⁱ | Hopkins, Thomas J.^a | Inman, Brant A.ⁱ | Jang, David W.^{i; k} | Kahmke, Russel R.ⁱ | Karikari, Isaac^k | Kawasaki, Amie^j | Klapper, Jacob A.ⁱ | Klifto, Christopher S.^h | Klinger, Rebecca^l | Knechtle, Stuart J.ⁱ | Lagoo-Deenadayalan, Sandhya A.ⁱ | Lee, Walter T.ⁱ | Levinson, Howard^{i; m; n} | Lewis, Brian D.^a | Lidsky, Michael E.ⁱ | Lipkin, Michael E.ⁱ | Mantyh, Christopher R.ⁱ | McDonald, Shelley R.^l | Migaly, Johnⁱ | Miller, Timothy E.^a | Mithani, Suhail K.ⁱ | Mosca, Paul J.ⁱ | Moul, Judd W.ⁱ | Novick, Thomas L.ⁱ | Olson, Steven A.^h | Pappas, Theodore N.ⁱ | Park, John J.^a | Peterson, Andrew C.ⁱ | Phillips, Brett T.ⁱ | Polascik, Thomas J.ⁱ | Potash, Peter^a | Preminger, Glenn M.ⁱ | Previs, Rebecca A.^j | Robertson, Cary N.ⁱ | Scales Jr, Charles D.^{i; o} | Shah, Kevin N.ⁱ | Scheri, Randall P.ⁱ | Siddiqui, Nazema Y.^j | Smani, Shayan^a | Southerland, Kevin W.ⁱ | Stang, Michael T.ⁱ | Syed, Ayesha^a | Szydlowska, Alicja^a | Thacker, Julie K.M.ⁱ | Terrando, Niccolò^a | Toulgoat-DuBois, Yanne^a | Visco, Anthony G.^j | Weidner, Alison C.^j | Yanamadala, Mamata^l | Zani Jr, Sabino^{i; p}

Affiliations: [a] Department of Anesthesiology, Duke University, Durham, NC, USA | [b] Duke Office of Clinical Research, Duke University, Durham, NC, USA | [c] Department of Neurology, Duke University, Durham, NC, USA | [d] Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA | [e] Department of Psychology and Neuroscience, Duke University, Durham, NC, USA | [f] Center for Cognitive Neuroscience, Duke University Medical Center, Durham, NC, USA | [g] Duke Clinical Research Institute, Durham, NC, USA | [h] Department of Orthopaedic Surgery, Duke University, Durham, NC, USA | [i] Department of Surgery, Duke University, Durham, NC, USA | [j] Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA | [j] Department of Obstetrics and Gynecology, Duke University, Durham, NC, USA | [k] Department of Neurosurgery, Duke University, Durham, NC, USA | [l] Department of Medicine, Duke University, Durham, NC, USA | [m] Department of Dermatology, Duke University, Durham, NC, USA | [n] Department of Pathology, Duke University, Durham, NC, USA | [o] Department of Population Health Sciences, Duke University, Durham, NC, USA | [p] Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA

Correspondence: [*] Correspondence to: Miles Berger, MD, PhD, Room 4317, Duke South Orange Zone, DUMC Box 3094, Durham, NC 27710, USA. Tel.: 919 684 8679; E-mail: [email protected]; Twitter: @RealMilesBerger

Abstract: 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.

Keywords: Alzheimer’s disease, Apolipoprotein E, Apolipoprotein E4, delirium, inflammation, neurocognitive disorders, surgery

DOI: 10.3233/JAD-191185

Journal: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1319-1328, 2020