Clinical Trial

. 2020;75(4):1319-1328.

doi: 10.3233/JAD-191185.

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

Keith W VanDusen¹, Sarada Eleswarpu¹, Eugene W Moretti¹, Michael J Devinney¹, Donna M Crabtree², Daniel T Laskowitz³, Marty G Woldorff^{4

5}, Kenneth C Roberts⁶, John Whittle¹, Jeffrey N Browndyke⁴, Mary Cooter¹, Frank W Rockhold⁷, Oke Anakwenze⁸, Michael P Bolognesi⁸, Mark E Easley⁸, Michael N Ferrandino⁹, William A Jiranek⁹, Miles Berger^{1

6

10}; MARBLE Study Investigators

Collaborators, Affiliations

Collaborators

MARBLE Study Investigators:
Samuel B Adams⁸, Cindy L Amundsen¹⁰, Pallavi Avasarala¹, Matthew D Barber¹⁰, Andrew Berchuck¹⁰, Daniel G Blazer Iii⁹, Rachele Brassard¹, Brian E Brigman⁸, Victor Cai¹, Soren K Christensen¹, Mitchel W Cox⁹, Brittany A Davidson¹⁰, James K DeOrio⁸, Detlev Erdmann⁹, Melissa M Erickson⁸, Bonita L Funk¹, Jeffrey Gadsden¹, Mark J Gage⁸, Jeff R Gingrich⁹, Rachel A Greenup⁹, Christine Ha¹, Ashraf Habib¹, Ralph Abi Hachem^{9

11}, Ashley E Hall¹, Matthew G Hartwig⁹, Laura J Havrilesky¹⁰, Mitchell T Heflin^{10

12}, Courtney Holland¹, Scott T Hollenbeck⁹, Thomas J Hopkins¹, Brant A Inman⁹, David W Jang^{9

11}, Russel R Kahmke⁹, Isaac Karikari¹¹, Amie Kawasaki¹⁰, Jacob A Klapper⁹, Christopher S Klifto⁸, Rebecca Klinger¹², Stuart J Knechtle⁹, Sandhya A Lagoo-Deenadayalan⁹, Walter T Lee⁹, Howard Levinson^{9

13

14}, Brian D Lewis¹, Michael E Lidsky⁹, Michael E Lipkin⁹, Christopher R Mantyh⁹, Shelley R McDonald¹², John Migaly⁹, Timothy E Miller¹, Suhail K Mithani⁹, Paul J Mosca⁹, Judd W Moul⁹, Thomas L Novick⁹, Steven A Olson⁸, Theodore N Pappas⁹, John J Park¹, Andrew C Peterson⁹, Brett T Phillips⁹, Thomas J Polascik⁹, Peter Potash¹, Glenn M Preminger⁹, Rebecca A Previs¹⁰, Cary N Robertson⁹, Charles D Scales Jr^{9

15}, Kevin N Shah⁹, Randall P Scheri⁹, Nazema Y Siddiqui¹⁰, Shayan Smani¹, Kevin W Southerland⁹, Michael T Stang⁹, Ayesha Syed¹, Alicja Szydlowska¹, Julie K M Thacker⁹, Niccolò Terrando¹, Yanne Toulgoat-DuBois¹, Anthony G Visco¹⁰, Alison C Weidner¹⁰, Mamata Yanamadala¹², Sabino Zani Jr^{9

16}

Affiliations

¹ Department of Anesthesiology, Duke University, Durham, NC, USA.
² Duke Office of Clinical Research, Duke University, Durham, NC, USA.
³ Department of Neurology, Duke University, Durham, NC, USA.
⁴ Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
⁵ Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
⁶ Center for Cognitive Neuroscience, Duke University Medical Center, Durham, NC, USA.
⁷ Duke Clinical Research Institute, Durham, NC, USA.
⁸ Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.
⁹ Department of Surgery, Duke University, Durham, NC, USA.
¹⁰ Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA.
¹¹ Department of Neurosurgery, Duke University, Durham, NC, USA.
¹² Department of Medicine, Duke University, Durham, NC, USA.
¹³ Department of Dermatology, Duke University, Durham, NC, USA.
¹⁴ Department of Pathology, Duke University, Durham, NC, USA.
¹⁵ Department of Population Health Sciences, Duke University, Durham, NC, USA.
¹⁶ Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA.

PMID: 32417770
PMCID: PMC7923142
DOI: 10.3233/JAD-191185

Clinical Trial

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

Keith W VanDusen et al. J Alzheimers Dis. 2020.

. 2020;75(4):1319-1328.

doi: 10.3233/JAD-191185.

Authors

Collaborators

MARBLE Study Investigators:
Samuel B Adams⁸, Cindy L Amundsen¹⁰, Pallavi Avasarala¹, Matthew D Barber¹⁰, Andrew Berchuck¹⁰, Daniel G Blazer Iii⁹, Rachele Brassard¹, Brian E Brigman⁸, Victor Cai¹, Soren K Christensen¹, Mitchel W Cox⁹, Brittany A Davidson¹⁰, James K DeOrio⁸, Detlev Erdmann⁹, Melissa M Erickson⁸, Bonita L Funk¹, Jeffrey Gadsden¹, Mark J Gage⁸, Jeff R Gingrich⁹, Rachel A Greenup⁹, Christine Ha¹, Ashraf Habib¹, Ralph Abi Hachem^{9

11}, Ashley E Hall¹, Matthew G Hartwig⁹, Laura J Havrilesky¹⁰, Mitchell T Heflin^{10

12}, Courtney Holland¹, Scott T Hollenbeck⁹, Thomas J Hopkins¹, Brant A Inman⁹, David W Jang^{9

11}, Russel R Kahmke⁹, Isaac Karikari¹¹, Amie Kawasaki¹⁰, Jacob A Klapper⁹, Christopher S Klifto⁸, Rebecca Klinger¹², Stuart J Knechtle⁹, Sandhya A Lagoo-Deenadayalan⁹, Walter T Lee⁹, Howard Levinson^{9

13

14}, Brian D Lewis¹, Michael E Lidsky⁹, Michael E Lipkin⁹, Christopher R Mantyh⁹, Shelley R McDonald¹², John Migaly⁹, Timothy E Miller¹, Suhail K Mithani⁹, Paul J Mosca⁹, Judd W Moul⁹, Thomas L Novick⁹, Steven A Olson⁸, Theodore N Pappas⁹, John J Park¹, Andrew C Peterson⁹, Brett T Phillips⁹, Thomas J Polascik⁹, Peter Potash¹, Glenn M Preminger⁹, Rebecca A Previs¹⁰, Cary N Robertson⁹, Charles D Scales Jr^{9

15}, Kevin N Shah⁹, Randall P Scheri⁹, Nazema Y Siddiqui¹⁰, Shayan Smani¹, Kevin W Southerland⁹, Michael T Stang⁹, Ayesha Syed¹, Alicja Szydlowska¹, Julie K M Thacker⁹, Niccolò Terrando¹, Yanne Toulgoat-DuBois¹, Anthony G Visco¹⁰, Alison C Weidner¹⁰, Mamata Yanamadala¹², Sabino Zani Jr^{9

16}

Affiliations

¹ Department of Anesthesiology, Duke University, Durham, NC, USA.
² Duke Office of Clinical Research, Duke University, Durham, NC, USA.
³ Department of Neurology, Duke University, Durham, NC, USA.
⁴ Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
⁵ Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
⁶ Center for Cognitive Neuroscience, Duke University Medical Center, Durham, NC, USA.
⁷ Duke Clinical Research Institute, Durham, NC, USA.
⁸ Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.
⁹ Department of Surgery, Duke University, Durham, NC, USA.
¹⁰ Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA.
¹¹ Department of Neurosurgery, Duke University, Durham, NC, USA.
¹² Department of Medicine, Duke University, Durham, NC, USA.
¹³ Department of Dermatology, Duke University, Durham, NC, USA.
¹⁴ Department of Pathology, Duke University, Durham, NC, USA.
¹⁵ Department of Population Health Sciences, Duke University, Durham, NC, USA.
¹⁶ Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA.

PMID: 32417770
PMCID: PMC7923142
DOI: 10.3233/JAD-191185

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.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST

Dr. Laskowitz is an officer of Aegis-CN, which provides study drug for MARBLE but maintains no editorial control over study design, execution, or the writing of this manuscript. Dr. Laskowitz is a co-inventor of the Duke-held patent for CN-105. Dr. Berger acknowledges private consulting income from two legal cases related to postoperative cognition, and material support from Masimo Inc. for another prior study.

Figures

**Figure 1.**
An overview of the MARBLE trial design. Precise time periods for each intervention or measurement are given in Table 1.

See this image and copyright information in PMC

References

1. Berger M, Nadler JW, Browndyke J, Terrando N, Ponnusamy V, Cohen HJ, Whitson HE, Mathew JP (2015) Postoperative Cognitive Dysfunction: Minding the Gaps in Our Knowledge of a Common Postoperative Complication in the Elderly. Anesthesiol Clin 33, 517–550. - PMC - PubMed
1. McDonagh DL, Mathew JP, White WD, Phillips-Bute B, Laskowitz DT, Podgoreanu MV, Newman MF, Neurologic Outcome Research G (2010) Cognitive function after major noncardiac surgery, apolipoprotein E4 genotype, and biomarkers of brain injury. Anesthesiology 112, 852–859. - PMC - PubMed
1. Inouye SK, Westendorp RGJ, Saczynski JS (2014) Delirium in elderly people. Lancet (London, England) 383, 911–922. - PMC - PubMed
1. Raats JW, van Eijsden WA, Crolla RMPH, Steyerberg EW, van der Laan L (2015) Risk Factors and Outcomes for Postoperative Delirium after Major Surgery in Elderly Patients. PloS one 10, e0136071–e0136071. - PMC - PubMed
1. Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS (2009) Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 110, 548–555. - PubMed

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

Collaborators

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

Authors

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Conflict of interest statement

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