CN-105 administration in older surgical patients was safe and feasible, resulting in significantly fewer grade 2 or higher adverse events per patient compared to placebo (median 1 vs 2, P=.03).
Does the apolipoprotein E mimetic peptide CN-105 reduce postoperative adverse events and delirium in older adults undergoing noncardiac or nonintracranial surgery?
In older adults undergoing noncardiac or nonintracranial surgery, the apolipoprotein E mimetic peptide CN-105 was safe and feasible, though it did not significantly reduce the incidence of postoperative delirium in this phase 2 trial.
Absolute Event Rate: 0% vs 0%
Importance The apolipoprotein E ( APOE ) gene ε4 allele leads to increased Alzheimer disease risk and neuroinflammation and is also believed to play a role in postoperative delirium. However, the safety and feasibility of modulating apoE protein signaling to reduce postoperative neuroinflammation and delirium in older adults are unclear. Objective To assess the safety and feasibility of the apoE mimetic peptide CN-105 for reducing delirium incidence and severity and neuroinflammation after noncardiac or nonintracranial surgery in older adults. Design, Setting, and Participants This triple-blind, escalating dose, phase 2 randomized clinical trial enrolled patients from April 17, 2019, to December 28, 2022, at a tertiary academic medical center. Included patients were 60 years or older and scheduled for a noncardiac or nonintracranial surgery. Exclusion criteria were incarceration, planned chemotherapy within 6 weeks after surgery, or inability to undergo lumbar punctures. Data analyses were based on a modified intention-to-treat approach and were performed from August 14, 2023, to August 22, 2025. Interventions Patients were randomly assigned 3:1 to the CN-105 group or placebo group. The CN-105 group received intravenous CN-105 doses of 0.1, 0.5, or 1 mg/kg starting within 1 hour before surgery and administered every 6 hours afterward until hospital discharge or 13 doses were received. Patients in the placebo group followed the same administration schedule. Main Outcomes and Measures The primary outcome was safety—the incidence and number of postoperative adverse events (AEs). Secondary outcomes included feasibility (rate of drug doses administered within 90 minutes of schedule), postoperative delirium incidence and severity, and postoperative changes in cerebrospinal fluid (CSF) cytokine levels (interleukin IL 6, granulocyte-colony stimulating factor G-CSF, monocyte chemoattractant protein-1 MCP-1, and IL-8). Results Among 203 enrolled patients, 186 (mean SD age, 68.7 5.2 years; 119 males 64.0%) were randomized (137 to the CN-105 group, 49 to the placebo group) and underwent surgery. The rates of grade 2 or higher AEs among patients in the CN-105 and placebo groups were 76.6% and 87.8% (relative risk RR, 0.87; 95% CI, 0.76-1.00; P = .10). The CN-105 vs placebo group had fewer grade 2 or higher AEs per patient (median IQR, 1 1-3 vs 2 1-5; P = .03). The percentage of CN-105 doses administered within the time window was 94.6% (860 of 909; 95% CI, 92.9%-96.0%) in the CN-105 group and 93.8% (346 of 369; 95% CI, 90.8%-96.0%) in the placebo group. Among patients in the CN-105 vs placebo group, the postoperative delirium incidence was 19.3% vs 26.5% (odds ratio OR, 0.66; 95% CI, 0.31-1.42; P = .29); the median (IQR) postoperative delirium severity scores were 1 (1-2) vs 2 (1-2) ( P = .19); and the median difference in preoperative to 24-hour postoperative CSF cytokine-level changes were as follows: −0.39 pg/mL (95% CI, −0.93 to 0.14 pg/mL, P = .12) for IL-6, −0.84 pg/mL (95% CI, −3.06 to 1.40 pg/mL; P = .18) for G-CSF,−23.32 pg/mL (95% CI, −94.36 to 44.93 pg/mL; P = .57) for IL-8, and −2.36 pg/mL (95% CI, −58.57 to 58.62 pg/mL; P = .50) for MCP-1. Conclusions and Relevance In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs. A phase 3 trial is warranted to further evaluate the efficacy of CN-105 for reducing postoperative AEs and to more precisely determine its effects on postoperative delirium incidence and severity. Trial Registration ClinicalTrials.gov Identifier: NCT03802396
Timko et al. (Fri,) reported a other. CN-105 administration in older surgical patients was safe and feasible, resulting in significantly fewer grade 2 or higher adverse events per patient compared to placebo (median 1 vs 2, P=.03).