Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients: The Phase 2 MARBLE Randomized Clinical Trial.

Summary

In a triple-blind phase 2 RCT of 186 older adults undergoing noncardiac/nonintracranial surgery, perioperative CN-105 was feasible, maintained on-time dosing, and did not increase adverse events versus placebo; grade ≥2 adverse events per patient were fewer with CN-105. While trends suggested lower delirium incidence and severity, differences were not statistically significant, and CSF cytokine changes did not differ.

Key Findings

• CN-105 achieved high on-time dosing (94.6%) and did not increase grade ≥2 adverse events versus placebo; per-patient grade ≥2 events were fewer (median 1 vs 2).
• Delirium incidence (19.3% vs 26.5%) and severity were numerically lower with CN-105 but not statistically significant.
• CSF cytokine changes (IL-6, G-CSF, IL-8, MCP-1) at 24 hours did not differ significantly between groups.

Clinical Implications

CN-105 may offer a novel neuroprotective strategy for high-risk older adults; current evidence supports safety/feasibility rather than efficacy. Clinicians should await phase 3 data but may consider trial participation and biomarker-informed stratification in future studies.

Limitations

• Single-center phase 2 trial not powered for definitive efficacy on delirium outcomes
• Male predominance and limited external generalizability; short biomarker follow-up (24 h)

Future Directions

Proceed to a multicenter phase 3 trial powered for delirium outcomes, with enriched enrollment (e.g., APOE ε4 carriers), longer biomarker trajectories, and mechanistic imaging to link neuroinflammation with clinical endpoints.