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

doi:10.1001/jamanetworkopen.2026.2289

Perioperative medicine & outcomes

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

JAMA Netw OpenPublished 1 Apr 2026Randomised controlled trial

Primary result · Grade 2 or higher AEsResultRelative risk 0.87 95% CI 0.76–1.00

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Authors' conclusion

In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs.

Study context

Population: Patients aged ≥60 years scheduled for noncardiac or nonintracranial surgery203 enrolled
Participants: 186 patients

Comparison: CN-105 vs Placebo
CN-105n = 137
Placebon = 49reference
Primary endpoint: Safety: incidence and number of postoperative adverse events (AEs)

Methodological detailstriple-blind, escalating dose, phase 2, 3:1 randomisation, single tertiary academic centre

Triple-blind
Escalating dose
Phase 2
3:1 randomisation
Single tertiary academic centre

Primary result

Grade 2 or higher AEs

Relative risk

0.87

95% CI 0.76–1.00

P = 0.10

By group

CN-10576.6%

Placebo87.8%

CN-105 vs Placebo

RR 0.87 (95% CI 0.76–1.00); P = 0.10

As reported in the abstract

Secondary outcomes

Outcome	CN-105	Placebo	← Lower odds with CN-105 ←→ Higher odds with CN-105 →	OR (95% CI)	P value
Postoperative delirium incidence	19.3%	26.5%	0.20.5125	0.66 (0.31–1.42)	P = 0.29
			0.20.5125Odds ratio (log scale)

Outcome	← Lower with CN-105 ←→ Higher with CN-105 →	Median difference (pg/mL) (95% CI)	P value
Change in CSF cytokine levels, preoperative to 24 h postoperative · IL-6	−100−50050100	−0.39 (−0.93 to 0.14 pg/mL)	P = 0.12
Change in CSF cytokine levels, preoperative to 24 h postoperative · G-CSF	−100−50050100	−0.84 (−3.06 to 1.40 pg/mL)	P = 0.18
Change in CSF cytokine levels, preoperative to 24 h postoperative · IL-8	−100−50050100	−23.32 (−94.36 to 44.93 pg/mL)	P = 0.57
Change in CSF cytokine levels, preoperative to 24 h postoperative · MCP-1	−100−50050100	−2.36 (−58.57 to 58.62 pg/mL)	P = 0.50
	−100−50050100Difference, pg/mL (linear scale)

Outcome	CN-105	Placebo	P value
Grade 2 or higher AEs per patientMedian	1 (IQR 1–3)	2 (IQR 1–5)	P = 0.03
Feasibility: doses administered within 90 min of schedule	94.6% (95% CI 92.9%–96.0%)	93.8% (95% CI 90.8%–96.0%)
Postoperative delirium severity scoreMedian	1 (IQR 1–2)	2 (IQR 1–2)	P = 0.19

Safety

Outcome	CN-105	Placebo	← Lower risk with CN-105 ←→ Higher risk with CN-105 →	RR (95% CI)	P value
Grade 2 or higher AEsPrimary outcome	76.6%	87.8%	0.512	0.87 (0.76–1.00)	P = 0.10
			0.512Relative risk (log scale)

Original publication

Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients: The Phase 2 MARBLE Randomized Clinical Trial. JAMA Netw Open. Published 1 April 2026. doi:10.1001/jamanetworkopen.2026.2289

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