Ramelteon for prevention of postoperative delirium in elderly cancer patients: A randomized, double-blind, placebo-controlled multicenter trial, JORTC-PON02/J-SUPPORT2103/NCCH2103.

LBA12002 Background: Delirium is a common and serious complication after major cancer surgery in older adults. Current guidelines, including the American Psychiatric Association guideline, do not recommend routine pharmacological prevention because of insufficient high-quality evidence. Ramelteon, a melatonin receptor agonist with a favorable safety profile, has suggested potential benefit in critically ill populations but has shown inconsistent results for prevention of postoperative delirium. Methods: This randomized, double-blind, placebo-controlled multicenter phase III trial enrolled cancer patients aged ≥65 years undergoing surgery under general anesthesia. Patients received ramelteon 8 mg or placebo nightly from 4–8 days before surgery through postoperative day 4. Randomization used minimization with prespecified stratification factors (age ≥75 years, surgical duration ≥6 h, benzodiazepine use, and study site). Guideline-based multicomponent delirium prevention care was implemented in all patients. The planned sample size was 678 patients aged ≥75 years (primary analysis set) plus 88 aged 65–74 years. The primary endpoint was DSM-5–defined delirium within 5 days after surgery. Between-group differences were analyzed using a Cochran–Mantel–Haenszel test adjusted for stratification factors. Results: Among patients aged ≥75 years, postoperative delirium occurred in 22.47% (71/316) of patients receiving ramelteon and 22.76% (71/312) receiving placebo, with no significant difference between groups (adjusted risk difference, ramelteon minus placebo, 0.05%; 95% CI, -6.50% to 6.59%; P = 0.9881). Among patients aged ≥65 years, delirium occurred in 22.54% (80/355) in the ramelteon group and 21.19% (75/354) in the placebo group (adjusted risk difference, ramelteon minus placebo, 1.57%; 95% CI, -4.52% to 7.65%; P = 0.6098). Conclusion: In this phase III randomized controlled trial, ramelteon did not reduce the incidence of postoperative delirium in older adults undergoing major cancer surgery, and these findings do not support routine pharmacological prevention with ramelteon in this setting. Clinical trial information: jRCTs031210673. Clinical trial information: jRCTs031210673 . Delirium within 5 days after surgery. Item Description Primary endpoint result (≥75 y) 22.47% (71/316) with ramelteon vs 22.76% (71/312) with placebo Secondary endpoint result (≥65 y) 22.54% (80/355) with ramelteon vs 21.19% (75/354) with placebo