Effect of melatonin versus placebo for the prevention of delirium among medically hospitalised older patients: a double-blinded randomised controlled trial (project RESTORE).

OBJECTIVES

To evaluate the efficacy of melatonin, a neurohormone regulating the sleep-wake cycle, in preventing delirium within 5 days of hospitalisation among older adult patients (≥65 years) admitted to general medical wards.

DESIGN

Single-centre, double-blinded, randomised, placebo-controlled trial.

SETTING

General medical wards of a tertiary hospital in Oman.

PARTICIPANTS

Patients aged ≥65 years admitted within 24 hours to general medical wards were screened. Key exclusion criteria included prevalent delirium, use of vasopressors, non-invasive ventilation, intensive or high-dependency unit admission and aphasia.

INTERVENTIONS: Participants were randomly assigned to receive either 5 mg or 8 mg of melatonin or a placebo nightly for up to 5 days during hospitalisation or until discharge, whichever occurred first.

PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the incidence of delirium within 5 days, assessed using the 3-Minute Diagnostic Confusion Assessment Method. Secondary outcomes included delirium treatment, average sleep duration or sleep maintained, 28-day mortality and 28-day readmission. Analyses followed the intention-to-treat (ITT) principle, with per-protocol (PP) analyses conducted for robustness.

RESULTS

The study was terminated early due to futility. At termination, a total of 115 participants were recruited, 109 of whom were included in the ITT analyses: 55 in the melatonin group (5 mg or 8 mg) and 54 in the placebo group. The overall incidence of delirium by day 5 was 2.75%, 3.64% in the melatonin group and 1.85% in the placebo group (p=1.000). No statistically significant differences were found in the average sleep duration (p=0.136), 28-day mortality (3.64% vs 1.85%, p=1.000) or 28-day readmission (21.82% vs 20.37%, p=0.853). PP analyses and subgroup sensitivity yielded similar findings.

CONCLUSIONS

In this trial, melatonin did not significantly reduce the incidence of delirium. The lower-than-expected numbers of outcome events and resultant early termination for futility limited the study's power. As a result, the study findings should be interpreted with caution, and further research is necessary before definitive recommendations can be made.

TRIAL REGISTRATION NUMBER: NCT06509191.