Melatonin for Prevention of Delirium in Critically Ill Patients (MELLOW-1)

Aktiv komparator: Enteral melatonin 0.5 mg

Melatonin 0.5 mg from the 1mg/mL oral suspension qs to 5 mL with Oral Mix SF (sugar-free flavoured suspending vehicle) (final concentration of 0.1 mg/mL; final volume in the oral syringe will be 5 mL)

Legemiddel: Melatonin

Study drug will be given at 21:00 - 23:59 daily, starting on the day of enrolment until ICU discharge, death, or up to 14 days, as most critically ill patients are at greatest risk of delirium in the first two weeks of admission. The study medication will be given by mouth (PO or per os) or if needed, via the feeding tube followed by a flush with 20mL water. Doses can be given up to midnight if administration needs to be delayed for procedures or investigations.

Andre navn:

• N-acetyl-5-metoksytryptamin

Aktiv komparator: Enteral melatonin 2 mg

Melatonin 2 mg from the 1mg/mL oral suspension qs to 5 mL with Oral Mix SF (sugar-free flavoured suspending vehicle) (final concentration 0.4 mg/mL; final volume in the oral syringe will be 5 mL)

Legemiddel: Melatonin

Study drug will be given at 21:00 - 23:59 daily, starting on the day of enrolment until ICU discharge, death, or up to 14 days, as most critically ill patients are at greatest risk of delirium in the first two weeks of admission. The study medication will be given by mouth (PO or per os) or if needed, via the feeding tube followed by a flush with 20mL water. Doses can be given up to midnight if administration needs to be delayed for procedures or investigations.

Andre navn:

• N-acetyl-5-metoksytryptamin

Placebo komparator: Enteral matched placebo

Melatonin 0 mg qs to 5 mL with Oral Mix SF (sugar-free flavoured suspending vehicle) (final concentration 0 mg/mL; final volume in the oral syringe will be 5 mL)

Legemiddel: Placebo

Study drug will be given at 21:00 - 23:59 daily, starting on the day of enrolment until ICU discharge, death, or up to 14 days, as most critically ill patients are at greatest risk of delirium in the first two weeks of admission. The study medication will be given by mouth (PO or per os) or if needed, via the feeding tube followed by a flush with 20mL water. Doses can be given up to midnight if administration needs to be delayed for procedures or investigations.

Feasibility: Study adherence

Investigators will calculate protocol adherence as the overall proportion of administered doses in the prescribed dose administration window (between 21:00 and to 23:59 hours) divided by total number of eligible study days.

Feasibility: Trial recruitment

Proportion of ICU patients screened that meet study inclusion criteria, the number of patients excluded and reasons for exclusion, and the consent rate of eligible participants.

Feasibility: Time in motion (minutes)

Research coordinators at each site will capture the amount of time (minutes) taken to screen, consent, and enrol patients, complete study procedures, and collect data.

Pharmacokinetic: Peak melatonin concentration (Cmax)

Peak melatonin concentration. Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site.

On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours).

Pharmacokinetic: Time of peak melatonin concentration (Tmax)

Time of peak melatonin concentration (Tmax). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site.

On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours).

Pharmacokinetic: Morning melatonin concentration (C9AM)

Morning melatonin concentration (C9AM). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site.

On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours).

Pharmacokinetic: Melatonin half-life (T½)

Melatonin half-life (T½). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site.

On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours).

Pharmacokinetic: Mean apparent clearance (CL/F)

Mean apparent clearance (CL/F). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site.

On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours).

Pharmacokinetic: Mean apparent volume distribution (V/F)

Mean apparent volume distribution (V/F). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site.

On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours).

Pharmacokinetic: Area under the concentration-time curve (AUC)

Area under the concentration-time curve (AUC). Plasma melatonin concentrations measured by mass spectrometry. N=5 from each study arm of Mount Sinai Hospital site.

On study day 1, eight blood samples (4 mL each) will be collected at the following intervals, from the time of first study drug dose to the following morning (time 0, 0.5, 1, 2, 4, 6, 8, 12 hours).

Clinical: Adverse events

Adverse events reported by the participant, family, or treating team. The following potential adverse effects will be collected: morning drowsiness (Sedation Agitation Scale (SAS) score <3 or patient's self report of drowsiness between 07:00h and 12:00h), headache, and vivid dreams.

Clinical: Delirium incidence

Intensive Care Delirium Screening Checklist (ICDSC) administered daily. Delirium defined as an ICDSC score ≥4.

Clinical: Delirium time to onset and duration (days)

Time to onset of first ICDSC score ≥4, and number of days with ICDSC score ≥4.

Clinical: Sleep

Richards Campbell Sleep Questionnaire (RCSQ) administered daily, where possible. Patients with or without the assistance of their nurse will be asked to complete the questions of the RCSQ each morning. Nurses will not complete the RCSQ if the patient is unable to verbalize, as poor correlation has been shown between patient and nursing scores.

Clinical: Duration of mechanical ventilation

Duration of mechanical ventilation (days)

Clinical: ICU length of stay

Duration of stay for index ICU admission (days)

Clinical: Hospital length of stay

Duration of stay for admission involving trial enrolment (days)

Clinical: ICU mortality

Number of deaths during index ICU admission

Clinical: Hospital mortality

Number of deaths during hospital admission