The purpose of this study is to determine the feasibility of conducting a randomized controlled trial (RCT) with melatonin for prevention of delirium in critically ill adult patients. The investigators hypothesize that melatonin, administered on a scheduled nightly basis during ICU admission, will be efficacious and safe for the prevention of delirium in critically ill adults.
The available evidence indicates melatonin may decrease the incidence of delirium in non-critically ill patient populations; however, trials in the critically ill are lacking. The investigators hypothesize that melatonin, administered on a scheduled nightly basis during ICU admission, will be efficacious and safe for the prevention of delirium in critically ill adults. The null hypothesis is that there is no difference in delirium incidence between placebo and melatonin. Prior to conducting an adequately powered multi-centre, blinded randomized, placebo-controlled trial in critically ill patients, there is a need for a better understanding of melatonin pharmacokinetics (PK) in critically ill patients. This will help to determine appropriate dosing, drug administration issues (specifically protocol adherence), adverse drug effects, and recruitment rates based on inclusion and exclusion criteria. The specific aim is to conduct a phase II triple blind, placebo-controlled randomized trial comparing two doses of melatonin (low dose = 0.5 mg and high dose = 2.0 mg) to assess the feasibility of a future full-scale RCT. Feasibility of the larger trial will be based on protocol adherence and participant recruitment rates. Data on PK properties of melatonin will be assessed to determine dosing for future studies of melatonin for delirium prevention in the critically ill.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
69
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.
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.
Mount Sinai Hospital
Toronto, Ontario, Canada
RECRUITINGSunnybrook Health Sciences Centre
Toronto, Ontario, Canada
RECRUITINGHôpital du Sacré-Coeur
Montreal, Quebec, Canada
NOT_YET_RECRUITINGFeasibility: 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.
Time frame: 1 year
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.
Time frame: 1 year
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.
Time frame: 1 year
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).
Time frame: 24 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).
Time frame: 24 hours
Pharmacokinetic: Morning melatonin concentration (C9AM)
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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).
Time frame: 24 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).
Time frame: 24 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).
Time frame: 24 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).
Time frame: 24 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).
Time frame: 24 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.
Time frame: 14 days
Clinical: Delirium incidence
Intensive Care Delirium Screening Checklist (ICDSC) administered daily. Delirium defined as an ICDSC score ≥4.
Time frame: 14 days
Clinical: Delirium time to onset and duration (days)
Time to onset of first ICDSC score ≥4, and number of days with ICDSC score ≥4.
Time frame: 14 days
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.
Time frame: 14 days
Clinical: Duration of mechanical ventilation
Duration of mechanical ventilation (days)
Time frame: ICU admission
Clinical: ICU length of stay
Duration of stay for index ICU admission (days)
Time frame: ICU admission
Clinical: Hospital length of stay
Duration of stay for admission involving trial enrolment (days)
Time frame: 1 year
Clinical: ICU mortality
Number of deaths during index ICU admission
Time frame: 1 year
Clinical: Hospital mortality
Number of deaths during hospital admission
Time frame: 1 year