Melatonin for Prevention of Delirium in Critically Ill Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Feasibility of Melatonin for Prevention of Delirium in Critically Ill Patients: a Multi-centre, Randomized, Placebo-controlled Study.

Conditions
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Delirium

Intervention / Treatment
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* Drug: Melatonin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Critically ill patients ≥18 years of age Anticipated ICU stay of >48 hours Able to receive enteral administration of study drug (i.e. by mouth or any feeding tube = naso- or oro- or percutaneous gastric or post-pyloric feeding tube) Consent to participate. Exclusion Criteria: ICU admission of >48 hours prior to screening Unable to assess for delirium (e.g. comatose defined as SAS 1 or 2 or either 'No Response' Score A or B on ICDSC, chemically paralyzed with neuromuscular blocking drugs) Screened delirium positive prior to randomization (ICDSC score ≥4 out of 8) Anticipated withdrawal in next 48 hours Known history of severe cognitive or neurodegenerative disease (e.g. dementia, Parkinson's disease) or severe structural brain injury (e.g. traumatic brain injury, intracranial hemorrhage) as the ICDSC assessment tool has not been validated in these patient populations Unable to communicate in English or French (Montreal site) Contraindications to receiving any enteral medication (defined as absolute contraindication to enteral nutrition such as gastrointestinal obstruction, perforation, recent upper GI surgery, no enteral access) Active seizures Known pregnancy Legal blindness Known allergy to melatonin

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enteral melatonin 0.5 mg<br>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) | Drug: Melatonin<br>* 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.<br>* Other names: N-acetyl-5-methoxytryptamine;|
| Active Comparator: Enteral melatonin 2 mg<br>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) | Drug: Melatonin<br>* 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.<br>* Other names: N-acetyl-5-methoxytryptamine;|
| Placebo Comparator: Enteral matched placebo<br>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) | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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). | 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). | 24 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). | 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). | 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). | 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). | 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). | 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. | 14 days | 
| Clinical: Delirium incidence | Intensive Care Delirium Screening Checklist (ICDSC) administered daily. Delirium defined as an ICDSC score ≥4. | 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. | 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. | 14 days | 
| Clinical: Duration of mechanical ventilation | Duration of mechanical ventilation (days) | ICU admission | 
| Clinical: ICU length of stay | Duration of stay for index ICU admission (days) | ICU admission | 
| Clinical: Hospital length of stay | Duration of stay for admission involving trial enrolment (days) | 1 year | 
| Clinical: ICU mortality | Number of deaths during index ICU admission | 1 year | 
| Clinical: Hospital mortality | Number of deaths during hospital admission | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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delirium, melatonin, pharmacokinetics, feasibility, prevention