Clinical trial NCT02615340: Melatonin for Prevention of Delirium in Critically Ill Patients
Official title: Feasibility of Melatonin for Prevention of Delirium in Critically Ill Patients: a Multi-centre, Randomized, Placebo-controlled Study.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Delirium
Keywords: delirium
melatonin
pharmacokinetics
feasibility
prevention
Lead sponsor: Mount Sinai Hospital, Canada
Sponsor class: OTHER
Collaborators: name: Sunnybrook Health Sciences Centre
name: Hopital du Sacre-Coeur de Montreal
First posted: 2015-11-26
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Critically ill patients ≥18 years of age
2. Anticipated ICU stay of \>48 hours
3. 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)
4. Consent to participate.

Exclusion Criteria:

1. ICU admission of \>48 hours prior to screening
2. 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)
3. Screened delirium positive prior to randomization (ICDSC score ≥4 out of 8)
4. Anticipated withdrawal in next 48 hours
5. 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
6. Unable to communicate in English or French (Montreal site)
7. 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)
8. Active seizures
9. Known pregnancy
10. Legal blindness
11. Known allergy to melatonin

Primary outcomes:
measure: Feasibility: Study adherence
timeFrame: 1 year
Secondary outcomes:
measure: Feasibility: Trial recruitment
timeFrame: 1 year
measure: Feasibility: Time in motion (minutes)
timeFrame: 1 year
measure: Pharmacokinetic: Peak melatonin concentration (Cmax)
timeFrame: 24 hours
measure: Pharmacokinetic: Time of peak melatonin concentration (Tmax)
timeFrame: 24 hours
measure: Pharmacokinetic: Morning melatonin concentration (C9AM)
timeFrame: 24 hours
measure: Pharmacokinetic: Melatonin half-life (T½)
timeFrame: 24 hours
measure: Pharmacokinetic: Mean apparent clearance (CL/F)
timeFrame: 24 hours
measure: Pharmacokinetic: Mean apparent volume distribution (V/F)
timeFrame: 24 hours
measure: Pharmacokinetic: Area under the concentration-time curve (AUC)
timeFrame: 24 hours
measure: Clinical: Adverse events
timeFrame: 14 days
measure: Clinical: Delirium incidence
timeFrame: 14 days
measure: Clinical: Delirium time to onset and duration (days)
timeFrame: 14 days
measure: Clinical: Sleep
timeFrame: 14 days
measure: Clinical: Duration of mechanical ventilation
timeFrame: ICU admission
measure: Clinical: ICU length of stay
timeFrame: ICU admission
measure: Clinical: Hospital length of stay
timeFrame: 1 year
measure: Clinical: ICU mortality
timeFrame: 1 year
measure: Clinical: Hospital mortality
timeFrame: 1 year
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Montréal
country: Canada
facility: Hôpital du Sacré-Coeur
state: Quebec
Study officials:
affiliation: MOUNT SINAI HOSPITAL
name: Lisa Burry, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burry L, Scales D, Williamson D, Foster J, Mehta S, Guenette M, Fan E, Detsky M, Azad A, Bernard F, Rose L. Feasibility of melatonin for prevention of delirium in critically ill patients: a protocol for a multicentre, randomised, placebo-controlled study. BMJ Open. 2017 Mar 30;7(3):e015420. doi: 10.1136/bmjopen-2016-015420.