Melatonin for Treatment of Delirium in Critically Ill Adult 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 treatment of delirium in critically ill adult patients. From a feasibility perspective, the investigators believe that the proposed design will achieve the minimum enrollment rate necessary to conduct a future RCT on a larger scale.

Detailed Description
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The prevalence of delirium is high in the intensive care unit (ICU), yet there is no pharmacological treatment that has been proven effective. The investigators hypothesize that melatonin, given on a daily basis at 21:00, will safely decrease the mean duration of a delirium episode in ICU patients. The current literature evaluating melatonin as a treatment for delirium is lacking, therefore more studies are needed. It is estimated that an alteration of sleep pattern can be found in up to 75% of patients with delirium. This raises the hypothesis that prevention and treatment of sleep disorders could potentially improve delirium. Sleep and circadian rhythm disturbances are associated with low endogenous melatonin secretion and studies have shown that it also occurs in patients with delirium. Thus, the objective is to conduct a phase II double blind, placebo-controlled randomized trial comparing melatonin 9 mg to placebo to evaluate the feasibility of a future large-scale RCT. Participants will be followed during their stay in the ICU and after their transfer on another unit up to a maximum of 14 days. Feasibility of the larger trial will mainly be based on enrollment rates.

Official Title
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DELIRE-ICU: A Randomised Controlled Feasibility Trial of Melatonin vs Placebo in the Treatment of Delirium in the Intensive Care Unit

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: Patients aged 18 years or older admitted to the intensive care unit; Anticipated ICU stay > 48 hours; ICDSC score greater than or equal to 4 for a maximum of 48 hours prior to randomization. Exclusion Criteria: Known allergy or hypersensitivity to melatonin or to ingredients in ORA-BLEND SF®; Use of melatonin within 24 hours prior to randomization; Presence of severe structural brain injury (intracranial hemorrhage or traumatic brain injury), severe major neurocognitive disorder, advanced neurodegenerative disease or hepatic encephalopathy; Diagnosis of schizophrenia, bipolar affective disorder, psychotic depression, uremic encephalopathy or alcohol withdrawal; Presence of active seizures, coma, aphasia or severe intellectual disability; Limited short-term vital prognosis; Diagnosis of delirium prior to ICU admission; Pregnancy or breastfeeding; Absolute contraindication to receive enteral medication; Inability to understand or speak English or French; Total blindness.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enteral melatonin 9 mg<br>Melatonin 9 mg from a 1 mg/mL oral suspension of melatonin in ORA-BLEND SF® (sugar-free flavoured suspending vehicle). Final volume in the oral syringe will be 9 mL. | Drug: Melatonin<br>* Study drug will be given at 21:00 daily, starting on the day of enrolment until delirium resolution, hospital discharge, death, or up to 14 days. The study medication will be given by mouth (PO or per os) or, if needed, via the feeding tube.<br>|
| Placebo Comparator: Enteral placebo<br>ORA-BLEND SF® (sugar-free flavoured suspending vehicle). Final volume in the oral syringe will be 9 mL. | Drug: Placebo<br>* Study drug will be given at 21:00 daily, starting on the day of enrolment until delirium resolution, hospital discharge, death, or up to 14 days. The study medication will be given by mouth (PO or per os) or, if needed, via the feeding tube.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility: Enrollment rate | Average enrollment rate of participants per month. | 8 months | 
| Clinical: Duration of delirium | Compare the average duration of an episode of delirium defined as the number of days with ICDSC score ≥4 between the 2 groups. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility: Study adherence | Proportion of administered doses in the prescribed dose administration window (between 19:00 and 23:00 hours) divided by total number of eligible study days. | 8 months | 
| Feasibility: Consent rate | Proportion of participants recruited among eligible patients. | 8 months | 
| Clinical: Adverse events | Incidence of adverse events reported in the Canadian melatonin monograph (i.e. headache and nausea) observed by the investigators or reported by the treating team. | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melatonin, Intensive care, Feasibility, Treatment, Critically ill, ICU