Prevention of Delirium in Intensive Care by Melatonin

Study Overview
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Brief Summary
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This is a double-blind, randomized, placebo-controlled, Phase 2b/3 two-part adaptive clinical trial. The trial is designed to investigate the pharmacokinetics and the efficacy of multiple dosing regimens of melatonin and to confirm the efficacy and safety of one dosing regimen in prevention for delirium.

Detailed Description
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Treatment of the study is a single daily fixed-hour (21h) dose of 15 mL of an oral syrup, at one of the 3 following concentrations of melatonin: 0 mg/ml i.e. 0 mg/day (placebo); 0.02 mg/ml, i.e. 0.3 mg/day (low dose of melatonin) or 0.2 mg/ml, i.e. 3 mg/day (high dose of melatonin). The three dosages will be identical in appearance and volume.Treatment will be administered up to Day-14 (or death or discharge if these occur before Day-14). Randomization will be stratified by center.

Official Title
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Prevention of Delirium in Intensive Care by Melatonin: a Prospective, Multicentre, Randomized, Double Blind, Placebo, Multi-arm, Multi-stage Study

Conditions
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Mechanically Ventilated Patients

Intervention / Treatment
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* Drug: MELATONIN (HIGH DOSE)
* Drug: MELATONIN (LOW DOSE)
* Drug: PLACEBO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Patient under invasive mechanical ventilation Anticipated stay in intensive care unit of at least 48 hours Informed consent signed by the patient or a relative or emergency consent Exclusion Criteria: Invasive mechanical ventilation for more than 48 hours known pregnancy or breastfeeding No understanding of the French language, deafness Dementia (Mini Mental State <20) or known chronic psychosis Delirium (positive CAM-ICU score) before or at the time of randomization Alcohol withdrawal syndrome before or at the time of randomization with Cushman score ≥5 Inability to use the enteral route, food intolerance with vomiting Severe hepatic insufficiency (prothrombin level <30%) Ongoing treatment with melatonin or a drug that interacts or modifies its metabolism (fluvoxamine, 5- or 8-methoxypsoralen, estrogen, cimetidine, carbamazepine, rifampicin) known allergy to melatonin moribund state Patient admitted to intensive care for cardiopulmonary arrest, stroke, head trauma, neurosurgery. Patient not affiliated to social security Patient participating in another interventional clinical study with melatonin and / or for whom delirium is the primary endpoint

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MELATONIN (LOW DOSE)<br>Daily administration of melatonin by enteral route at 0.3 mg/day (low dose arm), up to 14 days. | Drug: MELATONIN (LOW DOSE)<br>* Enteral melatonin (0.3mg ) will be given at 21:00h daily, starting on the day of enrolment until ICU discharge, death, or up to 14 days<br>* Other names: N-acetyl-5-methoxytryptamine;|
| Experimental: MELATONIN (HIGH DOSE)<br>Daily administration of melatonin by enteral route at 3 mg/day (high dose arm), up to 14 days. | Drug: MELATONIN (HIGH DOSE)<br>* Enteral melatonin (3mg) will be given at 21:00h daily, starting on the day of enrolment until ICU discharge, death, or up to 14 days<br>* Other names: N-acetyl-5-methoxytryptamine;|
| Placebo Comparator: PLACEBO<br>Daily administration of identical placebo up to 14 days. | Drug: PLACEBO<br>* Study drug will be given at 21:00h daily, starting on the day of enrolment until ICU discharge, death, or up to 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delirium incidence |  | up to 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Day 28 Mortality | Day 28 Mortality | at day 28 | 
| Hospital mortality | Hospital mortality | At day 28 | 
| ICU mortality | ICU mortality | at day 28 | 
| Evaluate number of days alive without coma nor delirium | days alive without coma nor delirium | Up to day 14 | 
| Duration of delirium | Duration of delirium | 14 days | 
| Duration of mechanical ventilation | Duration of mechanical ventilation | Up to day 28 | 
| Hospital length of stay | Hospital length of stay | at day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Delirium, Mechanical ventilation, Intensive care unit, Prevention, Pharmacokinetics, Melatonin