Prevention of Delirium in Intensive Care by Melatonin (DEMEL)

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

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.

Study Overview

• Status: Completed
• Conditions: Mechanically Ventilated Patients
• Intervention / Treatment: Drug: MELATONIN (LOW DOSE); Drug: MELATONIN (HIGH DOSE); Drug: PLACEBO

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 355
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• France
  • Val De Marne
    • Créteil, Val De Marne, France, 94000
      • Henri-Mondor Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Chair: France GUYOT, DRCI-Assistance Publique des Hopitaux de paris

Publications and helpful links

General Publications

• Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007 Jan;33(1):66-73. doi: 10.1007/s00134-006-0399-8. Epub 2006 Nov 11.
• Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004 Apr 14;291(14):1753-62. doi: 10.1001/jama.291.14.1753.
• Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med. 2001 May;27(5):859-64. doi: 10.1007/s001340100909.
• Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, Truman B, Speroff T, Gautam S, Margolin R, Hart RP, Dittus R. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001 Dec 5;286(21):2703-10. doi: 10.1001/jama.286.21.2703.
• Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, Truman B, Dittus R, Bernard R, Inouye SK. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Med. 2001 Dec;27(12):1892-900. doi: 10.1007/s00134-001-1132-2. Epub 2001 Nov 8.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2019
• Primary Completion (Actual): May 1, 2021
• Study Completion (Actual): May 20, 2021

Study Registration Dates

• First Submitted: April 25, 2018
• First Submitted That Met QC Criteria: May 14, 2018
• First Posted (Actual): May 15, 2018

Study Record Updates

• Last Update Posted (Actual): May 15, 2023
• Last Update Submitted That Met QC Criteria: May 12, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Melatonin; Pharmacokinetics; Prevention; Intensive care unit; Delirium; Mechanical ventilation
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: P160942J

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No