Clinical trial NCT03524937: Prevention of Delirium in Intensive Care by Melatonin
Official title: Prevention of Delirium in Intensive Care by Melatonin: a Prospective, Multicentre, Randomized, Double Blind, Placebo, Multi-arm, Multi-stage Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Mechanically Ventilated Patients
Keywords: Delirium
Mechanical ventilation
Intensive care unit
Prevention
Pharmacokinetics
Melatonin
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2018-05-15
Enrollment: 355
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Delirium incidence
timeFrame: up to 14 days
Secondary outcomes:
measure: Day 28 Mortality
timeFrame: at day 28
measure: Hospital mortality
timeFrame: At day 28
measure: ICU mortality
timeFrame: at day 28
measure: Evaluate number of days alive without coma nor delirium
timeFrame: Up to day 14
measure: Duration of delirium
timeFrame: 14 days
measure: Duration of mechanical ventilation
timeFrame: Up to day 28
measure: Hospital length of stay
timeFrame: at day 28
Other outcomes:
Locations:
city: Créteil
country: France
facility: Henri-Mondor Hospital
state: Val De Marne
Study officials:
affiliation: DRCI-Assistance Publique des Hopitaux de paris
name: France GUYOT
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.