Official Title: “Randomized, Controlled, Double Blind Trial to Evaluate Sedation and Quality of Life in High-Risk, Critically Ill Patients Treated With Oral Melatonin”

Sleep disruptions are extremely common in high-risk critically ill patients. We want to analyse oral melatonin potentialities as a sedative and a free-radicals scavenger for critically ill patients, and secondarily for preventing Delirium during their ICU stay and post-traumatic stress disorders after ICU discharge.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: July 2008

The physiological secretion of such melatonin follows a circadian rhythm: melatonin plasma concentration increases with the dark reaching a peak around to midnight and then gradually decreases (Reiter, 1996; Shigeta et al., 2001; Kunz et al., 2004; Brzezinski et al., 2005).

Administration of oral melatonin could be useful in critically ill high-risk patients in Intensive Care Units because these patients are often suffering from sleep disturbances (Weber et al., 1985; Bourne and Mills, 2004) possibly because of: - presence of underlying pathology with pain and anxiety, - presence of oral or nasal respiratory prosthesis, - execution of therapeutic procedures on 24 h. Moreover it has been demonstrated that in ICU patients melatonin rhythm is desynchronized (Bourne and Mills, 2000). This is probably related to sedation and-or mechanical ventilation. Furthermore, it has been showed that melatonin is a powerful anti-oxidant, therefore it could be potentially useful in critical patients usually characterized by increased production of oxygen free radicals.

AIM OF THE STUDY The study is aimed to estimate if the administration of oral melatonin in ICU patients is able to regularize the sleep-waking rhythm, improving sleep quality and reducing episodes of agitation/mental confusion. The main objectives are: assessment of sleep quality, prevalence of mental confusion/agitation, amount of daily sedative drugs administered and modification of redox status.

ENROLLMENT OF PATIENTS At the admission in ICU, obtained the informed consent, the patients will be randomly assigned to the "Treatment" group receiving melatonin 3mg BID by oral route (or nasogastric tube) or to the "Control" group receiving placebo. The sedation will be performed according to clinical standard.

EXPERIMENTAL PROTOCOLS

The following parameters will be monitored: - epidemiological data, - quality of the sleep estimated by wrist actigraphy, - EEG profile on 24h in order to estimate the distribution of sleep phases, - diurnal and nocturnal hours of sleep, - total amount of sedative drugs during 24 hours, particularly during nocturnal sedation, - assessment of sedation level (RASS) (Sessler et al., 2002; Ely et al., 2003), - episodes of psychomotor agitation and mental confusion (CAM-ICU) (Ely, 2001; 2004), - evaluation of blood redox state (GSH, GSSG, GSH/GSSG), - adverse events.

AT THE DISCHARGE FROM ICU, evaluation of: - SCID-I and SCID-II (Structured Clinical Interview for DSM), - CAPS (Clinician Administered PTSD Scales), - HAM-A and HAM-D (Hamilton Rating Scales for Anxiety and for Depression), - completion of the module for the stressors in ICU and for the transcription of the dreams.

3 MONTHS AFTER DISCHARGE FROM ICU, evaluation of: - SCID-I and II, - CAPS, - HAM-A and HAM-D, - TAT (Thematic Apperception Test), - completion of the module for the stressors in ICU and for the transcription of the dreams.

Intervention(s) in this Clinical Trial

• Drug: Oral melatonin 3mg BID
  • Identical tablets containing melatonin 3 mg. Nurses are requested to give two tablets daily, at 8 PM and 12 PM
• Drug: Placebo
  • Identical tablets without the active principles. Each evening nurses are requested to give 2 tablets at 8 PM and 12 PM

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: A
  • Identical tablets without the active principles. Each evening nurses are requested to give 2 tablets at 8 PM and 12 PM
• Active Comparator: B
  • Identical tablets containing melatonin 3 mg Nurses are requested to give two tablets daily, at 8 PM and 12 PM.

Primary Measures

• Overall sedatives daily doses
  • Time Frame: Discharge from ICU
    Safety Issue?: No
• Sleep quantity assessed by wrist actigraphy
  • Time Frame: Discharge from ICU
    Safety Issue?: Yes

Secondary Measures

• Prevalence of Delirium assessed with CAM-ICU
  • Time Frame: Discharge from ICU
    Safety Issue?: No
• Prevalence of mental disorders
  • Time Frame: 60 days after ICU discharge
    Safety Issue?: No
• ICU length of stay
  • Time Frame: Discharge from ICU
    Safety Issue?: No
• ICU mortality
  • Time Frame: Discharge from ICU
    Safety Issue?: No
• Hospital mortality
  • Time Frame: Hospital discharge
    Safety Issue?: No

Inclusion Criteria:

• High Treatment > 1 day
• Normal gastrointestinal function

Exclusion Criteria:

• Status asthmaticus
• Chronic renal failure under dialytic treatment
• Severe hepatopathy (Child-Pugh class = C)
• Comatous patients (GCS < 12)
• Head trauma, severe neurological diseases (ictus cerebri, SAH, ...)
• Intoxicated patients

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 85 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Milan

Overall Clinical Trial Officials and Contacts

Gaetano Iapichino, MD Study Chair University of Milan  

Overall Contact: Giovanni Mistraletti, MD 0039.02.50323134 giovanni.mistraletti@unimi.it

Information obtained from ClinicalTrials.gov on September 04, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00470821

Study ID Number: Mela-UniMi-0001

ClinicalTrials.gov Identifier: NCT00470821

Health Authority: Italy: Ethics Committee