Melatonin Treatment for Induced Transient Insomnia
Condition: Delayed Sleep Phase Disorder; Jet-lag; Shift-work Disorder
MeSH terms: Sleep Initiation and Maintenance Disorders
Study type: Interventional

Summary: 
      Melatonin supplements have been reported to be an effective treatment for circadian rhythm
      sleep disorders, including shift work dyssomnia, jet-lag, delayed sleep phase syndrome, and
      sleep disruption suffered by many blind individuals. However, the mechanism(s) by which
      melatonin affects the timing of sleep are not well-understood. The purpose of this study is
      to determine if melatonin improves sleep and performance on a schedule simulating eastward
      travel. This study will provide information regarding the mechanism of action of melatonin
      that will be critical for the use of melatonin as a treatment for circadian rhythm sleep
      disorders.
    

Detailed description: 
      This study uses a randomized, double-blind, placebo-controlled, parallel groups design. The
      independent variable will be melatonin treatment group (0.3 mg melatonin, 3.0 mg melatonin,
      or placebo). Day of treatment will be an independent variable in analysis of sleep, cortisol,
      performance and alertness data. The primary outcome variables will be sleep efficiency and
      the peak of the plasma cortisol rhythm. Subjective and objective measures of alertness and
      performance during wake time will also be assessed as part of an exploratory analysis. Safety
      of short-term melatonin treatment will be assessed. The experimental protocol is divided into
      5 segments, the ambulatory baseline segment, the laboratory adaptation segment, the initial
      constant posture (CP, to assess circadian phase), the melatonin/placebo intervention before
      advanced scheduled sleep, and second CP to assess final circadian phase.

      The experimental protocol is divided into 5 segments, the ambulatory baseline segment, the
      laboratory adaptation segment, the initial constant posture (CP) for circadian phase
      assessment, the melatonin/placebo intervention, and a final post-treatment CP for assessment
      of circadian phase.

      The Ambulatory Baseline consists of at least 21 days, outside the laboratory. During this
      segment, wrist activity and light levels will be recorded using an ambulatory recording
      device (Actiwatch-L) while the subject goes about his/her normal routine. During this
      segment, the subject will maintain a regular, self-selected sleep-wake/light-dark schedule
      (8h in bed, 16h awake), and a sleep diary. The subject will also call in to our time-stamped
      sleep-wake call-in telephone system just prior to each bedtime and immediately after each
      wake time.

      The Laboratory Adaptation begins upon admission to the laboratory (Day 1 on protocol
      schematic in Figure 13) and continues until Day 3. The subject will be scheduled to sleep and
      wake at his/her regular times (determined during the ambulatory baseline). This segment of
      the study is designed to allow the subject to adapt to the laboratory environment and to
      allow all subjects to experience a standardized lighting regime prior to initial circadian
      phase assessment. We believe another reason the baseline days are essential is because prior
      to study individual subjects will experience varying light exposure patterns and levels. The
      standardized lighting conditions during baseline days allow stabilization of the subjects'
      circadian phase and phase of entrainment, and also control immediate lighting history prior
      to the study interventions. Ambient lighting during waking on the baseline days will be
      provided by ceiling panels and will be of ordinary indoor level, and all lights will be
      turned off (darkness) during the scheduled sleep episodes (black boxes on double raster plot
      of protocol). For all scheduled sleep episodes, polysomnographic recording of sleep will be
      taken. Due to the nature of the study, the exact timing of the beginning and ending of each
      study will be based on the individual subject's habitual sleep-wake schedule. Beginning on
      Day 1 of the study, saliva samples will be taken hourly during waking, and blood samples will
      be collected twice hourly for baseline melatonin and cortisol phase/amplitude estimation.
      Subjective alertness assessments will be collected twice per waking hour, and neurobehavioral
      performance testing will be conducted every 2 waking hours.

      The initial Constant Posture (CP) circadian phase estimation begins eight hours before
      habitual sleep time on Day 3 and continues for 22 h (shown in the cross-hatched bars in
      Figure 13). Throughout the CP, the subject will be restricted to a semi-recumbent position in
      bed in very dim indoor light (see Lighting Conditions section below for description) and will
      be fed equivalent hourly snacks. This segment of the study is designed to allow assessment of
      circadian phase by either eliminating factors known or suspected to obscure or mask circadian
      rhythms (changes in posture, activity, food intake, light level) or by distributing such
      factors across all circadian phases. The subject will be attended by a trained staff member
      to ensure wakefulness throughout the CP. Collection of plasma melatonin and cortisol,
      subjective alertness and neurobehavioral performance data will continue as in the Laboratory
      Adaptation Segment. After the CP is complete, the subject will be allowed to be ambulatory
      for another 6 hours before an 8-hour sleep episode. We chose to use CPs rather than a
      Constant Routine in order to avoid sleep deprivation, the recovery from which would obscure
      the results of the treatment conditions.

      The melatonin/placebo intervention days follow the initial CP. On experimental Day 4-5,
      scheduled sleep will occur 5 hours before habitual bedtime. Melatonin or placebo will be
      administered 30 minutes before lights-out. Twelve hours after waking the following day (Day
      5), the CP to asses final circadian phase will begin and continue for 22 hours. The final
      sleep episode will be scheduled from 18:00 to 02:00 h to ensure that post-treatment phase
      estimates are in no way compromised by change of sleep time. Subjects will be informed that
      they are likely to experience sleep disruption, impaired alertness and other symptoms of
      jetlag for up to several days after they are discharged from the laboratory. Four hours after
      the CP on Day 7, the subject will be discharged home.
    

Intervention name(s): Low Dose Melatonin; Placebo; High Dose Melatonin
Intervention type(s): Biological; Biological; Biological
Intervention description(s): Melatonin and placebo will be delivered as capsules on 4 successive days. All groups will receive placebo on days 1-3. Placebo group will continue to receive placebo on days 4, while low dose group will receive 0.5mg melatonin on day 4 and high dose group will receive 3.0mg melatonin on day 4.; Melatonin and placebo will be delivered as capsules on 4 successive days. All groups will receive placebo on days 1-3. Placebo group will continue to receive placebo on days 4, while low dose group will receive 0.5mg melatonin on day 4 and high dose group will receive 3.0mg melatonin on day 4.; Melatonin and placebo will be delivered as capsules on 4 successive days. All groups will receive placebo on days 1-3. Placebo group will continue to receive placebo on days 4, while low dose group will receive 0.5mg melatonin on day 4 and high dose group will receive 3.0mg melatonin on day 4.
Intervention MeSH terms: Melatonin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: sleep; alertness; performance; vigilance; circadian