Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial

Thomas Roth, Tali Nir, Nava Zisapel, Thomas Roth, Tali Nir, Nava Zisapel

Abstract

Introduction: Melatonin, secreted by the pineal gland during the night phase, is a regulator of the biological clock and sleep tendency. Totally blind subjects frequently report severe, periodic sleep problems, with 50%-75% of cases displaying non-24-hour sleep-wake disorder (N24HSWD) due to inability to synchronize with the environmental day-night cycle. Melatonin immediate-release preparations are reportedly effective in N24HSWD. Here, we studied the efficacy and safety of prolonged-release melatonin (PRM), a registered drug for insomnia, for sleep disorders in totally blind subjects living in normal social environments. The primary endpoint was demonstration of clinically meaningful effects on sleep duration (upper confidence interval [CI] limit >20 minutes whether significant or not) to allow early decision-making on further drug development in this indication.

Trial registration: ClinicalTrials.gov registry - NCT00972075.

Methods: In a randomized, double-blind, placebo-controlled proof-of-principle study, 13 totally blind subjects had 2 weeks' placebo run-in, 6 weeks' randomized (1:1) PRM (Circadin(®)) or placebo nightly, and 2 weeks' placebo run-out. Outcome measures included daily voice recorded sleep diary, Clinical Global Impression of Change (CGIC), WHO-Five Well-being Index (WHO-5), and safety.

Results: Mean nightly sleep duration improved by 43 minutes in the PRM and 16 minutes in the placebo group (mean difference: 27 minutes, 95% CI: -14.4 to 69 minutes; P=0.18; effect size: 0.82) meeting the primary endpoint. Mean sleep latency decreased by 29 minutes with PRM over placebo (P=0.13; effect size: 0.92) and nap duration decreased in the PRM but not placebo group. The variability in sleep onset/offset and latency tended to decrease during PRM but not placebo treatment. The potentially beneficial effects of PRM persisted during the 2 weeks of discontinuation period, consistent with clock stabilizing effects. PRM was well-tolerated, adverse events were of mild or moderate severity and similar between PRM and placebo.

Conclusion: Nightly use of PRM may potentially improve patient-reported sleep difficulties in totally blind individuals trying to adhere to normal social lifestyle. A larger study powered to demonstrate a statistically significant effect is warranted.

Keywords: biological clock; melatonin; non-24-hour sleep–wake disorder; sleep.

Figures

Figure 1
Figure 1
Overall study patient disposition. Notes: The study comprised of 2 weeks placebo run-in period followed by randomization 1:1 to receive PRM (Circadin® 2 mg) or placebo for 6 weeks followed by a 2-week washout period. Abbreviations: FAS, full analysis set; PRM, prolonged-release melatonin.
Figure 2
Figure 2
Endpoint of sleep variables: sleep duration. Notes: (A) Change from baseline for the total night sleep duration (± SEM). Treatment period took place from weeks 3–8; WO period from weeks 9–10. (B) Individual changes from baseline to end of treatment in total nighttime sleep duration for the PRM and placebo groups. Abbreviations: PRM, prolonged-release melatonin; SEM, standard error of the mean; WO, washout.
Figure 3
Figure 3
Endpoint of sleep variables: sleep latency and daytime naps. Notes: (A) Change from baseline for night sleep latency (± SEM) (B) Change from baseline for the total duration of naps (± SEM). Treatment period is calculated as weeks 3–8; WO period is calculated as weeks 9–10. Abbreviations: PRM, prolonged-release melatonin; SEM, standard error of the mean; WO, washout.
Figure 4
Figure 4
Onset and offset of treatment effects on sleep. Notes: Analysis week-by-week (mean ± SEM) in (A) total night sleep duration and (B) sleep latency. BL period is from weeks 1–2; treatment period is from weeks 3–8; WO period is from weeks 9–10. Abbreviations: PRM, prolonged-release melatonin; BL, baseline; SEM, standard error of the mean; WO, washout.
Figure 5
Figure 5
Mean SD of the individual changes in sleep onset/offset and latency variability during baseline and the last 2 weeks of PRM and placebo treatment. Notes: Data from all individual patients in the study in the PRM (top panels) and placebo (bottom panels) treatment are depicted using logarithmic scales. The different colored lines in the figure represent different patients. Abbreviations: PRM, prolonged-release melatonin; SD, standard deviation.

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