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

Thomas Roth,1 Tali Nir,2 Nava Zisapel2,3 1Henry Ford Sleep Disorders Center, Detroit, MI, USA; 2Neurim Pharmaceuticals Ltd, Tel Aviv, Israel; 3Department of Neurobiology Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel Introduction: Melatonin, secreted by the pineal gland during the...

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Autores principales:	Roth T, Nir T, Zisapel N
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2015
Materias:	Psychiatry RC435-571 Neurophysiology and neuropsychology QP351-495
Acceso en línea:	https://doaj.org/article/48d79137c0b14b28ac9a2635994df194
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spelling	oai:doaj.org-article:48d79137c0b14b28ac9a2635994df1942021-12-02T00:56:42ZProlonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial1179-1608https://doaj.org/article/48d79137c0b14b28ac9a2635994df1942015-01-01T00:00:00Zhttp://www.dovepress.com/prolonged-release-melatonin-for-improving-sleep-in-totally-blind-subje-peer-reviewed-article-NSShttps://doaj.org/toc/1179-1608 Thomas Roth,1 Tali Nir,2 Nava Zisapel2,3 1Henry Ford Sleep Disorders Center, Detroit, MI, USA; 2Neurim Pharmaceuticals Ltd, Tel Aviv, Israel; 3Department of Neurobiology Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel 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, non-24-hour sleep–wake disorder, sleep, melatoninRoth TNir TZisapel NDove Medical PressarticlePsychiatryRC435-571Neurophysiology and neuropsychologyQP351-495ENNature and Science of Sleep, Vol 2015, Iss default, Pp 13-23 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Psychiatry RC435-571 Neurophysiology and neuropsychology QP351-495
spellingShingle	Psychiatry RC435-571 Neurophysiology and neuropsychology QP351-495 Roth T Nir T Zisapel N Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial
description	Thomas Roth,1 Tali Nir,2 Nava Zisapel2,3 1Henry Ford Sleep Disorders Center, Detroit, MI, USA; 2Neurim Pharmaceuticals Ltd, Tel Aviv, Israel; 3Department of Neurobiology Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel 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, non-24-hour sleep–wake disorder, sleep, melatonin
format	article
author	Roth T Nir T Zisapel N
author_facet	Roth T Nir T Zisapel N
author_sort	Roth T
title	Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial
title_short	Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial
title_full	Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial
title_fullStr	Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial
title_full_unstemmed	Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial
title_sort	prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial
publisher	Dove Medical Press
publishDate	2015
url	https://doaj.org/article/48d79137c0b14b28ac9a2635994df194
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Prolonged release melatonin for improving sleep in totally blind subjects: a pilot placebo-controlled multicenter trial

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