The Effects of Tasimelteon in Participants With REM Behavior Disorder (RBD)
Study Details
Study Description
Brief Summary
To assess the effects of a daily single oral dose of 20 mg tasimelteon compared to baseline on events of dream enactment on patients with REM Behavior Disorder, as measured by a daily log.
To assess the effects of 20 mg tasimelteon compared to baseline on insomnia= symptoms, as measured by validated questionnaires (Insomnia Severity Index [ISI], Pittsburgh Sleep Quality Inventory [PSQI], Epworth Sleepiness Scale [ESS], Clinical Global Impression of Change Scale (CGI-C), Patient Global Impression of Change Scale (PGI-C)) as well as rest/activity pattern from actigraphy.
-
To assess the effects of 20 mg tasimelteon on patients who have a reduced or aberrant melatonin secretion compared to normal secretion by measuring salivary DLMO at baseline and correlating with the degree of change in RBD symptoms by end of the study.
-
To assess for any role a patient's unique genome may play in their response to tasimelteon; obtained via whole genome sequencing.
-
To assess the safety and tolerability of a daily single oral dose of 20 mg tasimelteon.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Early Phase 1 |
Detailed Description
REM behavior disorder (RBD) is characterized by abnormal behaviors that emerge from REM sleep and can lead to injury and disturbed sleep. Most patients have frequent events - typically more than once per week. Abnormalities can be seen almost nightly and consist of intermittent loss of the normal atonia of REM sleep. This phenomenon is used as diagnostic criterion even in the absence of an overt clinical event during the night.
RBD has serious consequences for the health of the patient. Besides risk of sometimes severe injury, a direct consequence of a violent nocturnal movement, it often leads to sleep disruption. Furthermore, it is commonly seen in association with Parkinson's disease and many experts in the field consider it a prodrome of neurodegenerative conditions. Other comorbidities may include a higher risk of cerebral hemorrhage as well as stroke. Multiple factors may contribute to the risk of RBD. Aside from neurodegenerative conditions, RBD is seen in association with disorders of REM sleep regulations: narcolepsy, post-traumatic stress disorder, or with use of selective serotonin reuptake inhibitors (SSRIs).
In healthy individuals, REM sleep is closely linked to circadian phase, with a peak a little after the nadir of the core body temperature, and thus also around the time when melatonin secretion is maximal. Studies using a forced desynchrony protocol suggest that the circadian system has a primary effect of REM sleep regulation with a modifying effect from the homeostatic factors. Various other factors affect REM sleep, including complex interactions with the serotonergic system, primarily from the raphe nuclei in the medulla, which inhibit the REM generating pontine tegmentum nuclei. Clinically, patients treated with antidepressants, particularly with serotononergic properties (particularly SSRIs), tend to suppress REM sleep and may also lead to REM without atonia and/or trigger RBD events.
The melatonin MT1 and MT2 receptors likely both affect the NREM/REM ratio with activation of the MT2 leading to earlier and more abundant NREM sleep, while MT1 receptors favoring REM sleep. Furthermore, RBD is common in patients with Parkinson's disease, and a reduced number of melatonin receptors have been found in the areas involved in the neurodegeneration: a recent study found a reduced number of MT1 receptor expression in the striatum and amygdala, and a reduced MT2 receptor expression in the substantia nigra and amygdala. In addition to circadian phase shift, activation of melatonin MT1 and MT2 receptors has been implicated as a potential protective mechanism against multiple other progressive neurodegenerative disorders, while MT2 receptors have been implicated in neurogenesis. Thus, REM suppression and/or disruption, as a result of the neurodegenerative process, that also involves impaired MT1 and MT2 receptor function may be a key mechanism for RBD pathophysiology and potential therapeutic target.
Treatment options for RBD are limited. The most commonly used agent is clonazepam, which has to be used in caution in patient with dementia symptoms and has many potentially serious side effects. Due to the strong association with neurodegenerative conditions, RBD patients are likely to have contraindications for benzodiazepine treatment. This creates a need for other medications that can be safely used in patients who are elderly and/or have neurodegenerative comorbid conditions. If the mechanism for RBD include REM sleep disruption, can improved REM sleep regulation lead to a better treatment? Melatonin is the most common therapeutic alternative to clonazepam for RBD. Initial studies may have been partially prompted by its high clinical convenience: a very favorable side effect profile, and availability in the US. It was first reported as effective in a case report in 1997, of a 64 year old man who experienced improvement of his RBD symptoms after treatment with 3 mg melatonin, without any change in his REM proportion on polysomnography. Further studies have included open label case series. In one recent study, melatonin was found to be equally effective as clonazepam for RBD treatment. However, studies have been small, open label, sometimes retrospective, and generally the timing of melatonin is not consistently reported.
Use of melatonin has a number of clinical challenges, since the medication is over the counter, not regulated, and dose and bioavailability can vary widely. Can melatonin agonists, which have a higher affinity to melatonin receptors also be used for treatment? Indeed, ramelteon has been reported successful in some cases. In 2013, Nomura et al used ramelteon, 8 mg in two patients who had polysomnographically confirmed RBD in association with parkinsonian syndromes. One of them had multisystem atrophy, and could not tolerate clonazepam due to the lability of her blood pressure, and the other had persistent symptoms despite clonazepam treatment. Both individuals had improvement of their RBD symptoms, including the RBD severity scale (RBDSS). Later Esaki et al treated 12 consecutive patients with idiopathic RBD in an open label trial, using 8 mg ramelteon given 30 minutes before bedtime and reported a trend towards improvement. Yet another study examined the effect of ramelteon on motor and non-motor symptoms in patients with Parkinson's disease, with or without RBD, and reported improvement in a variety of measures after treatment, including a statistically significant RBD improvement.
Novel data has emerged in the past two years regarding the chronotherapeutic aspects of RBD, suggesting that a potential not only for improved symptom control, but also long-term benefit in terms of decreasing neurodegeneration.
However, due to a large first pass effect, the mean systemic availability of ramelteon following an oral dose is less than 2%, and there is a large degree of inter-subject variability in plasma concentration after exposure. Thus, another melatonin agonist could be very helpful for patients with REM behavior disorder, potentially providing a more effective treatment option for this disease, and allowing safer control of the symptoms for those who cannot use benzodiazepines. A potent activator of the MT1 receptors, such as tasimelteon, could be an ideal RBD treatment. To better evaluate this important clinical question, I propose to evaluate the efficacy of tasimelteon as a potential treatment for RBD.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment Phase Tasimelteon will be administered in 20 mg capsules on a nightly basis for 4 weeks during the treatment phase. |
Drug: Tasimelteon
20 mg capsules taken on a nightly basis
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Daily Sleep Diary - Visual Fill-In [Daily for 8 weeks (both baseline and treatment phases)]
The daily sleep diary contains a diagram similar to a calendar that the participant can track their intake of caffeine, medicine, and alcohol, if they exercised, when they went to bed, fell asleep, or took a nap, and when they woke up. All recordings will be measured as number of events/time of day.
- Daily Sleep Diary - Time Keeping [Daily for 8 weeks (both baseline and treatment phases)]
The daily sleep diary also contains a series of questions. Some of them ask the participant to record the time the diary is completed, the time they took the study drug, and the time that they think they had a dream reenactment event. All of these will be recorded in 24:00 format.
- Daily Sleep Diary - Sleep Questions [Daily for 8 weeks (both baseline and treatment phases)]
The daily sleep diary also asks participants subjective questions like did you sleep last night, did you wake up naturally, and did you take the study drug last night? These will be recorded as yes/no responses.
- Daily Sleep Diary - Dream Enactment [Daily for 8 weeks (both baseline and treatment phases)]
The daily sleep diary also asks participants to recall how many dream enactments they had the previous night if any at all. This will be recorded as a numerical value.
Secondary Outcome Measures
- Clinical Global Impression of Change [1 Month after study]
Investigator-rated Assessment of Global Improvement in participant symptoms
Eligibility Criteria
Criteria
Inclusion criteria:
-
Diagnosis of REM sleep behavior disorder, confirmed polysomnography
-
Ability to participate in the trial
Exclusion criteria:
-
Contraindication to tasimelteon
-
medical or psychiatric conditions that limit ability to participate or increase risk to the individual
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Brigham and Women's Hospital | Boston | Massachusetts | United States | 02115 |
Sponsors and Collaborators
- Brigham and Women's Hospital
- Vanda Pharmaceuticals
Investigators
- Principal Investigator: Milena Pavlova, M.D., Brigham and Women's Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
- Adi N, Mash DC, Ali Y, Singer C, Shehadeh L, Papapetropoulos S. Melatonin MT1 and MT2 receptor expression in Parkinson's disease. Med Sci Monit. 2010 Feb;16(2):BR61-7.
- Arnaldi D, Fama F, De Carli F, Morbelli S, Ferrara M, Picco A, Accardo J, Primavera A, Sambuceti G, Nobili F. The Role of the Serotonergic System in REM Sleep Behavior Disorder. Sleep. 2015 Sep 1;38(9):1505-9. doi: 10.5665/sleep.5000.
- Boeve BF, Molano JR, Ferman TJ, Lin SC, Bieniek K, Tippmann-Peikert M, Boot B, St Louis EK, Knopman DS, Petersen RC, Silber MH. Validation of the Mayo Sleep Questionnaire to screen for REM sleep behavior disorder in a community-based sample. J Clin Sleep Med. 2013 May 15;9(5):475-80. doi: 10.5664/jcsm.2670.
- Boeve BF, Silber MH, Ferman TJ. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med. 2003 Jul;4(4):281-4. doi: 10.1016/s1389-9457(03)00072-8.
- Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder-neurodegenerative disease association, evolving concepts, controversies, and future directions. Ann N Y Acad Sci. 2010 Jan;1184:15-54. doi: 10.1111/j.1749-6632.2009.05115.x.
- Carskadon MA, Dement WC. Sleep studies on a 90-minute day. Electroencephalogr Clin Neurophysiol. 1975 Aug;39(2):145-55. doi: 10.1016/0013-4694(75)90004-8.
- Chiu HF, Wing YK, Lam LC, Li SW, Lum CM, Leung T, Ho CK. Sleep-related injury in the elderly--an epidemiological study in Hong Kong. Sleep. 2000 Jun 15;23(4):513-7.
- Czeisler CA, Zimmerman JC, Ronda JM, Moore-Ede MC, Weitzman ED. Timing of REM sleep is coupled to the circadian rhythm of body temperature in man. Sleep. 1980;2(3):329-46.
- Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci. 1995 May;15(5 Pt 1):3526-38. doi: 10.1523/JNEUROSCI.15-05-03526.1995.
- Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005 Jul;27(2):101-10. doi: 10.1385/ENDO:27:2:101.
- Esaki Y, Kitajima T, Koike S, Fujishiro H, Iwata Y, Tsuchiya A, Hirose M, Iwata N. An Open-Labeled Trial of Ramelteon in Idiopathic Rapid Eye Movement Sleep Behavior Disorder. J Clin Sleep Med. 2016 May 15;12(5):689-93. doi: 10.5664/jcsm.5796.
- Haba-Rubio J, Frauscher B, Marques-Vidal P, Toriel J, Tobback N, Andries D, Preisig M, Vollenweider P, Postuma R, Heinzer R. Prevalence and determinants of rapid eye movement sleep behavior disorder in the general population. Sleep. 2018 Feb 1;41(2):zsx197. doi: 10.1093/sleep/zsx197.
- Hogl B, Stefani A. REM sleep behavior disorder (RBD): Update on diagnosis and treatment. Somnologie (Berl). 2017;21(Suppl 1):1-8. doi: 10.1007/s11818-016-0048-6. Epub 2016 Apr 28.
- Kashihara K, Nomura T, Maeda T, Tsuboi Y, Mishima T, Takigawa H, Nakashima K. Beneficial Effects of Ramelteon on Rapid Eye Movement Sleep Behavior Disorder Associated with Parkinson's Disease - Results of a Multicenter Open Trial. Intern Med. 2016;55(3):231-6. doi: 10.2169/internalmedicine.55.5464. Epub 2016 Feb 1.
- Kunz D, Bes F. Melatonin as a therapy in REM sleep behavior disorder patients: an open-labeled pilot study on the possible influence of melatonin on REM-sleep regulation. Mov Disord. 1999 May;14(3):507-11. doi: 10.1002/1531-8257(199905)14:33.0.co;2-8.
- Kunz D, Bes F. Melatonin effects in a patient with severe REM sleep behavior disorder: case report and theoretical considerations. Neuropsychobiology. 1997;36(4):211-4. doi: 10.1159/000119383.
- Lee CH, Yoo KY, Choi JH, Park OK, Hwang IK, Kwon YG, Kim YM, Won MH. Melatonin's protective action against ischemic neuronal damage is associated with up-regulation of the MT2 melatonin receptor. J Neurosci Res. 2010 Sep;88(12):2630-40. doi: 10.1002/jnr.22430.
- Lee K, Baron K, Soca R, Attarian H. The Prevalence and Characteristics of REM Sleep without Atonia (RSWA) in Patients Taking Antidepressants. J Clin Sleep Med. 2016 Mar;12(3):351-5. doi: 10.5664/jcsm.5582.
- Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol. 2016;56:361-83. doi: 10.1146/annurev-pharmtox-010814-124742. Epub 2015 Oct 23.
- Ma C, Pavlova M, Liu Y, Liu Y, Huangfu C, Wu S, Gao X. Probable REM sleep behavior disorder and risk of stroke: A prospective study. Neurology. 2017 May 9;88(19):1849-1855. doi: 10.1212/WNL.0000000000003902. Epub 2017 Apr 7.
- Marion MH, Qurashi M, Marshall G, Foster O. Is REM sleep behaviour disorder (RBD) a risk factor of dementia in idiopathic Parkinson's disease? J Neurol. 2008 Feb;255(2):192-6. doi: 10.1007/s00415-008-0629-9. Epub 2008 Jan 29.
- McGrane IR, Leung JG, St Louis EK, Boeve BF. Melatonin therapy for REM sleep behavior disorder: a critical review of evidence. Sleep Med. 2015 Jan;16(1):19-26. doi: 10.1016/j.sleep.2014.09.011. Epub 2014 Oct 13.
- Nightingale S, Orgill JC, Ebrahim IO, de Lacy SF, Agrawal S, Williams AJ. The association between narcolepsy and REM behavior disorder (RBD). Sleep Med. 2005 May;6(3):253-8. doi: 10.1016/j.sleep.2004.11.007.
- Nomura T, Kawase S, Watanabe Y, Nakashima K. Use of ramelteon for the treatment of secondary REM sleep behavior disorder. Intern Med. 2013;52(18):2123-6. doi: 10.2169/internalmedicine.52.9179.
- Postuma RB, Arnulf I, Hogl B, Iranzo A, Miyamoto T, Dauvilliers Y, Oertel W, Ju YE, Puligheddu M, Jennum P, Pelletier A, Wolfson C, Leu-Semenescu S, Frauscher B, Miyamoto M, Cochen De Cock V, Unger MM, Stiasny-Kolster K, Fantini ML, Montplaisir JY. A single-question screen for rapid eye movement sleep behavior disorder: a multicenter validation study. Mov Disord. 2012 Jun;27(7):913-6. doi: 10.1002/mds.25037. Epub 2012 May 30.
- Postuma RB, Gagnon JF, Montplaisir J. Rapid eye movement sleep behavior disorder as a biomarker for neurodegeneration: the past 10 years. Sleep Med. 2013 Aug;14(8):763-7. doi: 10.1016/j.sleep.2012.09.001. Epub 2012 Oct 8.
- Rajaratnam SM, Polymeropoulos MH, Fisher DM, Roth T, Scott C, Birznieks G, Klerman EB. Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. Lancet. 2009 Feb 7;373(9662):482-91. doi: 10.1016/S0140-6736(08)61812-7. Epub 2008 Dec 4. Erratum In: Lancet. 2009 Apr 11;373(9671):1252.
- Stiasny-Kolster K, Mayer G, Schafer S, Moller JC, Heinzel-Gutenbrunner M, Oertel WH. The REM sleep behavior disorder screening questionnaire--a new diagnostic instrument. Mov Disord. 2007 Dec;22(16):2386-93. doi: 10.1002/mds.21740.
- Takeuchi N, Uchimura N, Hashizume Y, Mukai M, Etoh Y, Yamamoto K, Kotorii T, Ohshima H, Ohshima M, Maeda H. Melatonin therapy for REM sleep behavior disorder. Psychiatry Clin Neurosci. 2001 Jun;55(3):267-9. doi: 10.1046/j.1440-1819.2001.00854.x.
- 2022P001873