Clinical trials in REM sleep behavioural disorder: challenges and opportunities

Abstract

The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.

A critical review of the pharmacological treatment of REM sleep behavior disorder in adults: time for more and larger randomized placebo-controlled trials

“…Despite the widespread use of both clonazepam and melatonin for treating RBD, until recently there was a lack of good quality trial data [24]. Current international guidelines are still based on evidence from mainly small case-series and open-label studies [25], which are at high risk of bias and have demonstrated inconsistencies in the clinical effectiveness levels reported. In fact, many patients with RBD were considered refractory to these first-line treatment options, which led clinicians to trial a multitude of other pharmacological agents off-label [26][27][28][29].…”

“…In fact, many patients with RBD were considered refractory to these first-line treatment options, which led clinicians to trial a multitude of other pharmacological agents off-label [26][27][28][29]. Past reviews have not consistently accounted for such reports when calculating the number of responders for these commonly prescribed treatments [25,30], or were conducted more than 10 years ago [7]. Thus, there is a need to re-assess whether the existing evidence supports the current recommended guidelines for the pharmacological management of RBD.…”

Ethical Considerations in Screening for Rapid Eye Movement Sleep Behavior Disorder in the General Population

“…8 Currently, screening for RBD is often used to recruit participants for studies aiming to better understand the prodromal phase of α-synucleinopathies. 9 However, screening for RBD, particularly in the general population, raises many ethical dilemmas. For instance, how should participants be informed if they screen positive for RBD?…”

Conversion to Parkinsonism and Dementia in REM-Sleep Behavior Disorder Using the Chronobiotic Melatonin

“…The clinical signs of parkinsonism and dementia occur when the underlying neurodegenerative process is already far advanced (Braak et al ., 2003). Hence, a major challenge of research in this field is to identify prodromal biomarkers to aid early diagnosis, to monitor disease progression, and to find a means for preventive treatment (Postuma and Berg, 2019; Videnovic et al ., 2020).…”

“…The mainstay of treatment in RBD is the prevention of injuries by modifying patients’ sleep environment and suppressing motor activity during sleep with muscle relaxants, usually clonazepam (Iranzo et al ., 2016; Videnovic et al ., 2020). Clonazepam immediately improves motor behavior during the first night of treatment.…”