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Review
Clinical trials in REM sleep behavioural disorder: challenges and opportunities
  1. Aleksandar Videnovic1,
  2. Yo-El S Ju2,
  3. Isabelle Arnulf3,4,
  4. Valérie Cochen-De Cock5,6,
  5. Birgit Högl7,
  6. Dieter Kunz8,
  7. Federica Provini9,10,
  8. Pietro-Luca Ratti11,
  9. Mya C Schiess12,
  10. Carlos H Schenck13,14,
  11. Claudia Trenkwalder15,16
  12. on behalf of the Treatment and Trials Working Group of the International RBD Study Group
  1. 1Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
  2. 2Department of Neurology, Washington University in Saint Louis, Saint Louis, Missouri, USA
  3. 3Assistance Publique Hôpitaux de Paris, Service des pathologies du Sommeil, Hôpital Pitié-Salpêtrière, Paris, France
  4. 4UMR S 1127, CNRS UMR 7225, ICM, Sorbonne Universités, UPMC University Paris, Paris, France
  5. 5Neurologie et sommeil, Clinique Beau Soleil, Montpellier, France
  6. 6Laboratoire Movement to Health (M2H), EuroMov, Université Montpellier, Montpellier, France
  7. 7Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
  8. 8Clinic for Sleep and Chronomedicine, Berlin, Germany
  9. 9IRCCS Institute of Neurological Sciences of Bologna, University of Bologna, Bologna, Italy
  10. 10Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
  11. 11Neurocenter of Southern Switzerland, Lugano, Switzerland
  12. 12Department of Neurology, University of Texas Medical School at Houston, Houston, Texas, USA
  13. 13Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota, USA
  14. 14Minnesota Regional Sleep Disorders Center, Minneapolis, Minnesota, USA
  15. 15Paracelsus Elena Klinik, Kassel, Germany
  16. 16Department of Neurosurgery, University Medical Center, Göttingen, Germany
  1. Correspondence to Dr Aleksandar Videnovic, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114-2696, USA; AVIDENOVIC{at}mgh.harvard.edu

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.

  • randomised trials
  • Parkinson's disease
  • Lewy body dementia
  • sleep disorders
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Footnotes

  • Contributors AV: planning, conduct and reporting of the study; responsible for the overall content as guarantor. Y-ESJ: planning, conduct and reporting of the study. IA: planning, conduct and reporting of the study. VC-DC: planning, conduct and reporting of the study. BH: planning, conduct and reporting of the study. FP: planning, conduct and reporting of the study. P-LR: planning, conduct and reporting of the study. MS: planning, conduct and reporting of the study. CS: planning, conduct and reporting of the study. CT: planning, conduct and reporting of the study.

  • Funding This study was supported by these research grants from the National Institutes of Health: K23NS089922, R21 NS108022, R34AG056639, UL1RR024992 Sub-Award KL2TR000450, UL1TR000448.

  • Competing interests AV reports personnel fees from Acorda, Acadia, Pfizer, Theranexus, Jazz and Wilson Therapeutics. IA reports personal fees from Roche Pharma and UCB Pharma. BH reports personal fees from Jazz, Ono, Axovant, Benevolent Bio, Mundipharma, Roche, Takeda, AoP Orphan, Jazz, Abbvie, AoP, Lundbeck, Eli Lilly, Otsuka, Janssen Cilag, Inspire and Habel Medizintechnik. FP reports personal fees from Vanda Pharmaceutical, Sanofi, Zambon, Fidia, Bial, Eisai Japan and Italfarmaco. CHS reports personal fees from Axovant. CT reports personal fees from Britannia, Roche, UCB, Gruenenthal and Otsuka.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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