BACKGROUND: Excessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide. OBJECTIVE: The aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS. METHODS: The method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score. RESULTS: Both doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: -1.4 [-2.49; -0.31], P = 0.012) but did not change significantly with the 200/18 dosage. CONCLUSIONS: THN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society.

Department of Neurology and Movement Disorders La Timone Hospital Assistance Publique Hôpitaux de Marseille NS PARK FCRIN Network Marseille France

Department of Neurology and Movement Disorders Lille University Medical Center NS PARK FCRIN Network Lille France

Department of Neurology C Pierre Wertheimer Neurological Hospital Hospices Civils de Lyon NS PARK FCRIN Network Univ Lyon CNRS Institut des Sciences Cognitives Marc Jeannerod Bron France

Department of Neurology Centre d'Investigation Clinique Neurosciences NS PARK FCRIN Network Sorbonne Université Assistance Publique Hôpitaux de Paris Paris Brain Institute ICM INSERM CNRS Hôpital Pitié Salpêtrière Paris France

Department of Neurology Charité Universitätsmedizin Berlin Campus Benjamin Franklin Berlin Germany

Department of Neurology Charles University Faculty of Medicine and University Hospital Hradec Kralove Czechia

Department of Neurology Massachusetts General Hospital Boston Massachusetts USA

Department of Neurology Medical School University of Pecs Pecs Hungary

Department of Neurology Rouen University Hospital and University of Rouen NS PARK FCRIN Network Rouen France

Departments of Neurology and Clinical Pharmacology Centre of Clinique Investigations NS Park FCRIN Network Centre of Excellence for Neurodegenerative Disorders of Toulouse CHU de Toulouse Toulouse 3 University NS PARK FCRIN Network Toulouse France

Movement Disorders Division University of Kansas Medical Center Kansas City Kansas USA

Movement Disorders Methodist Neurological Institute Weill Cornel Medical School Houston Texas USA

Scope International Mannheim Germany

Sleep Wake Disorders Center Department of Neurology Gui de Chauliac Hospital CHU Montpellier University of Montpellier Montpellier France

Theranexus SA Lyon France

See more in PubMed

Chahine LM, Amara AW, Videnovic A. A systematic review of the literature on disorders of sleep and wakefulness in Parkinson's disease from 2005-2015. Sleep Med Rev 2017;35:33-50.

Chaudhuri KR, Prieto-Jurcynska C, Naidu Y, et al. The nondeclaration of nonmotor symptoms of Parkinson's disease to health care professionals: an international study using the non-motor symptoms questionnaire. Mov Disord 2010;25:697-701.

Gallagher DA, Lees AJ, Schrag A. What are the most important nonmotor symptoms in patients with Parkinson's disease and are we missing them? Mov Disord 2010;25:2493-2500.

Spindler M, Gooneratne NS, Siderowf A, Duda JE, Cantoe C, Dahodwala N. Daytime sleepiness is associated with falls in Parkinson's disease. J Parkinsons Dis 2013;3:387-391.

Ghorayeb I, Loundou A, Auquier P, Dauvilliers Y, Bioulac B, Tison F. A nationwide survey of excessive daytime sleepiness in Parkinson's disease in France. Mov Disord 2007;22:1567-1572.

Knie B, Mitra MT, Logishetty K, Chaudhuri KR. Excessive daytime sleepiness in patients with Parkinson's disease. CNS Drugs 2011;25:203-212.

Högl B, Saletu M, Brandauer E, et al. Modafinil for the treatment of daytime sleepiness in Parkinson's disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002;25:905-909.

Adler CH, Caviness JN, Hentz JG, Lind M, Tiede J. Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease. Mov Disord 2003;18:287-293.

Ondo WG, Fayle R, Atassi F, Jankovic J. Modafinil for daytime somnolence in Parkinson's disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry 2005;76:1636-1639.

Liu X, Petit JM, Ezan P, Gyger J, Magistretti P, Giaume C. The psychostimulant modafinil enhances gap junctional communication in cortical astrocytes. Neuropharmacology 2013;75:533-538.

Duchêne A, Perier M, Zhao Y, et al. Impact of astroglial connexins on modafinil pharmacological properties. Sleep 2016;39:1283-1292.

Charvériat M, Naus CC, Leybaert L, Saez JC, Giaume C. Connexin-dependent neuroglial networking as a new therapeutic target. Front Cell Neurosci 2017;11:174.

Ghézali G, Vasile F, Curry N, et al. Neuronal activity drives Astroglial Connexin 30 in Perisynaptic processes and shapes its functions. Cereb Cortex 2020;30:753-766.

Vodovar D, Duchêne A, Wimberley C, et al. Cortico-amygdala-striatal activation by Modafinil/Flecainide combination. Int J Neuropsychopharmacol 2018;21:687-696.

Sauvet F, Erblang M, Gomez-Merino D, et al. Efficacy of THN102 (a combination of modafinil and flecainide) on vigilance and cognition during 40-hour total sleep deprivation in healthy subjects: glial connexins as a therapeutic target. Br J Clin Pharmacol 2019;85:2623-2633.

Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 2015;30:1591-1601.

Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-545.

Goetz CG, Poewe W, Rascol O, et al. Movement Disorder Society task force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 2004;19:1020-1028.

Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695-699.

Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of the unified Parkinson's disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008;23:2129-2170.

Posner K, Brown GK, Stanley B, et al. The Columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 2011;168:1266-1277.

Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for impulsive-compulsive disorders in Parkinson's disease-rating scale. Mov Disord 2012;27:242-247.

Basner M, Dinges DF. Maximizing sensitivity of the psychomotor vigilance test (PVT) to sleep loss. Sleep 2011;34:581-591.

Scrima L, Emsellem HA, Becker PM, et al. Identifying clinically important difference on the Epworth sleepiness scale: results from a narcolepsy clinical trial of JZP-110. Sleep Med 2017;38:108-112.