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2020.04.06.20055715V1.Full.Pdf medRxiv preprint doi: https://doi.org/10.1101/2020.04.06.20055715; this version posted April 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 1 Mo%on Sifnos: A randomized, double-blind, placebo-controlled study demonstra%ng the effec%veness of tradipitant in the treatment of mo%on sickness Vasilios M. Polymeropoulos*1, Mark É. Czeisler1#a, Mary M. Gibson1¶, Aus%n A. Anderson1¶, Jane Miglo1#b, Jingyuan Wang1, Changfu Xiao1, Christos M. Polymeropoulos1, Gunther Birznieks1, Mihael H. Polymeropoulos1 1 Vanda Pharmaceu%cals, Washington, District of Columbia, United States of America #a The Ins%tute for Breathing and Sleeping, Aus%n Health, Heidelberg, Victoria, Australia #b College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, United States of America *Corresponding author Email: [email protected] (VMP) ¶These authors contributed equally to this work. NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.04.06.20055715; this version posted April 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 2 Abstract Background Novel therapies are needed for the treatment of mo%on sickness given the inadequate relief, and bothersome and dangerous adverse effects of currently approved therapies. Neurokinin-1 (NK1) receptor antagonists have the poten%al to be effec%ve in improving the symptoms of mo%on sickness, given the involvement of Substance P in nauseogenic and eme%c pathways and the expression of NK1 receptors in the gastrointes%nal system. Here, we evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preven%ng mo%on sickness in variable sea condi%ons. Methods A total of 126 adults par%cipated in the Mo%on Sifnos Study. Groups of par%cipants were assigned to one of seven boat trips las%ng approximately four hours on the Pacific Ocean. Par%cipants were randomized 1:1 to tradipitant 170 mg or placebo and completed the Mo%on Sickness Severity Scale (MSSS) every 30 minutes, in addi%on to other assessments. Severity of mo%on sickness was assessed with the incidence of vomi%ng and the MSSS. Results Par%cipants on tradipitant had a significantly lower incidence of vomi%ng as compared to those on placebo across all boat trips (tradipitant=17.5%, placebo=39.7%, p=0.0039). For trips exposed to rough sea condi%ons, the difference in the incidence of vomi%ng between the groups was more drama%c (tradipitant=15.79%, placebo=72.22%, p=0.0009). Across these trips, mo%on sickness symptoms were significantly lower in the tradipitant group compared to the placebo group (tradipitant=3.19, placebo=4.57, p=0.0235). Discussion medRxiv preprint doi: https://doi.org/10.1101/2020.04.06.20055715; this version posted April 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 3 Tradipitant has the poten%al to be an effec%ve therapy for the preven%on of vomi%ng and treatment of nausea in people with mo%on sickness. medRxiv preprint doi: https://doi.org/10.1101/2020.04.06.20055715; this version posted April 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 4 Introduc8on Mo%on sickness is a disorder that has been plaguing travelers in various vehicles since an%quity [1]. Nausea and vomi%ng are the core symptoms of mo%on sickness [2]. Other symptoms may include swea%ng, dizziness, headache, irritability, and loss of appe%te. The e%ology and pathogenesis of disease are most commonly theorized as an aggrega%on of conflic%ng sensory informa%on that leads to an unpleasant physiological reac%on resul%ng in the symptoms described above [3-4]. Travelers with mo%on sickness have impaired cogni%ve performance [5], which can be of increased burden and danger in professional environments. Although there is a significant demand for efficacious therapies, the only currently approved treatments in the United States are dimenhydrinate (Dramamine), hyoscine (Scopolamine), and meclizine (Dramamine non-drowsy). These therapies carry incomplete efficacy and can have bothersome and dangerous adverse effects, such as drowsiness and dizziness [6]. An ideal therapy would be efficacious in the treatment of the cardinal symptoms of nausea and vomi%ng without inducing the array of adverse effects as seen with current medica%ons. NK1 receptor antagonists have the poten%al to be effec%ve in the treatment of mo%on sickness in humans. NK1 receptors are expressed in the network of brainstem nuclei including the area postrema and nucleus tractus solitarius (NTS) that are involved in the regula%on of vomi%ng [7]. Transmission of emetogenic sensory and emo%onal signals from higher cor%cal centers to the NTS can result in reflexive vomi%ng. The ves%bular centers in the brainstem send signals to the NTS to trigger emesis in response to ver%go, dizziness, or visuospa%al disorienta%on [8]. When the NTS receives the direct input from those sources, Substance P (SP), the most abundant neurokinin, is released [9]. Substance P preferen%ally binds to the NK1 receptors densely located in the NTS, which triggers this cascade of physiological responses, including emesis [8]. NK1 receptor antagonists are effec%ve and approved for the treatment of nausea and vomi%ng in other indica%ons. Maropitant is an approved NK1 receptor antagonist shown to be effec%ve for the preven%on of vomi%ng in dogs and cats due to mo%on sickness [10]. The NK1 receptor antagonist aprepitant is approved for the preven%on of post-opera%ve nausea and vomi%ng [11]. medRxiv preprint doi: https://doi.org/10.1101/2020.04.06.20055715; this version posted April 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 5 Tradipitant (VLY-686) is a novel NK1 receptor antagonist in development for the treatment of gastroparesis and atopic derma%%s. Tradipitant was shown to be effec%ve in the treatment of nausea and vomi%ng in gastroparesis in a 4-week randomized study [12]. Given this evidence to support the use of tradipitant as an NK1 receptor antagonist to treat nausea and vomi%ng and specifically in mo%on sickness, we designed and conducted the Mo%on Sifnos Study. Regarding the elec%on of modality to induce mo%on sickness, we conducted the study in natural sea condi%ons in the Pacific Ocean for several reasons: (1) seasickness is the classical archetype to induce mo%on sickness (2) exposure to natural sea mo%on supports the study condi%ons as ecologically valid, and (3) simula%on in real-world condi%ons offers the unique opportunity to evaluate the medica%on as it would be used once available to the public. Further, sea travel consists of ver%cal sinusoidal mo%ons induced by waves. The amplitude of these mo%ons is related to the wave height and corresponds to heave (linear ver%cal mo%on), which is the strongest s%mulus to induce mo%on sickness, contribu%ng more to provoca%on than the angular accelera%ons of pitch, roll, and yaw [13]. The frequency and accelera%on of ver%cal sinusoidal mo%ons can also be assessed. In an evalua%on of mo%on sickness incidence as a func%on of the frequency and accelera%on of ver%cal sinusoidal mo%on, wave frequencies around 0.2 Hz were most provoca%ve, and mo%on sickness incidence increased with accelera%on (propor%onal to the amplitude of the waves) across all wave frequencies [14]. The goal of the Mo%on Sifnos Study was to examine the effects of tradipitant in trea%ng the symptoms of mo%on sickness, with a focus on the core symptoms. medRxiv preprint doi: https://doi.org/10.1101/2020.04.06.20055715; this version posted April 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 6 Materials and methods The Mo%on Sifnos Study (NCT03772340) was a randomized, double-blind placebo-controlled study on the Pacific Ocean near Los Angeles, California to evaluate the efficacy and safety of tradipitant in the treatment of mo%on sickness. Par8cipants Eligible par%cipants were adults aged between 18 and 75 years with a history of mo%on sickness, otherwise in good health (determined by medical and psychiatric history, physical examina%on, electrocardiography, serum chemistry, hematology, urinalysis, and urine toxicology) and lacking any major nausea-inducing disorders.
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