{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T17:42:05Z","timestamp":1781199725933,"version":"3.54.1"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T00:00:00Z","timestamp":1560211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"DOI":"10.3389\/fneur.2019.00597","type":"journal-article","created":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T04:27:37Z","timestamp":1560227257000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial of CX-8998, a Selective Modulator of the T-Type Calcium Channel in Inadequately Treated Moderate to Severe Essential Tremor: T-CALM Study Design and Methodology for Efficacy Endpoint and Digital Biomarker Selection"],"prefix":"10.3389","volume":"10","author":[{"given":"Spyros","family":"Papapetropoulos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret S.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Boyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan J.","family":"Newbold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2019,6,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1056\/NEJMcp1707928","article-title":"Essential tremor","volume":"378","author":"Haubenberger","year":"2018","journal-title":"N Engl J Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1002\/mds.27121","article-title":"Consensus statement on the classification of tremors, from the task force on tremor of the international parkinsonian and movement disorder society","volume":"33","author":"Bhatia","year":"2018","journal-title":"Mov Disord"},{"key":"B3","doi-asserted-by":"publisher","first-page":"S92","DOI":"10.1016\/j.parkreldis.2017.07.014","article-title":"The etiology of essential tremor: genes versus environment","volume":"46","author":"Hopfner","year":"2018","journal-title":"Parkinsonism Relat Disord."},{"key":"B4","doi-asserted-by":"publisher","first-page":"43","DOI":"10.4137\/JCNSD.S6561","article-title":"Pharmacotherapy of essential tremor","volume":"5","author":"Hedera","year":"2013","journal-title":"J Central Nerv Syst Dis"},{"key":"B5","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1353\/nhr.2011.0002","article-title":"Neuronal T-type calcium channels: what's new?","volume":"4","author":"Iftinca","year":"2011","journal-title":"J Med Life"},{"key":"B6","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1007\/s12311-011-0277-y","article-title":"T-type calcium channel as a new therapeutic target for tremor","volume":"10","author":"Miwa","year":"2011","journal-title":"Cerebellum"},{"key":"B7","doi-asserted-by":"publisher","first-page":"172","DOI":"10.3389\/fncir.2013.00172","article-title":"The potential roles of T-type Ca2+ channels in motor coordination","volume":"7","author":"Park","year":"2013","journal-title":"Front Neural Circuits"},{"key":"B8","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/s12311-015-0735-z","article-title":"Linking essential tremor to the cerebellum: neurochemical evidence","volume":"15","author":"Marin-Lahoz","year":"2016","journal-title":"Cerebellum"},{"key":"B9","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/nrd.2015.5","article-title":"Targeting voltage-gated calcium channels in neurological and psychiatric diseases","volume":"15","author":"Zamponi","year":"2016","journal-title":"Nat Rev Drug Discov"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1002\/mds.25648","article-title":"Task force report: scales for screening and evaluating tremor: critique and recommendations","volume":"28","author":"Elble","year":"2013","journal-title":"Mov Disord"},{"key":"B11","doi-asserted-by":"publisher","first-page":"34","DOI":"10.29245\/2572.942X\/2016\/4.1038","article-title":"The essential tremor rating assessment scale","volume":"1","author":"Elble","year":"2016","journal-title":"J Neurol Neuromed."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1002\/mds.26671","article-title":"Transducer-based evaluation of tremor","volume":"31","author":"Haubenberger","year":"2016","journal-title":"Mov Disord"},{"key":"B13","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1002\/mds.22838","article-title":"How common is the most common adult movement disorder?","volume":"25","author":"Louis","year":"2010","journal-title":"Mov Disord."},{"key":"B14","doi-asserted-by":"publisher","first-page":"259","DOI":"10.7916\/D8TT4P4B","article-title":"How many people in the USA have essential tremor?","volume":"4","author":"Louis","year":"2014","journal-title":"Tremor Other Hyperkinet Mov"},{"key":"B15","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1093\/brain\/117.4.805","article-title":"A study of hereditary essential tremor","volume":"117","author":"Bain","year":"1994","journal-title":"Brain"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1002\/mds.20884","article-title":"Quality of life and personality in essential tremor patients","volume":"21","author":"Lorenz","year":"2006","journal-title":"Mov Disord."},{"key":"B17","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/j.parkreldis.2015.04.019","article-title":"Tremor-related quality of life: A comparison of essential tremor vs. Parkinson's disease patients","volume":"21","author":"Louis","year":"2015","journal-title":"Parkinsonism Relat Disord"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1212\/WNL.0b013e318236f0fd","article-title":"Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology","volume":"77","author":"Zesiewicz","year":"2011","journal-title":"Neurology"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.7916\/D89W0D7W","article-title":"Cognitive features of essential tremor: a review of the clinical aspects and possible mechanistic underpinnings","author":"Bermejo-Pareja","year":"2012","journal-title":"Tremor Other Hyperkinet Mov."},{"key":"B20","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1111\/j.1600-0404.2011.01573.x","article-title":"Non-motor features in essential tremor","volume":"125","author":"Chandran","year":"2012","journal-title":"Acta Neurol Scand"},{"key":"B21","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.parkreldis.2011.03.012","article-title":"It is time to remove the benign from the essential tremor label","volume":"17","author":"Louis","year":"2011","journal-title":"Parkinsonism Relat Disord"},{"key":"B22","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1093\/brain\/72.2.113","article-title":"Observations on essential (heredofamial) tremor","volume":"72","author":"Critchley","year":"1949","journal-title":"Brain."},{"key":"B23","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1002\/mds.22370","article-title":"Intention tremor in essential tremor: Prevalence and association with disease duration","volume":"24","author":"Louis","year":"2009","journal-title":"Mov Disord."},{"key":"B24","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1001\/archneur.60.3.405","article-title":"Rest tremor in patients with essential tremor: prevalence, clinical correlates and electrophysiologic characteristics","volume":"60","author":"Cohen","year":"2003","journal-title":"Arch Neurol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1002\/mds.870090212","article-title":"Gait abnormality in essential tremor","volume":"9","author":"Singer","year":"1994","journal-title":"Mov Disord"},{"key":"B26","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1002\/mds.1184","article-title":"Correlates of functional disability in essential tremor","volume":"16","author":"Louis","year":"2001","journal-title":"Mov Disord."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1002\/mds.21079","article-title":"Intention tremor of the head in patients with essential tremor","volume":"21","author":"Leegwater-Kim","year":"2006","journal-title":"Mov Disord"},{"key":"B28","doi-asserted-by":"publisher","first-page":"401","DOI":"10.2147\/NDT.S4795","article-title":"Overview of essential tremor","volume":"6","author":"Zesiewicz","year":"2010","journal-title":"Neuropsychiatr Dis Treat"},{"key":"B29","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1177\/1756285616679123","article-title":"Emerging strategies in the management of essential tremor","volume":"10","author":"Hedera","year":"2017","journal-title":"Ther Adv Neurol Disord"},{"key":"B30","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1056\/NEJMoa1600159","article-title":"A randomized trial of focused ultrasound thalatomy for essential tremor","volume":"375","author":"Elias","year":"2016","journal-title":"N Engl J Med"},{"key":"B31","first-page":"1206","article-title":"Essential tremor","volume":"2015","author":"Zesiewicz","year":"2015","journal-title":"BMJ Clin Evid."},{"key":"B32","year":"2011","journal-title":"Inderal\u00ae (Propranolol Hydrochloride) Tablets FDA Package Insert."},{"key":"B33","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3389\/fneur.2011.00091","article-title":"Treatment of essential tremor: are there issues we are overlooking?","volume":"2","author":"Louis","year":"2011","journal-title":"Front Neurol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"331","DOI":"10.7916\/D87080M9","article-title":"Defining the treatment gap: what essential tremor patients want they are not getting","volume":"5","author":"Louis","year":"2015","journal-title":"Tremor Other Hyperkinet Mov"},{"key":"B35","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.parkreldis.2014.12.001","article-title":"Medication non-adherence in essential tremor","volume":"21","author":"Louis","year":"2015","journal-title":"Parkinsonism Relat Disord"},{"key":"B36","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1161\/01.RES.83.1.103","article-title":"Cloning and characterization of alpha 1H from human heart, a member of the T-type Ca2+ channel gene family","volume":"83","author":"Gribbs","year":"1998","journal-title":"Circ Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"3289","DOI":"10.1172\/JCI46482","article-title":"Modulation of subthalamic T-type Ca2+ channels remedies locomotor deficits in a rat model of Parkinson disease","volume":"121","author":"Tai","year":"2011","journal-title":"J Clin Invest"},{"key":"B38","doi-asserted-by":"publisher","first-page":"10731","DOI":"10.1073\/pnas.1002995107","article-title":"Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive","volume":"107","author":"Park","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"B39","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/sj.emboj.7600515","article-title":"Silencing of the Cav3.2 T-type calcium channel gene in sensory neurons demonstrates its major role in nociception","volume":"24","author":"Bourinet","year":"2005","journal-title":"EMBO J"},{"key":"B40","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.neuropharm.2010.05.012","article-title":"T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor","volume":"59","author":"Handforth","year":"2010","journal-title":"Neuropharmacology"},{"key":"B41","first-page":"267","article-title":"[Thalamo-cortical dysrhythmia syndrom: neuropsychiatric features] [Article in Spanish]","volume":"120","author":"Llinas","year":"2003","journal-title":"An R Acad Nac Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"17819","DOI":"10.1073\/pnas.0707945104","article-title":"\u03b3-Band deficiency and abnormal thalamocortical activity in P\/Q-type channel mutant mice","volume":"104","author":"Llinas","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"B43","doi-asserted-by":"publisher","first-page":"10898","DOI":"10.1523\/JNEUROSCI.22-24-10898.2002","article-title":"Rhythmicity without synchrony in the electrically uncoupled inferior olive","volume":"22","author":"Long","year":"2002","journal-title":"J Neurosci"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7916\/D8TD9W2P","article-title":"Harmaline tremor: underlying mechanisms in a potential animal model of essential tremor","volume":"2","author":"Handforth","year":"2012","journal-title":"Tremor Other Hyperkinet Mov"},{"key":"B45","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1002\/mds.22418","article-title":"Zonisamide for essential tremor: an evaluator blinded study","volume":"24","author":"Handforth","year":"2009","journal-title":"Mov Disord"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/MD.0000000000001809","article-title":"Efficacy and safety of topiramate for essential tremor: a meta-analysis of randomized controlled trials","volume":"94","author":"Chang","year":"2015","journal-title":"Medicine"},{"key":"B47","doi-asserted-by":"publisher","first-page":"3692","DOI":"10.1021\/jm800419w","article-title":"Design, synthesis, and evaluation of a novel 4-aminomethyl-4-fluoropiperidine as a T-Type Ca2+ channel antagonist","volume":"51","author":"Shipe","year":"2008","journal-title":"J. Med. Chem."},{"key":"B48","unstructured":"CX-8998, a potent, selective T-type calcium channel antagonist dose-dependently suppresses seizures in the WAG\/Rij genetic model of epilepsyP5.281\n            LeeM\n            PapapetropoulosS\n          Neurology902018"},{"key":"B49","unstructured":"Therapeutic exposures of CX-8998, a potent, selective and state dependent Cav3 channel anatagonist in development for essential tremor and Parkinson's disease tremor in Cav3 driven neurological models\n            LeeM\n            NewboldE\n            PapapetropoulosS\n          Mov Disord332018"},{"key":"B50","unstructured":"Reversal of allodynia and neurophysiological outcomes by CX-8998, a potent, selective T-type calcium channel modulator, in a model of bortezomib induced peripheral neuropathyS7.004\n            LeeM\n            MaricichY\n            CavalettiG\n            PapapetropoulosS\n          Neurology152018"},{"key":"B51","unstructured":"CX-8998 and CX-5395, potent, selective T-type calcium channel antagonists suppress seizures in genetic models of epilepsy\n            LeeM\n            NewboldE\n            PapapetropoulosS\n          Soc Neurosci2018"},{"key":"B52","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/hup.2289","article-title":"Randomized controlled study of the T-type calcium channel antagonist MK-8998 for the treatment of acute psychosis in patients with schizophrenia","volume":"28","author":"Egan","year":"2013","journal-title":"Hum Psychopharmacol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1002\/mds.25162","article-title":"Reliability of a new scale for essential tremor","volume":"27","author":"Elble","year":"2012","journal-title":"Mov Disord"},{"key":"B54","doi-asserted-by":"publisher","first-page":"4378","DOI":"10.1109\/IEMBS.2011.6091086","article-title":"Objective measure of upper extremity motor impairment in Parkinsons disease with inertial sensors","volume":"2011","author":"Hoffman","year":"2011","journal-title":"Conf Proc IEEE Eng Med Biol Soc"},{"key":"B55","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1002\/mds.22445","article-title":"Clinically deployable Kinesia technology for automated tremor assessment","volume":"24","author":"Giufridda","year":"2009","journal-title":"Mov Disord"},{"key":"B56","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.parkreldis.2011.04.017","article-title":"Essential tremor quantification during activities of daily living","volume":"17","author":"Heldman","year":"2011","journal-title":"Parkinsonism Relat Disord."},{"key":"B57","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.parkreldis.2005.05.009","article-title":"Quality of life in Essential Tremor Questionnaire (QUEST): development and initial validation","volume":"11","author":"Tr\u00f6ster","year":"2005","journal-title":"Parkinsonism Relat Disord"},{"key":"B58","volume-title":"Assessment Manual for Psychopharmacology","author":"Guy","year":"1976"},{"key":"B59","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1007\/BF01530764","article-title":"Goal attainment scaling: a general method for evaluating comprehensive community mental health programs","volume":"4","author":"Kiresuk","year":"1968","journal-title":"Commun Ment Health J"},{"key":"B60","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.parkreldis.2013.09.009","article-title":"Continuous in-home monitoring of essential tremor","volume":"20","author":"Pullam","year":"2014","journal-title":"Parkinsonism Relat Disord"},{"key":"B61","doi-asserted-by":"publisher","first-page":"273","DOI":"10.3389\/fneur.2017.00273","article-title":"Biometric digital health technology for measuring motor function in Parkinson's disease: results from a feasibility and patient satisfaction study","volume":"13","author":"Mitsi","year":"2017","journal-title":"Front. Neurol."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1176\/appi.ajp.2011.10111704","article-title":"The Columbia suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults","volume":"168","author":"Posner","year":"2011","journal-title":"Am J Pschiatry"},{"key":"B63","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.smrv.2013.08.002","article-title":"Evaluation of the measurement properties of the Epworth sleepiness scale: a systematic review","volume":"18","author":"Kenderska","year":"2014","journal-title":"Sleep Med Rev"},{"key":"B64","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/1471-2377-8-21","article-title":"A questionnaire-based (UM-PDHQ) study of hallucinations in Parkinson's disease","volume":"8","author":"Papapetropoulos","year":"2008","journal-title":"BMC Neurol"},{"key":"B65","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/B978-0-444-64189-2.00016-0","article-title":"Essential tremor and the cerebellum","volume":"155","author":"Louis","year":"2018","journal-title":"Handb Clin Neurol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/mdc3.12560","article-title":"Comparison of the Fahn-Tolosa-Marin clinical rating scale and the essential tremor rating assessment scale","volume":"5","author":"Ondo","year":"2018","journal-title":"Mov Disord Clin Pract"},{"key":"B67","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7916\/D8WM1C41","article-title":"Tremor: clinical phenomenology and assessment techniques","volume":"2","author":"Hess","year":"2012","journal-title":"Tremor Other Hyperkinet Mov."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fneur.2019.00597\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T04:27:44Z","timestamp":1560227264000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fneur.2019.00597\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,11]]},"references-count":67,"alternative-id":["10.3389\/fneur.2019.00597"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2019.00597","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,11]]},"article-number":"597"}}