{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T11:39:10Z","timestamp":1763811550530,"version":"3.40.5"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T00:00:00Z","timestamp":1728950400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:p>Degenerative cerebellar ataxias comprise a heterogeneous group of rare and ultra\u2010rare genetic diseases. While disease\u2010modifying treatments are now on the horizon for many ataxias, robust trial designs and analysis methods are lacking. To better inform trial designs, we applied item response theory (IRT) modeling to evaluate the natural history progression of several ataxias, assessed with the widely used scale for assessment and rating of ataxia (SARA). A longitudinal IRT model was built utilizing real\u2010world data from the large autosomal recessive cerebellar ataxia (ARCA) registry. Disease progression was evaluated for the overall cohort as well as for the 10 most common ARCA genotypes. Sample sizes were calculated for simulated trials with autosomal recessive spastic ataxia Charlevoix\u2013Saguenay (ARSACS) and polymerase gamma (POLG) ataxia, as showcased, across multiple design and analysis scenarios. Longitudinal IRT models were able to describe the changes in the latent variable underlying SARA as a function of time since ataxia onset for both the overall ARCA cohort and the common genotypes. The typical progression rates varied across genotypes between relatively high in POLG (~\u20090.98 SARA points\/year at SARA\u2009=\u200920) and very low in COQ8A ataxia (~\u20090.003 SARA points\/year at SARA\u2009=\u200920). Smaller trial sizes were required in case of faster progression, longer trials (~\u200975\u201390% less with 5\u2009years vs. 2\u2009years), and larger drug effects (~\u200970\u201380% less with 100% vs. 50% inhibition). Simulating under the developed IRT model, the longitudinal IRT model had the highest power, with a well\u2010controlled type I error, compared to total score models or end\u2010of\u2010treatment analyses. The established longitudinal IRT framework allows efficient utilization of natural history data and ultimately facilitates the design and analysis of treatment trials in rare and ultra\u2010rare genetic ataxias.<\/jats:p>","DOI":"10.1002\/cpt.3466","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T09:10:43Z","timestamp":1728983443000},"page":"1593-1605","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Longitudinal Analysis of Natural History Progression of Rare and Ultra\u2010Rare Cerebellar Ataxias Using Item Response Theory"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3102-2707","authenticated-orcid":false,"given":"Alzahra","family":"Hamdan","sequence":"first","affiliation":[{"name":"Pharmacometrics Research Group, Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0951-7514","authenticated-orcid":false,"given":"Niels","family":"Hendrickx","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, IAME, Inserm  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2676-5912","authenticated-orcid":false,"given":"Andrew C.","family":"Hooker","sequence":"additional","affiliation":[{"name":"Pharmacometrics Research Group, Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0663-0532","authenticated-orcid":false,"given":"Xiaomei","family":"Chen","sequence":"additional","affiliation":[{"name":"Pharmacometrics Research Group, Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9150-9886","authenticated-orcid":false,"given":"Emmanuelle","family":"Comets","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, IAME, Inserm  Paris France"},{"name":"Univ Rennes, Inserm, EHESP, Irset \u2013 UMR_S 1085  Rennes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8165-5898","authenticated-orcid":false,"given":"Andreas","family":"Trasch\u00fctz","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Center for Neurology and Hertie Institute for Clinical Brain Research University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7781-2766","authenticated-orcid":false,"given":"Rebecca","family":"Sch\u00fcle","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Center for Neurology and Hertie Institute for Clinical Brain Research University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"Division of Neurodegenerative Diseases, Department of Neurology Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"ARCA Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"EVIDENCE\u2010RND Consortium","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7045-1275","authenticated-orcid":false,"given":"France","family":"Mentr\u00e9","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, IAME, Inserm  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2280-7273","authenticated-orcid":false,"given":"Matthis","family":"Synofzik","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Diseases, Center for Neurology and Hertie Institute for Clinical Brain Research University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1258-8297","authenticated-orcid":false,"given":"Mats O.","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Pharmacometrics Research Group, Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,10,15]]},"reference":[{"key":"e_1_2_12_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101123"},{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.104698"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1006610"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.01.049"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.677551"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000219042.60538.92"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12311-023-01547-z"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2021.35841"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2016.03.005"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2020.09.001"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00457-9"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000006210"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-023-07399-6"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.29397"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26712"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25751"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011528"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00027-2"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000415"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12280"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-020-09697-x"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2011.05.2409"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-017-2216-1"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-017-0058-8"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-016-9977-z"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-014-1315-5"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13162"},{"key":"e_1_2_12_28_1","unstructured":"Hamdan A.et al.Item Response Theory Analysis of the Scale for the Assessment and Rating of Ataxia in Autosomal Recessive Cerebellar Ataxias. In p. Abstr 10626. <www.page\u2010meeting.org\/?abstract=10626>."},{"key":"e_1_2_12_29_1","unstructured":"US Food and Drug Administration.U.S. Food and Drug AdministrationFDA; Patient\u2010Focused Drug Development: Selecting Developing or Modifying Fit\u2010for\u2010Purpose Clinical Outcome Assessments. Changes in rheumatoid factor activity during the course of sarcoidosis 44 60 67 <https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/patient\u2010focused\u2010drug\u2010development\u2010selecting\u2010developing\u2010or\u2010modifying\u2010fit\u2010purpose\u2010clinical\u2010outcome> (2022) Accessed Feb 2 2023."},{"key":"e_1_2_12_30_1","unstructured":"US Food and Drug Administration.US Food and Drug AdministrationFDA; Submitting Clinical Trial Datasets and Documentation for Clinical Outcome Assessments Using Item Response Theory <https:\/\/www.fda.gov\/regulatory\u2010information\/search\u2010fda\u2010guidance\u2010documents\/submitting\u2010clinical\u2010trial\u2010datasets\u2010and\u2010documentation\u2010clinical\u2010outcome\u2010assessments\u2010using\u2010item> (2023). Accessed July 7 2024."},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-023-00883-6"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12422"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1214\/14-EJS890"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9255-z"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.24"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-016-9487-8"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9542-0"},{"key":"e_1_2_12_38_1","unstructured":"Karlsson M.O.&Nordgren R.Perl\u2010speaks\u2010NONMEM: User documentation: SSE user guide<https:\/\/uupharmacometrics.github.io\/PsN\/docs.html> Accessed December 11 2023."},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-016-9468-y"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-024-00925-7"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-021-00555-3"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab404"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12601"},{"key":"e_1_2_12_44_1","unstructured":"Lilly's Kisunla\u2122 (donanemab\u2010azbt) Approved by the FDA for the Treatment of Early Symptomatic Alzheimer's Disease | Eli Lilly and Company<https:\/\/investor.lilly.com\/news\u2010releases\/news\u2010release\u2010details\/lillys\u2010kisunlatm\u2010donanemab\u2010azbt\u2010approved\u2010fda\u2010treatment\u2010early> Accessed July 24 2024."},{"key":"e_1_2_12_45_1","unstructured":"LECANEMAB CONFIRMATORY PHASE 3 CLARITY AD STUDY MET PRIMARY ENDPOINT SHOWING HIGHLY STATISTICALLY SIGNIFICANT REDUCTION OF CLINICAL DECLINE IN LARGE GLOBAL CLINICAL STUDY OF 1 795 PARTICIPANTS WITH EARLY ALZHEIMER'S DISEASE | Biogen<https:\/\/investors.biogen.com\/news\u2010releases\/news\u2010release\u2010details\/lecanemab\u2010confirmatory\u2010phase\u20103\u2010clarity\u2010ad\u2010study\u2010met\u2010primary> Accessed July 24 2024."},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51897"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3466","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T06:22:27Z","timestamp":1731651747000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3466"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,15]]},"references-count":46,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1002\/cpt.3466"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3466","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"type":"print","value":"0009-9236"},{"type":"electronic","value":"1532-6535"}],"subject":[],"published":{"date-parts":[[2024,10,15]]},"assertion":[{"value":"2024-05-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}