{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:02:19Z","timestamp":1768464139036,"version":"3.49.0"},"reference-count":19,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T00:00:00Z","timestamp":1681257600000},"content-version":"unspecified","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2023,3,27]]},"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Obtaining level 1 evidence on efficacy of glycosaminoglycan (GAG) therapy is difficult, due to low incidence of bladder pain syndrome\/interstitial cystitis (BPS\/IC) and heterogeneous symptoms experienced by patients with BPS\/IC. Currently, because of a lack of high-grade evidence, the recommendation for applying GAG therapy in most guidelines is \u2018low grade\u2019. An aggregated N-of-1 trial is a multicrossover design that yields similar level 1 evidence as a traditional randomised controlled trial (RCT), while requiring far less patients. The goal of this study is to investigate the efficacy of intravesical GAG therapy (Ialuril) for patients with BPS\/IC with Hunner lesions using a dual RCT and aggregated N-of-1 trial design to obtain level 1 evidence.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and analysis<\/jats:title>\n                  <jats:p>The GETSBI study is a double-blind multidesign multicentre randomised placebo-controlled study to assess the short-term and long-term efficacy of hyaluronic acid (1.6%) + chondroitin sulfate (2%) therapy (Ialuril Prefill, IBSA, Goodlife) in patients with symptomatic BPS\/IC with Hunner lesions. It starts as a standard RCT (n=80), but continues as an aggregated N-of-1 trial. There are three parallel arms, receiving blinded treatment for three periods (1\u2009x\/week for 6\u2009weeks, ratio placebo to intervention in periods of 2:1). Followed by an open prospective part for the long-term efficacy. The primary study outcome is the maximum bladder pain experienced in the last 3\u2009days measured using the visual analogue pain scale (0\u201310).<\/jats:p>\n                  <jats:p>This study is a collaboration with the Dutch government and will deliver evidence for the decision to reimburse the therapy. Furthermore, this multidesign study will allow us to compare the two main methods to evaluate applicability for future study designs for BPS\/IC research.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Ethics and dissemination<\/jats:title>\n                  <jats:p>Ethical approval was given by METC Oost-Nederland, file number: 2020-7265, NL-number: NL76290.091.20. Findings from this study will be disseminated via publication, reports and conference presentations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>ClinicalTrials.gov identifier (NCT number): <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05518864\">NCT05518864<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/bmjopen-2022-068546","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T13:15:18Z","timestamp":1681305318000},"page":"e068546","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Study protocol of a multicentre double-blind RCT, comparing a traditional RCT with an aggregated N-of-1 trial: GAG therapy Efficacy Trial Solution for Bladder pain syndrome\/Interstitial cystitis (GETSBI study)"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct05518864","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6416-7892","authenticated-orcid":false,"given":"Charlotte","family":"van Ginkel","sequence":"first","affiliation":[{"name":"Urology, Radboudumc, Nijmegen, Gelderland, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cl\u00e9o","family":"Baars","sequence":"additional","affiliation":[{"name":"Urology, Radboudumc, Nijmegen, Gelderland, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Heesakkers","sequence":"additional","affiliation":[{"name":"Urology, Maastricht UMC+, Maastricht, Limburg, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Martens","sequence":"additional","affiliation":[{"name":"Urology, Radboudumc, Nijmegen, Gelderland, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dick","family":"Janssen","sequence":"additional","affiliation":[{"name":"Urology, Radboudumc, Nijmegen, Gelderland, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2023,4,12]]},"reference":[{"key":"2025101812541848000_13.4.e068546.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2007.09.019"},{"key":"2025101812541848000_13.4.e068546.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2013.04.035"},{"key":"2025101812541848000_13.4.e068546.3","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0022-5347(01)66551-0","article-title":"Discrimination between the ulcerous and the nonulcerous forms of interstitial cystitis by noninvasive findings","volume":"155","author":"Koziol","year":"1996","journal-title":"J Urol"},{"key":"2025101812541848000_13.4.e068546.4","doi-asserted-by":"publisher","DOI":"10.1016\/0090-4295(78)90286-8"},{"key":"2025101812541848000_13.4.e068546.5","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/nau.1930090302","article-title":"Interstitial cystitis: clinical manifestations and diagnostic criteria in over 200 cases","volume":"9","author":"Parsons","year":"1990","journal-title":"Neurourol Urodyn"},{"key":"2025101812541848000_13.4.e068546.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)65006-9"},{"key":"2025101812541848000_13.4.e068546.7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/iju.13969","article-title":"Phenotyping of interstitial cystitis\/bladder pain syndrome","volume":"26 Suppl 1","author":"Akiyama","year":"2019","journal-title":"Int J Urol"},{"key":"2025101812541848000_13.4.e068546.8","first-page":"72","article-title":"The primary antibacterial defense mechanism of the bladder","volume":"13","author":"Parsons","year":"1975","journal-title":"Invest Urol"},{"key":"2025101812541848000_13.4.e068546.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2006.03.084"},{"key":"2025101812541848000_13.4.e068546.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2010.03.016"},{"key":"2025101812541848000_13.4.e068546.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.urology.2012.01.059"},{"key":"2025101812541848000_13.4.e068546.12","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1002\/nau.23091","article-title":"A randomized, open-label, multicenter study of the efficacy and safety of intravesical hyaluronic acid and chondroitin sulfate versus dimethyl sulfoxide in women with bladder pain syndrome\/interstitial cystitis","volume":"36","author":"Cervigni","year":"2017","journal-title":"Neurourol Urodyn"},{"key":"2025101812541848000_13.4.e068546.13","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.330.7492.644"},{"key":"2025101812541848000_13.4.e068546.14","unstructured":"Howick J et al . 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