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Guidelines justify empiric short-term PPI therapy in other cases to control symptoms. Yet, there is insufficient PPI down-titration and\/or cessation. As such, concerns have risen related to the impact of PPIs on the healthcare budget and increasing number of risks and side effects. This study aims to provide evidence to determine which strategy provides the most effective approach for stopping chronic intake of PPIs in patients in whom there is no firm medical indication for their continued use.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This is a multicentre, pragmatic, randomised clinical trial. General practitioners will randomise 609 to one of three PPI deprescription strategies. Patients on a high-dose PPI are allowed to participate after down-titrating their dose to a maintenance dose for 1\u2009month before being randomised. Patients unable to decrease the high-dose PPI are not to be randomised. Following randomisation, patients will be requested to adapt their PPI intake for 1\u2009month to the allocated deprescription scheme: (a) on-demand PPI intake, (b) replace PPI to alginate intake and (c) intermittent PPI intake with a fixed scheme. After successfully following the deprescription strategy, patients are requested to completely stop their use of PPI. Patients are followed up for 1 year. The primary endpoint of the study is the percentage of patients achieving a successful therapeutic outcome, defined as limited PPI intake and willingness to continue the therapy, at the end of the follow-up period. Data will be collected using a study-specific online platform and analysed using the intention-to-treat approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>\n                      This trial was approved through the platform for Clinical Trials in the European Union by a Belgian ethics committee (CTIS reference: 2022-502375-37-00). Study results will be disseminated via open-access, peer-reviewed publications and conference presentations. Trial registration number\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05629143\">NCT05629143<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05629143\">NCT05629143<\/jats:ext-link>\n                      , clinicaltrial.gov.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-101266","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:25:18Z","timestamp":1776435918000},"page":"e101266","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Primary carE PPi dEprescRibing (PEPPER) trial: a protocol for determining the optimal strategy for stopping chronic proton pump inhibitor therapy in primary care patients"],"prefix":"10.1136","volume":"16","clinical-trial-number":[{"clinical-trial-number":"nct05629143","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05629143","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05629143","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1790-7904","authenticated-orcid":false,"given":"Florencia","family":"Carbone","sequence":"first","affiliation":[{"name":"TARGID, CROMETA, KU Leuven, Leuven, Belgium"},{"name":"Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janne","family":"Scheepers","sequence":"additional","affiliation":[{"name":"TARGID, CROMETA, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Van den Houte","sequence":"additional","affiliation":[{"name":"TARGID, CROMETA, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annouschka","family":"Laenen","sequence":"additional","affiliation":[{"name":"Leuven Biostatistics and Statistical Bioinformatics Centre (L-BioStat), KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Tack","sequence":"additional","affiliation":[{"name":"TARGID, CROMETA, KU Leuven, Leuven, Belgium"},{"name":"Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"2026041707250900000_16.4.e101266.1","doi-asserted-by":"publisher","DOI":"10.3399\/bjgp22X721157"},{"key":"2026041707250900000_16.4.e101266.2","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0270252","article-title":"Trends in proton pump inhibitor use, reflux esophagitis, and various upper gastrointestinal symptoms from 2010 to 2019 in Japan","volume":"17","author":"Yamamichi","year":"2022","journal-title":"PLOS ONE"},{"key":"2026041707250900000_16.4.e101266.3","doi-asserted-by":"crossref","DOI":"10.57187\/smw.2023.40119","article-title":"Inappropriate proton-pump inhibitor prescribing in primary care \u2013 an observational study with quality circles","volume":"153","author":"Vidonscky L\u00fcthold","year":"2023","journal-title":"Swiss Med Wkly"},{"key":"2026041707250900000_16.4.e101266.4","unstructured":"RIZIV\/INAMI . 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