{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T13:03:14Z","timestamp":1772024594160,"version":"3.50.1"},"reference-count":39,"publisher":"BMJ","issue":"8","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2019,6,26]]},"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Idiopathic nephrotic syndrome (INS) is characterised by a high relapse rate up to 80% after initial response to standard therapy with corticosteroids. Steroid toxicity is common and causes a great burden of disease that negatively influences the health-related quality of life (HRQoL). Recently, studies have shown that levamisole, an anthelminthic drug, significantly improves relapse-free survival in children with frequent relapses or steroid dependency. Compared with other steroid-sparing drugs, levamisole has relatively few side effects. We hypothesise that adding levamisole to standard therapy with corticosteroids in children with a first episode of INS will prevent relapses, decrease cumulative dosage of steroids used and improve HRQoL. This paper presents the study protocol for the LEARNS study (LEvamisole as Adjuvant therapy to Reduce relapses of Nephrotic Syndrome).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>An international, double-blind, placebo-controlled randomised trial will be conducted in 20 participating hospitals in the Netherlands and Belgium. Participants (n=92) with a first episode of INS, aged 2\u201316 years, who achieve remission after 4 weeks of oral prednisolone will be randomly assigned (1:1) to receive either levamisole 2.5\u2009mg\/kg alternate day or placebo added to prednisolone (18-week tapering schedule) for a total of 24 weeks. Follow-up will be until 2 years after first presentation. Additionally, parents and\/or children will fill out five HRQoL questionnaires. Primary outcome of the LEARNS study is occurrence of relapses within 12 months after first presentation. Secondary outcomes include time to first relapse, cumulative steroid dose after 2 years, safety parameters and quality of life scores.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The trial was approved by the Medical Ethical Committee. Results of the study will be published in a peer-reviewed journal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>NL6826, 2017-001025-41<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2018-027011","type":"journal-article","created":{"date-parts":[[2019,8,2]],"date-time":"2019-08-02T07:41:36Z","timestamp":1564731696000},"page":"e027011","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Prevention of relapses with levamisole as adjuvant therapy in children with a first episode of idiopathic nephrotic syndrome: study protocol for a double blind, randomised placebo-controlled trial (the LEARNS study)"],"prefix":"10.1136","volume":"9","author":[{"given":"Floor","family":"Veltkamp","sequence":"first","affiliation":[{"name":"Paediatric Nephrology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Djera H","family":"Khan","sequence":"additional","affiliation":[{"name":"Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christa","family":"Reefman","sequence":"additional","affiliation":[{"name":"Paediatric Nephrology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Veissi","sequence":"additional","affiliation":[{"name":"Paediatric Nephrology, Radboudumc, Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hedy A","family":"van Oers","sequence":"additional","affiliation":[{"name":"Psychosocial Department, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Levtchenko","sequence":"additional","affiliation":[{"name":"Paediatric Nephrology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron A A","family":"Math\u00f4t","sequence":"additional","affiliation":[{"name":"Hospital Pharmacy, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandrine","family":"Florquin","sequence":"additional","affiliation":[{"name":"Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna A E","family":"van Wijk","sequence":"additional","affiliation":[{"name":"Paediatric Nephrology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michiel F","family":"Schreuder","sequence":"additional","affiliation":[{"name":"Paediatric Nephrology, Radboudumc, Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lotte","family":"Haverman","sequence":"additional","affiliation":[{"name":"Psychosocial Department, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonia H M","family":"Bouts","sequence":"additional","affiliation":[{"name":"Paediatric Nephrology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2019,8,1]]},"reference":[{"key":"2025121512152562000_9.8.e027011.1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-011-1851-8"},{"key":"2025121512152562000_9.8.e027011.2","doi-asserted-by":"publisher","DOI":"10.1038\/kisup.2012.9"},{"key":"2025121512152562000_9.8.e027011.3","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1978.23"},{"key":"2025121512152562000_9.8.e027011.4","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012070646"},{"key":"2025121512152562000_9.8.e027011.5","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0b013e3282f51031"},{"key":"2025121512152562000_9.8.e027011.6","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.kint.2017.08.011","article-title":"A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome","volume":"93","author":"Gruppen","year":"2018","journal-title":"Kidney Int"},{"key":"2025121512152562000_9.8.e027011.7","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1007\/s00467-017-3616-5","article-title":"Efficacy of higher-dose levamisole in maintaining remission in steroid-dependant nephrotic syndrome","volume":"32","author":"Abeyagunawardena","year":"2017","journal-title":"Pediatric Nephrology"},{"key":"2025121512152562000_9.8.e027011.8","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1007\/s11255-012-0241-x","article-title":"Short- and long-term efficacy of levamisole in children with steroid-sensitive nephrotic syndrome","volume":"45","author":"Elmas","year":"2013","journal-title":"Int Urol Nephrol"},{"key":"2025121512152562000_9.8.e027011.9","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.2000.00042.x"},{"key":"2025121512152562000_9.8.e027011.10","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.intimp.2015.12.015","article-title":"Levamisole promotes murine bone marrow derived dendritic cell activation and drives Th1 immune response in vitro and in vivo","volume":"31","author":"Fu","year":"2016","journal-title":"Int Immunopharmacol"},{"key":"2025121512152562000_9.8.e027011.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.nephro.2005.06.003"},{"key":"2025121512152562000_9.8.e027011.12","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1016\/0140-6736(91)93257-A","article-title":"Levamisole for corticosteroid-dependent nephrotic syndrome in childhood","volume":"337","year":"1991","journal-title":"The Lancet"},{"key":"2025121512152562000_9.8.e027011.13","doi-asserted-by":"publisher","DOI":"10.1367\/1539-4409(2003)003<0329:TPAAPP>2.0.CO;2"},{"key":"2025121512152562000_9.8.e027011.14","doi-asserted-by":"publisher","DOI":"10.1080\/0954026021000046128"},{"key":"2025121512152562000_9.8.e027011.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2013.06.011"},{"key":"2025121512152562000_9.8.e027011.16","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2431-9-68"},{"key":"2025121512152562000_9.8.e027011.17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12955-017-0654-4","article-title":"Health related quality of life in Dutch infants, toddlers, and young children","volume":"15","author":"Schepers","year":"2017","journal-title":"Health Qual Life Outcomes"},{"key":"2025121512152562000_9.8.e027011.18","doi-asserted-by":"publisher","DOI":"10.1007\/s00787-003-0341-3"},{"key":"2025121512152562000_9.8.e027011.19","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s12955-018-0948-1","article-title":"Dutch norms for the Strengths and Difficulties Questionnaire (SDQ) - parent form for children aged 2-18\u00a0years","volume":"16","author":"Maurice-Stam","year":"2018","journal-title":"Health Qual Life Outcomes"},{"key":"2025121512152562000_9.8.e027011.20","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s11136-016-1405-4","article-title":"Dutch normative data and psychometric properties for the Distress Thermometer for Parents","volume":"26","author":"van Oers","year":"2017","journal-title":"Qual Life Res"},{"key":"2025121512152562000_9.8.e027011.21","doi-asserted-by":"publisher","DOI":"10.1037\/cpp0000043"},{"key":"2025121512152562000_9.8.e027011.22","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1681\/ASN.V85769","article-title":"Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children","volume":"8","author":"Tarshish","year":"1997","journal-title":"J Am Soc Nephrol"},{"key":"2025121512152562000_9.8.e027011.23","doi-asserted-by":"publisher","DOI":"10.1007\/s004670100021"},{"key":"2025121512152562000_9.8.e027011.24","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2014.240"},{"key":"2025121512152562000_9.8.e027011.25","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2014.260"},{"key":"2025121512152562000_9.8.e027011.26","doi-asserted-by":"crossref","unstructured":"Hahn D , Hodson EM , Willis NS , et al . Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev 2015:CD001533.doi:10.1002\/14651858.CD001533.pub5","DOI":"10.1002\/14651858.CD001533.pub5"},{"key":"2025121512152562000_9.8.e027011.27","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2005090922"},{"key":"2025121512152562000_9.8.e027011.28","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2018-024882","article-title":"Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial (INTENT study)","volume":"8","author":"Ehren","year":"2018","journal-title":"BMJ Open"},{"key":"2025121512152562000_9.8.e027011.29","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1007\/s00467-015-3186-3","article-title":"Health-related quality of life in patients with pediatric onset of end-stage renal disease: state of the art and recommendations for clinical practice","volume":"31","author":"Tjaden","year":"2016","journal-title":"Pediatr Nephrol"},{"key":"2025121512152562000_9.8.e027011.30","doi-asserted-by":"crossref","first-page":"285","DOI":"10.4103\/1319-2442.152420","article-title":"The impact of pediatric nephrotic syndrome on parents' health-related quality of life and family functioning: an assessment made by the PedsQL 4.0 family impact module","volume":"26","author":"Mishra","year":"2015","journal-title":"Saudi J Kidney Dis Transpl"},{"key":"2025121512152562000_9.8.e027011.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2004.08.022"},{"key":"2025121512152562000_9.8.e027011.32","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-015-3074-x"},{"key":"2025121512152562000_9.8.e027011.33","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1007\/s00467-011-1841-x","article-title":"The impact of pediatric nephrotic syndrome on families","volume":"26","author":"Mitra","year":"2011","journal-title":"Pediatr Nephrol"},{"key":"2025121512152562000_9.8.e027011.34","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1007\/s00467-017-3616-5","article-title":"Efficacy of higher-dose levamisole in maintaining remission in steroid-dependant nephrotic syndrome","volume":"32","author":"Abeyagunawardena","year":"2017","journal-title":"Pediatr Nephrol"},{"key":"2025121512152562000_9.8.e027011.35","doi-asserted-by":"crossref","first-page":"243","DOI":"10.5114\/ceji.2016.63122","article-title":"Levamisole therapy in children with frequently relapsing and steroid-dependent nephrotic syndrome: a single-center experience","volume":"3","author":"Ku\u017ama-Mroczkowska","year":"2016","journal-title":"Central European Journal of Immunology"},{"key":"2025121512152562000_9.8.e027011.36","doi-asserted-by":"publisher","DOI":"10.1007\/s004670050307"},{"key":"2025121512152562000_9.8.e027011.37","first-page":"153","article-title":"Levamisole therapy as a second-line immunosuppressive agent in corticosteroid-sensitive nephrotic syndrome in children","volume":"14","author":"Al-Ibrahim","year":"2003","journal-title":"Saudi J Kidney Dis Transpl"},{"key":"2025121512152562000_9.8.e027011.38","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1042\/CS20140749","article-title":"Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte","volume":"128","author":"Jiang","year":"2015","journal-title":"Clin Sci"},{"key":"2025121512152562000_9.8.e027011.39","unstructured":"Lilien MR , Vande W . Nefrotisch syndroom. In: Werkboek Kindernefrologie, 2010:124\u201331."}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2018-027011","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T20:15:35Z","timestamp":1765829735000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2018-027011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8]]},"references-count":39,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,8,1]]},"published-print":{"date-parts":[[2019,8]]}},"alternative-id":["10.1136\/bmjopen-2018-027011"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2018-027011","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8]]}}}