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)

Introduction 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). Methods and analysis 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 2–16 years, who achieve remission after 4 weeks of oral prednisolone will be randomly assigned (1:1) to receive either levamisole 2.5 mg/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. Ethics and dissemination The trial was approved by the Medical Ethical Committee. Results of the study will be published in a peer-reviewed journal. Trial registration number NL6826, 2017-001025-41

[1]  J. Craig,et al.  Corticosteroid therapy for nephrotic syndrome in children. , 2020, The Cochrane database of systematic reviews.

[2]  L. Weber,et al.  Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial (INTENT study) , 2018, BMJ Open.

[3]  H. Maurice‐Stam,et al.  Dutch norms for the Strengths and Difficulties Questionnaire (SDQ) – parent form for children aged 2–18 years , 2018, Health and Quality of Life Outcomes.

[4]  A. Bagga,et al.  A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome. , 2017, Kidney international.

[5]  H. Maurice‐Stam,et al.  Health related quality of life in Dutch infants, toddlers, and young children , 2017, Health and Quality of Life Outcomes.

[6]  R. Schwarzer,et al.  Women with family cancer history are at risk for poorer physical quality of life and lower self-efficacy: a longitudinal study among men and women with non-small cell lung cancer , 2017, Health and Quality of Life Outcomes.

[7]  S. Tennakoon,et al.  Efficacy of higher-dose levamisole in maintaining remission in steroid-dependant nephrotic syndrome , 2017, Pediatric Nephrology.

[8]  P. Skrzypczyk,et al.  Levamisole therapy in children with frequently relapsing and steroid-dependent nephrotic syndrome: a single-center experience , 2016, Central-European journal of immunology.

[9]  M. Grootenhuis,et al.  Dutch normative data and psychometric properties for the Distress Thermometer for Parents , 2016, Quality of Life Research.

[10]  Xiaojie Shi,et al.  Levamisole promotes murine bone marrow derived dendritic cell activation and drives Th1 immune response in vitro and in vivo. , 2016, International immunopharmacology.

[11]  J. Groothoff,et al.  Health-related quality of life in patients with pediatric onset of end-stage renal disease: state of the art and recommendations for clinical practice , 2015, Pediatric Nephrology.

[12]  P. Mathieson,et al.  Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte. , 2015, Clinical science.

[13]  B. Reeve,et al.  The impact of disease duration on quality of life in children with nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study , 2015, Pediatric Nephrology.

[14]  B. Rath,et al.  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. , 2015, Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia.

[15]  E. Ota,et al.  A multicenter randomized trial indicates initial prednisolone treatment for childhood nephrotic syndrome for two months is not inferior to six-month treatment , 2014, Kidney international.

[16]  Y. Tabel,et al.  Short- and long-term efficacy of levamisole in children with steroid-sensitive nephrotic syndrome , 2013, International Urology and Nephrology.

[17]  Jai Radhakrishnan,et al.  Notice , 2012, Kidney International Supplements.

[18]  Sushmita Banerjee,et al.  The impact of pediatric nephrotic syndrome on families , 2011, Pediatric Nephrology.

[19]  D. Kuik,et al.  Nephrotic syndrome in The Netherlands: a population-based cohort study and a review of the literature , 2011, Pediatric Nephrology.

[20]  M. M. Haentjens,et al.  Health related quality of life of Dutch children: psychometric properties of the PedsQL in the Netherlands , 2009, BMC pediatrics.

[21]  K. Saag,et al.  The epidemiology of glucocorticoid-associated adverse events , 2008, Current opinion in rheumatology.

[22]  P. Hoyer,et al.  Initial treatment of idiopathic nephrotic syndrome in children: prednisone versus prednisone plus cyclosporine A: a prospective, randomized trial. , 2006, Journal of the American Society of Nephrology : JASN.

[23]  É. Berard,et al.  Syndrome néphrotique pur (ou néphrose) corticosensible de l'enfant: Protocole de traitement proposé par la Société de Néphrologie Pédiatrique☆ , 2005 .

[24]  M. Kemper,et al.  Health-related quality of life and psychosocial adjustment in steroid-sensitive nephrotic syndrome. , 2004, The Journal of pediatrics.

[25]  R. Goodman,et al.  Dutch version of the Strengths and Difficulties Questionnaire (SDQ) , 2003, European Child & Adolescent Psychiatry.

[26]  Michael Seid,et al.  The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity. , 2003, Ambulatory pediatrics : the official journal of the Ambulatory Pediatric Association.

[27]  Alia Al-Ibrahim,et al.  Levamisole Therapy as a Second-line Immunosuppressive Agent in Corticosteroid-sensitive Nephrotic Syndrome in Children. , 2003, Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia.

[28]  H Meltzer,et al.  Using the Strengths and Difficulties Questionnaire (SDQ) to screen for child psychiatric disorders in a community sample , 2003, International review of psychiatry.

[29]  P. McKinney,et al.  Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire, UK , 2001, Pediatric nephrology (Berlin, West).

[30]  C. Szeto,et al.  Levamisole induces interleukin‐18 and shifts type 1/type 2 cytokine balance , 2000, Immunology.

[31]  A. Bagga,et al.  Levamisole therapy in corticosteroid-dependent nephrotic syndrome , 1997, Pediatric Nephrology.

[32]  J. Tobin,et al.  Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children. , 1997, Journal of the American Society of Nephrology : JASN.

[33]  British Association For Paediatric Nephrology.  Levamisole for corticosteroid-dependent nephrotic syndrome in childhood , 1991, The Lancet.

[34]  H. L. Barnett.  International study of kidney disease in children. , 1979, Nihon Jinzo Gakkai shi.

[35]  S. A. Schepers.  Implementation of electronic patient reported outcomes in pediatric daily clinical practice: the KLIK Experience , 2016 .

[36]  A. Sinha,et al.  Extending initial prednisolone treatment in a randomized control trial from 3 to 6 months did not significantly influence the course of illness in children with steroid-sensitive nephrotic syndrome. , 2015, Kidney international.

[37]  W. Hop,et al.  Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome. , 2013, Journal of the American Society of Nephrology : JASN.

[38]  L. Haverman,et al.  UvA-DARE ( Digital Academic Repository ) Electronic patient and parent reported outcomes in pediatric clinical practice , 2013 .

[39]  Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. , 1978, Kidney international.