Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetil  versus  prednisone: protocol for a randomised, controlled, multicentre trial (INTENT study)

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Abstract

Introduction

Idiopathic nephrotic syndrome is the most common glomerular disease in childhood with an incidence of 1.8 cases per 100 000 children in Germany. The treatment of the first episode implies two aspects: induction of remission and sustainment of remission. The recent Kidney Disease Improving Global Outcomes, American Academy of Pediatrics and German guidelines for the initial treatment of the first episode of a nephrotic syndrome recommend a 12-week course of prednisone. Despite being effective, this treatment is associated with pronounced glucocorticoid-associated toxicity due to high-dose prednisone administration over a prolonged period of time. The aim of the INTENT study (Initial treatment of steroid-sensitive idiopathic nephrotic syndrom in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial) is to show that an alternative treatment regimen with mycophenolic acid is not inferior regarding sustainment of remission, but with lower toxicity compared with treatment with glucocorticoids only.

Methods and design

The study is designed as an open, randomised, controlled, multicentre trial. 340 children with a first episode of steroid-sensitive nephrotic syndrome and who achieved remission by a standard prednisone regimen will be enrolled in the trial and randomised to one of two treatment arms. The standard care group will be treated with prednisone for a total of 12 weeks; in the experimental group the treatment is switched to mycophenolate mofetil, also for a total of 12 weeks in treatment duration. The primary endpoint is the occurrence of a treated relapse within 24 months after completion of initial treatment.

Ethics and dissemination

Ethics approval for this trial was granted by the ethics committee of the Medical Faculty of the University of Heidelberg (AFmu-554/2014). The study results will be published in accordance with the Consolidated Standards of Reporting Trials statement and the Standard Protocol Items: Recommendations for Interventional Trials guidelines. Our findings will be submitted to major international paediatric nephrology and general paediatric conferences and submitted for publication in a peer-reviewed, open-access journal.

Trial registration number

DRKS0006547; EudraCT2014-001991-76; Pre-result.

Date of registration

30 October 2014; 24 February 2017.

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Most cited references 21

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Management of childhood onset nephrotic syndrome.

Susan F Massengill, Paul V Miles, Delbert Wigfall … (2009)

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Children's Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a children's primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

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Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome.

Nynke Teeninga, Joana Kist-van Holthe, Nienske van Rijswijk … (2013)

Prolonged prednisolone treatment for the initial episode of childhood nephrotic syndrome may reduce relapse rate, but whether this results from the increased duration of treatment or a higher cumulative dose remains unclear. We conducted a randomized, double-blind, placebo-controlled trial in 69 hospitals in The Netherlands. We randomly assigned 150 children (9 months to 17 years) presenting with nephrotic syndrome to either 3 months of prednisolone followed by 3 months of placebo (n=74) or 6 months of prednisolone (n=76), and median follow-up was 47 months. Both groups received equal cumulative doses of prednisolone (approximately 3360 mg/m(2)). Among the 126 children who started trial medication, relapses occurred in 48 (77%) of 62 patients who received 3 months of prednisolone and 51 (80%) of 64 patients who received 6 months of prednisolone. Frequent relapses, according to international criteria, occurred with similar frequency between groups as well (45% versus 50%). In addition, there were no statistically significant differences between groups with respect to the eventual initiation of prednisolone maintenance and/or other immunosuppressive therapy (50% versus 59%), steroid dependence, or adverse effects. In conclusion, in this trial, extending initial prednisolone treatment from 3 to 6 months without increasing cumulative dose did not benefit clinical outcome in children with nephrotic syndrome. Previous findings indicating that prolonged treatment regimens reduce relapses most likely resulted from increased cumulative dose rather than the treatment duration.

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Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome.

Jutta Gellermann, Lutz Weber, Lars Pape … (2013)

The severe side effects of long-term corticosteroid or cyclosporin A (CsA) therapy complicate the treatment of children with frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). We conducted a randomized, multicenter, open-label, crossover study comparing the efficacy and safety of a 1-year treatment with mycophenolate mofetil (MMF; target plasma mycophenolic acid trough level of 1.5-2.5 µg/ml) or CsA (target trough level of 80-100 ng/ml) in 60 pediatric patients with FR-SSNS. We assessed the frequency of relapse as the primary endpoint and evaluated pharmacokinetic profiles (area under the curve [AUC]) after 3 and 6 months of treatment. More relapses per patient per year occurred with MMF than with CsA during the first year (P=0.03), but not during the second year (P=0.14). No relapses occurred in 85% of patients during CsA therapy and in 64% of patients during MMF therapy (P=0.06). However, the time without relapse was significantly longer with CsA than with MMF during the first year (P 50 µg⋅h/ml; P<0.05). There were no significant differences between groups with respect to BP, growth, lipid levels, or adverse events. However, cystatin clearance, estimated GFR, and hemoglobin levels increased significantly with MMF compared with CsA. These results indicate that MMF is inferior to CsA in preventing relapses in pediatric patients with FR-SSNS, but may be a less nephrotoxic treatment option.

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open

Journal ID (iso-abbrev): BMJ Open

Journal ID (hwp): bmjopen

Journal ID (publisher-id): bmjopen

Title: BMJ Open

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2044-6055

Publication date Collection: 2018

Publication date (Electronic): 10 October 2018

Volume: 8

Issue: 10

Electronic Location Identifier: e024882

Affiliations

[1 ] departmentDepartment of Pediatrics , University Children’s Hospital Köln, University Hospital Köln , Köln, Germany

[2 ] departmentDepartment of Pediatrics I , University Children’s Hospital Heidelberg , Heidelberg, Germany

[3 ] departmentDepartment of Pediatrics , University Children’s Hospital Berlin, University Hospital Berlin Charité , Berlin, Germany

[4 ] departmentDepartment of Pediatrics , University Children’s Hospital Hannover, University Hospital Hannover , Hannover, Germany

[5 ] departmentDepartment of Pediatrics , University Children’s Hospital Essen, University Hospital Essen , Essen, Germany

[6 ] departmentKKS (Coordination Center for Clinical Trials) , University Hospital of Heidelberg , Heidelberg, Germany

[7 ] departmentDepartment of Pediatrics , Asklepios Klinik Nord – Heidberg , Hamburg, Germany

[8 ] departmentDepartment of Pediatrics , University Children’s Hospital Münster, University Hospital Münster , Münster, Germany

[9 ] departmentInstitute of Medical Biometry and Informatics , University of Heidelberg , Heidelberg, Germany

Author notes

[Correspondence to ] Dr Rasmus Ehren; rasmus.ehren@ 123456uk-koeln.de

Author information

Rasmus Ehren http://orcid.org/0000-0002-3245-7481

Article

Publisher ID: bmjopen-2018-024882

DOI: 10.1136/bmjopen-2018-024882

PMC ID: 6252704

PubMed ID: 30309995

SO-VID: 475f3dce-ba71-41ea-9b83-5e67b995c8db

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 21 June 2018

Date revision received : 30 August 2018

Date accepted : 04 September 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;

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ScienceOpen disciplines: Medicine

Keywords: mycophenolate mofetil,steroid-sensitive nephrotic syndrome,steroids,alternative treatment

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ScienceOpen disciplines: Medicine

Keywords: mycophenolate mofetil, steroid-sensitive nephrotic syndrome, steroids, alternative treatment

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Initial treatment of steroid-sensitive idiopathic nephrotic syndrome in children with mycophenolate mofetil versus prednisone: protocol for a randomised, controlled, multicentre trial (INTENT study)

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Abstract

Introduction

Methods and design

Ethics and dissemination

Trial registration number

Date of registration

Related collections

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Most cited references 21

Management of childhood onset nephrotic syndrome.

Extending prednisolone treatment does not reduce relapses in childhood nephrotic syndrome.

Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome.

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