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Randomised Controlled Trial Comparing Ofatumumab to Rituximab

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Randomised Controlled Trial Comparing Ofatumumab to Rituximab Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2016-013319 on 17 March 2017. Downloaded from Randomised controlled trial comparing ofatumumab to rituximab in children with steroid-dependent and calcineurin inhibitor-dependent idiopathic nephrotic syndrome: study protocol Pietro Ravani,1 Alice Bonanni,2,3 Gian Marco Ghiggeri2,3 To cite: Ravani P, Bonanni A, ABSTRACT Strengths and limitations of this study Ghiggeri GM. Randomised Introduction: Oral steroids induce remission in about controlled trial comparing 90% of children with idiopathic nephrotic syndrome ▪ ofatumumab to rituximab in This study will be conducted as a multicentre (INS), which is characterised by severe proteinuria and children with steroid- randomised controlled trial coordinated by a dependent and calcineurin hypoalbuminaemia. Some children become steroid- large national referral centre for paediatric inhibitor-dependent idiopathic dependent (SD) and require addition of calcineurin nephrology. nephrotic syndrome: study inhibitors (CNI) to maintain remission. Since these oral ▪ It will provide patients and healthcare providers protocol. BMJ Open 2017;7: agents are toxic, alternative interventions are needed with important information on benefits and e013319. doi:10.1136/ for long-term treatment. The anti-CD20 antibody harms of two anti-CD20 antibodies in idiopathic bmjopen-2016-013319 rituximab has shown promising steroid-sparing nephrotic syndrome (INS). properties in clinical trials, but benefits are less ▪ Disease relapse is an important outcome for chil- ▸ Prepublication history and convincing in complicated forms of SD-INS. dren with INS for its social, psychological and additional material is Ofatumumab, a new anti-CD20 antibody with stronger clinical implications. available. To view please visit affinity to CD20, may be superior to rituximab in ▪ More important outcomes such as end-stage the journal (http://dx.doi.org/ maintaining oral steroid-free and CNI-free disease kidney failure or death are difficult to include in 10.1136/bmjopen-2016- remission in children with SD-INS. randomised controlled trials in children as they 013319). Methods and analysis: This open-label, two- occur relatively late in the disease course. http://bmjopen.bmj.com/ parallel-arm, controlled, phase II randomised clinical ▪ Limitations related to lack of blinding are miti- trial will enrol children with SD-INS maintained in Received 4 July 2016 gated by the objective outcomes chosen and Revised 14 November 2016 remission with oral steroids and CNI. Children will be blinding of outcome assessors. Accepted 18 November 2016 randomised to either ofatumumab or rituximab infusion. After infusion of either antibody, steroids will be maintained for 30 days and then tapered off by INTRODUCTION 0.3 mg/kg/week until complete withdrawal. 1 week after Idiopathic nephrotic syndrome (INS) is a complete steroid withdrawal, CNI will be decreased by disease characterised by episodes of severe on September 24, 2021 by guest. Protected copyright. 50% and withdrawn within 2 additional weeks. We will proteinuria and hypoalbuminaemia (serum enrol 140 children to detect as significant at the 2- albumin <2.5 g/dL), often associated with sided p value of 0.01 with a power of >0.8, a reduction in the risk of 1-year relapse (primary end point) of at dyslipidaemia and hypercoagulability. In – least 0.3 (ie, from 0.65 to 0.35; (risk ratio 0.54)) in the Western countries, INS affects 2 2.7 new chil- ofatumumab arm when compared with the rituximab dren per 100 000 children per year and has a 1 arm. We will compare the amount of steroids required prevalence of 16 cases per 100 000. Oral to maintain complete disease remission at 6 and corticosteroids are the cornerstone of 24 months, relapse-free period, relapse rate per year as therapy, inducing remission of INS in ∼90% secondary end points. Circulating cell populations will of children.2 However, up to 85% of cases be studied as biomarkers or predictors of the anti- relapse within 5 years3 and many will develop CD20 response. steroid dependence (SD). SD-INS relapses Ethics and dissemination: The trial received ethics within 2 weeks of steroid withdrawal and For numbered affiliations see approval from the local ethics board. We will publish requires continuation of treatment. Clinical end of article. study results and present them at international practice guidelines suggest using low-dose scientific meetings. prednisone to maintain remission in SD-INS Correspondence to Trial registration numbers: NCT02394119; 2015- Dr Gian Marco Ghiggeri; 000624-28; Pre-results. (evidence 2C-D), and use of steroid-sparing [email protected] agents (ie, calcineurin inhibitors; CNI) for Ravani P, et al. BMJ Open 2017;7:e013319. doi:10.1136/bmjopen-2016-013319 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2016-013319 on 17 March 2017. Downloaded from children who develop steroid-related adverse effects (evi- Head-to-head comparison between rituximab and ofa- dence 1B).4 Given the toxicity of steroids and CNI, there tumumab is justified on the basis of available trials sup- is a need to investigate alternative treatment options. porting the use of anti-CD20 antibodies to maintain – The interest in the anti-CD20 chimeric antibody rituxi- remission of INS without steroids and CNI.19 21 mab followed the observation of a dramatic reduction in proteinuria in children with nephrotic syndrome who Objectives received rituximab to treat idiopathic thrombocytopenic This trial will test whether ofatumumab is superior to purpura5 or a post-transplant lymphoproliferative dis- rituximab in maintaining oral drug-free disease remis- – order.67More recent observational studies8 17 con- sion (complete or partial remission) at 12 months firmed potential benefits in mixed populations with (primary objective) and reduce the risk of relapse in a nephrotic syndrome, but clinical trials did not confirm longer follow-up of 24 months (secondary objective) in expected benefits in steroid-resistant (SR) forms of children with SD and CNI-dependent INS. This study INS.18 Although recent randomised controlled trials will also collect information on occurrence of side support the use of rituximab in SD-INS, benefits may be effects (ie, acute and long-term drug-related adverse suboptimal, especially in complicated forms of the events) and need to restart the use of steroids or CNI disease. While a single infusion of rituximab allowed following the infusion of the trial interventions. steroid withdrawal and was non-inferior to steroids in maintaining remission in a trial of children with uncom- Design plicated forms of SD-INS,19 in children with frequently This is an open-label, two-parallel-arm, controlled, phase relapsing and complicated forms of SD-INS requiring II randomised clinical trial testing the superiority of ofa- the use of CNI, benefits of rituximab are less tumumab over rituximab in maintaining steroid-free and convincing.20 21 CNI-free disease remission in children with SD-INS Ofatumumab is a fully humanised anti-CD20 monoclo- (figure 1). Eligible participants will enter a 1-month nal IgG1(k) antibody of last generation. Ofatumumab run-in period, during which instruction on urine collec- binds with more affinity to CD20, potentially leading to tion and dipstick readings will be carefully reviewed, com- more efficient complement-dependent cytotoxicity. In pliance assessed and CNI and prednisone doses will be small series, ofatumumab induced remission in children reduced to the minimum doses required to maintain with SR-INS who did not respond to rituximab.22 23 From complete remission (usually the minimum doses used in an economic point of view, ofatumumab is not superior the previous 6 months). After run-in, children will be ran- to rituximab as the cost of the two drugs for square domised in a 1:1 ratio to either the intervention arm (ofa- metres of body surface is similar. Ofatumumab is cur- tumumab) or the active comparator arm (rituximab). rently in phase III clinical trials for the treatment of After infusion of intervention or comparator, steroids chronic lymphocytic leukaemia, relapsing lymphoma and will be maintained at the baseline (post-run-in) dose for http://bmjopen.bmj.com/ rheumatoid arthritis.24 Owing to its stronger affinity for 30 days and then tapered off by 0.3 mg/kg/week until the CD20 and its fully humanised structure, ofatumumab complete withdrawal. One week after the steroid with- may be used in larger doses with minimal risk of side drawal, CNI will be decreased by 50% and withdrawn effects leading to potentially larger benefits, that is, within 2 additional weeks. All children will be followed for longer remission period, than the chimeric antibody up to 24 months. In the case of relapses during the study rituximab. Some studies support this conclusion.25 26 The (see outcome section) children will be treated with oral aim of this trial is to test whether ofatumumab is superior prednisone (60 mg/m2), in order to achieve remission. At to rituximab in maintaining complete disease remission remission, children will be treated with another infusion on September 24, 2021 by guest. Protected copyright. in children with steroid and CNI-dependent INS. of either ofatumumab or rituximab, according to the allo- cation arm. After infusion of intervention or comparator, steroids will be maintained at initial dose for 30 days and METHODS AND DESIGN then tapered off by 0.3 mg/kg/week until complete with- Rationale and justification of the active comparator drawal. One week after the steroid withdrawal, CNI will be Owing to its fully humanised structure and stronger decreased by 50% and withdrawn within 2 additional affinity for the CD20 antigen, ofatumumab can be used weeks. Inability to withdraw CNI or need to restart CNI in larger doses than the chimeric antibody rituximab (development of steroid resistance) will be considered a with minimal risk of side effects. Knowledge generation relapse (primary end point) and a reason to terminate to support the use of new steroid-sparing agents is an the study.
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