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Rituximab versus steroids and cyclophosphamide for the treatment of primary membranous nephropathy: protocol of a pilot randomised controlled trial.

ABSTRACT: INTRODUCTION:Primary membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease may have different long-term outcomes. After 10 years of follow-up, 35%-50% of the untreated patients with persistent nephrotic syndrome may die or progress to end stage renal disease. The 2012 KDIGO (Kidney Disease Improving Global Outcomes) guidelines recommend that initial therapy should consist of alternating steroids and an alkylating agent for 6 months. Recent observational studies showed that the anti-CD20 antibody rituximab may be effective in inducing remission. We designed a pilot multicentre randomised trial to inform the design of a larger trial testing the efficacy and safety of treatment with steroids and cyclophosphamide versus rituximab in patients with primary MN and heavy proteinuria (>3.5?g/24?hours). METHODS AND ANALYSIS:This pilot, open-label, two-parallel-arm, randomised clinical trial will enrol 70 patients with primary MN and heavy proteinuria. Patients will be randomised in a 1:1 ratio to either the intervention arm (rituximab) or the active comparator arm (corticosteroid/alkylating-agent therapy). The study will provide estimates of the probability of complete remission of proteinuria and risk of serious side effects at 12 months to inform the design of a larger trial. We will also assess the recruitment potential of each participating centre to address study feasibility. ETHICS AND DISSEMINATION:The trial received ethics approval from the local ethics boards. We will publish pilot data to inform the design of a larger clinical trial. TRIAL REGISTRATION NUMBERS:NCT03018535; 2011-006115-59.

SUBMITTER: Scolari F

PROVIDER: S-EPMC6924835 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Rituximab versus steroids and cyclophosphamide for the treatment of primary membranous nephropathy: protocol of a pilot randomised controlled trial.

Scolari Francesco F Dallera Nadia N Gesualdo Loreto L Santoro Domenico D Pani Antonello A Santostefano Marisa M Feriozzi Sandro S Mani Laila-Yasmin LY Boscutti Giuliano G Messa Piergiorgio P Magistroni Riccardo R Quaglia Marco M Ponticelli Claudio C Ravani Pietro P

BMJ open 20191204 12

<h4>Introduction</h4>Primary membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease may have different long-term outcomes. After 10 years of follow-up, 35%-50% of the untreated patients with persistent nephrotic syndrome may die or progress to end stage renal disease. The 2012 KDIGO (Kidney Disease Improving Global Outcomes) guidelines recommend that initial therapy should consist of alternating steroids and an alkylating agent for 6 months. Recent observation ...[more]

PMID: 31806605

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Project description:Primary membranous nephropathy (PMN) is the most common cause for adult nephrotic syndrome. Rituximab has demonstrated promising clinical efficacy by random controlled trials and the off-label use is widely adopted in PMN. However, the standard dosage is borrowed from B cell lymphoma treatment with far more antigens and is oversaturated for PMN treatment, accompanied with additional safety risk and unnecessary medical cost. More than 15% serious adverse events were observed under standard dosage and low dose therapies were explored recently. Dose optimization by clinical trials is extremely time- and cost-consuming and can be significantly accelerated with the aid of model-informed drug development. Here, we aim to establish the first population pharmacokinetic and pharmacodynamic (PPK/PD) model for rituximab in PMN to guide its dosage optimization. Rituximab pharmacokinetic and pharmacodynamic data from 41 PMN patients in a retrospective study under a newly proposed monthly mini-dose were used to construct quantitative dose-exposure-response relationship via mechanistic target-mediated drug disposition (TMDD) model followed by regression between the reduction of anti-PLA2R titer and time after the treatment. The final model, validated by goodness-of-fit plots, visual predictive checks and bootstrap, was used to recommend the optimized dosing regimen by simulations. The model was well validated for PK/PD prediction. The systemic clearance and half-life are 0.54 L/h and 14.7 days, respectively. Simulation of a novel regimen (6 monthly doses of 100 mg) indicated the comparable ability and superior duration time of CD20+ B cell depletion compared with standard dosage, while the cumulative dosage and safety risk was significantly decreased. We established the first PPK/PD model and provide evidence to support the dosage optimization based on monthly mini-dose. Our study can also efficiently accelerate dosage optimization of novel anti-CD20 antibodies in PMN and other indications.

Dataset Information

Rituximab versus steroids and cyclophosphamide for the treatment of primary membranous nephropathy: protocol of a pilot randomised controlled trial.

Publications

Rituximab versus steroids and cyclophosphamide for the treatment of primary membranous nephropathy: protocol of a pilot randomised controlled trial.

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