Safety and efficacy of belimumab after B cell depletion therapy in systemic LUPUS erythematosus (BEAT-LUPUS) trial: statistical analysis plan

Patrick Muller,Michael R Ehrenstein,Caroline Gordon,Caroline J Doré,Kashfia Chowdhury

doi:10.1186/s13063-020-04391-2

Abstract

BackgroundThere is limited evidence that rituximab, a B cell depletion therapy, is an effective treatment for systemic lupus erythematosus (SLE). Data on the mechanisms of B cell depletion in SLE indicate that the combination of rituximab and belimumab may be more effective than rituximab alone. The safety and efficacy of belimumab after B cell depletion therapy in systemic LUPUS erythematosus (BEAT-LUPUS) trial aims to determine whether belimumab is superior to placebo, when given 4–8 weeks after treatment with rituximab. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written prior to the end of patient follow-up, while the outcome of the trial is still unknown.Design and methodsBEAT-LUPUS is a randomised, double-blind, phase II trial of 52 weeks of belimumab versus placebo, initiated 4–8 weeks after rituximab treatment. The primary outcome is anti-dsDNA antibodies at 52 weeks post randomisation. Secondary outcomes include lupus flares and damage, adverse events, doses of concomitant medications, quality of life, and clinical biomarkers. We describe the trial’s clinical context, outcome measures, sample size calculation, and statistical modelling strategy, and the supportive analyses planned to evaluate for mediation of the treatment effect through changes in concomitant medication doses and bias from missing data.DiscussionThe analysis will provide detailed information on the safety and effectiveness of belimumab. It will be implemented from July 2020 when patient follow-up and data collection is complete.Trial registrationISRCTN: 47873003. Registered on 28 November 2016.EudracT: 2015-005543-14. Registered on 19 November 2018.

Highlights

There is limited evidence that rituximab, a B cell depletion therapy, is an effective treatment for systemic lupus erythematosus (SLE)
By publishing it we aim to increase transparency of the data analysis, and demonstrate appropriate approaches for the challenges of: evaluating lupus activity; concomitant medications, which can vary between treatment arms post randomisation due to the trial treatment given and affect the primary outcome; and high expected loss to follow-up, a common feature of trials on severe SLE
By evaluating several measures of lupus activity, and using up-to-date statistical techniques to evaluate mediation of the treatment effect through changes in prednisolone dose and bias from missing data, we will return comprehensive and robust information on the safety and effectiveness of belimumab compared to placebo

Summary

Introduction

There is limited evidence that rituximab, a B cell depletion therapy, is an effective treatment for systemic lupus erythematosus (SLE). Data on the mechanisms of B cell depletion in SLE indicate that the combination of rituximab and belimumab may be more effective than rituximab alone. The safety and efficacy of belimumab after B cell depletion therapy in systemic LUPUS erythematosus (BEAT-LUPUS) trial aims to determine whether belimumab is superior to placebo, when given 4–8 weeks after treatment with rituximab. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written prior to the end of patient follow-up, while the outcome of the trial is still unknown

Objectives

Methods

Findings

Conclusion