Impact of standard of care treatments and disease variables on outcomes in systemic lupus erythematosus trials: analysis from the Lupus Foundation of America Collective Data Analysis Initiative

Abstract

Objective: Most clinical trials for systemic lupus erythematosus (SLE) study the efficacy and safety of investigational agents added to variable background immunosuppressants, which has resulted in high response rates in patients treated with placebo plus standard of care (SOC) plus rescue measures. This project compared the impact of different SOC treatments and disease variables on the outcomes of SLE trials.Material and Methods: Data were obtained from 981 patients receiving only SOC treatments in three nephritis and three general SLE trials to compare response and flare rates on the basis of the British Isles Lupus Assessment Group (BILAG) index, a measure common to all trials.Results: For subjects enrolled in general SLE trials (n=173), those receiving mycophenolate mofetil (MMF) had more severe baseline disease, included more patients of African descent, and were administered higher baseline steroid doses compared with those receiving azathioprine (AZA) or methotrexate (MTX). BILAG responses at week 12 were MMF 35%, AZA 49%, MTX 34%, and no immunosuppressant (NIS) 65%. At week 52, MMF response rates increased to 41% despite reducing the steroid doses, but fell in all others (p=0.07, adjusted for steroids). Patients with severe disease activity at baseline (SDAB) who were defined as ≥1 BILAG A (severe) organ score had lower response rates to AZA or MTX but higher rates to MMF or NIS. In nephritis trials (n=808), MMF subjects received less steroids than intravenous cyclophosphamide and response rates were similar, but MMF-treated patients had fewer severe flares (p=0.03). Conclusion:Compared with MMF, AZA and MTX were associated with lower response rates at week 52. AZA-treated subjects had fewer flares and remained more stable in trials while engendering lower placebo plus SOC responses. MMF-treated subjects had frequent responses but more flares, suggesting that flares should be included in endpoint definitions. Given the likelihood of treatment selection bias, these data do not provide conclusions regarding efficacy but may help future trial designs by distinguishing factors definable at entry that are predictive of outcomes.

Evaluating duration of response to treatment in systemic lupus erythematosus clinical trials

“…The LFA established the CDAI so that data from the placebo/SoC arms of previous SLE clinical trials can be used to improve the design and conduct of future studies. 4 5 Permissible SoC included non-steroidal anti-inflammatory drugs, corticosteroids, antimalarials and immunosuppressants (eg, azathioprine, methotrexate, mycophenolate mofetil). Increases to the steroid dose were allowed only during the first 24 weeks of the trial.…”

Evaluation of oxygen extraction fraction in systemic lupus erythematosus patients using quantitative susceptibility mapping

“…On the basis of the SLEDAI and BILAG index scores, we categorised the SLE patients into a severe group (SLEDAI score ≥ 11 or BILAG index score ≥ 6) and a non-severe group (SLEDAI score < 11 or BILAG index score < 6) according to the previous reports. 28,29 We also divided the patients with NPS and without NPS into two groups according to their neuro BILAG (nBILAG) index scores (A, B and C vs. D and E). 16 For treatment, patients were divided into two groups based on whether they had a history of pulse steroid therapy.…”

Brief Report: Longitudinal Patterns of Response to Standard of Care Therapy for Systemic Lupus Erythematosus: Implications for Clinical Trial Design

“…A variable for study/trial was included regardless of statistical significance to account for any systematic differences between the trials. Background immunosuppressant was also deemed to be clinically important given our prior findings . Given sample size constraints and nonlinear patterns in response rates across the total number of BILAG A and B scores, this variable was categorized as 1 A or 1 B score; 2 B scores; 2 A scores or 1 A and 1 B score; and ≥3 A or B scores.…”

“…A major goal of the Collective Data Analysis Initiative (CDAI) of the Lupus Foundation of America (LFA) is to improve future trials by learning from data from the placebo plus standard of care arms of completed phase II/III studies. In an earlier CDAI study, Kalunian et al evaluated the effects of different background medications on British Isles Lupus Assessment Group (BILAG)–based response and flare rates . In the present study, we examine data from 52‐week trials in the CDAI database to assess the longitudinal patterns of response to standard of care therapy, estimate the correlation in response status at different time points, and identify characteristics that differentiate nonresponders from persistent responders treated with placebo plus standard of care.…”