Lead Investigator: Luís Inês, University of Beira Interior
Title of Proposal Research: Derivation and validation of the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) severe disease activity category: post-hoc analysis of the anifrolumab clinical trials in active systemic lupus erythematosus.
Vivli Data Request: 7779
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Systemic lupus erythematosus (SLE) or lupus is a chronic, systemic autoimmune disease that occurs when patient’s immune system attacks his or her own tissues and organs. The estimated prevalence of SLE ranges from 48 to 366.6 cases per 100.000 individuals. Inflammation caused by lupus can virtually affect any organ of the body. SLE patients present with variable clinical manifestations ranging from mild skin disease to catastrophic organ failure.
The assessment of disease activity in lupus patients has a central role in clinical practice and trials. During the last decades, multiple disease monitoring instruments have been developed, all presenting important limitations. Recently, our research group derived and validated a new instrument for measuring global lupus disease activity as a continuous score, the SLE Disease Activity Score (SLE-DAS). The SLE-DAS showed higher accuracy in measuring SLE disease activity, better sensitivity-to-change, and higher predictive value for damage accrual, as compared to the currently most used disease activity instrument, the SLE Disease Activity Index 2000 (SLEDAI-2K). The SLE-DAS definitions for classifying remission, low disease activity (LDA), mild, and moderate-to-severe disease activity also presented very high performance. However, the SLE-DAS cut-off for severe disease activity has not yet been derived and validated.
Our intent is to derive and validate the SLE-DAS cut-off for severe disease activity category. We will perform a post-hoc analysis of the aggregated data from the anifrolumab trials in moderate-to-severe SLE. Anifrolumab is a human monoclonal antibody to type 1 interferon receptor subunit 1 approved for the treatment of SLE. These trials will provide a large convenience sample of high-quality prospective data that includes all the measures needed to retrospectively calculate the SLE-DAS and achieve the study aim. The definition of the SLE-DAS cut-off for severe disease activity will represent the value of SLE-DAS above which there is a major organ-threatening or life-threatening disease, and will facilitate the identification of patients requiring more intensive treatment regimens in the clinical setting and the selection of candidates for lupus clinical trials.
Statistical Analysis Plan:
Sample size: We estimated a needed sample size of 309 SLE patients: 114 patients in remission/LDA/mild/moderate disease activity and 195 patients with severe disease activity). This sample size was calculated to test for an excellent discriminative ability of the SLE-DAS (area under the ROC curve (AUC) >0.8) and for a statistical power of 0.90 at a 5% level of significance, considering the results of a preliminary analysis, in which the ratio of sample sizes for the two groups was 0.58 and the AUC was 0.873. The placebo arms of the phase II and phase III trials of anifrolumab in SLE (NCT01438489, NCT02446912 and NCT02446899) will provide us the needed sample size considering the number of dropouts.
Statistical analysis: Descriptive statistics will be used to summarize demographic variables, disease measures, manifestations, and pharmacological treatment. Receiver operating characteristic (ROC) analysis will be applied using BILAG index as gold standard to derive the SLE-DAS cut-off for severe disease activity, and classification performance of the derived cut-off will be assessed evaluating the sensitivity, specificity and other measures of classification performance.
Statistical tools: In order to perform the statistical analysis described, we would like to request the following R packages, not available in the Vivli Research Environment: “cutpointr” and the “prroc”.
Missing data: We will assume that missing data in the randomized clinical trials are missing completely at random. For missing outcomes data, we will use intent-to-treat analysis, and the last observation carried forward approach. Additionally, if possible, we will compare these results with analysis excluding patients with missing values. Multiple imputation will also be considered as an alternative analysis.
Requested Studies:
Efficacy and Safety of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus
Data Contributor: AstraZeneca
Study ID: NCT02446912
Efficacy and Safety of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus
Data Contributor: AstraZeneca
Study ID: NCT02446899
A Study of the Efficacy and Safety of MEDI-546 in Systemic Lupus Erythematosus
Data Contributor: AstraZeneca
Study ID: NCT01438489
Public Disclosures:
- Jesus, D., Matos, A., Henriques, C., Doria, A. and Inês, L.S., 2024. P127 The SLE-DAS enables easy identification of SLE patients with moderate-to-severe disease activity and worse HR-QoL in the screening for SLE clinical trials: a post-hoc study in the phase 2 and 3 anifrolumab trials. Doi : 10.1136/lupus-2024-el.181
- Jesus, D., Henriques, C., Matos, A., Doria, A. and Inês, L.S., 2024. P67 The SLE-DAS enables easy identification of SLE patients with severe disease activity and worse health-related quality of life: derivation and validation in post-hoc study of anifrolumab phase 2 and 3 clinical trials. Doi : 10.1136/lupus-2024-el.121
- Jesus, D., Henriques, C., Matos, A., Doria, A. and Inês, L.S., 2024. O21 Is SLE-DAS better than BILAG-2004 to identify severe SLE disease activity? Post-hoc analysis of 438 SLE patients from the anifrolumab clinical trials. Doi : 10.1136/lupus-2024-el.31