Efficacy of Belimumab on Mucocutaneous Involvement in Patients with Systemic Lupus Erythematosus (MUCOBEL)

Proposal
1206

Title of Proposed Research

Lead Researcher

Kuhn, Annegret

Affiliation

Interdisciplinary Center of Clinical Trials (IZKS), University Clinic of Mainz, Germany

Funding Source

Research and analysis are funded by GSK.

Potential Conflicts of Interest

GSK: Research Grant, Honoraria, Travel Fees

Data Sharing Agreement Date

2 Sep 2015

Lay Summary

Aim of the study
The aim of the study is to retrospectively analyze data on the efficacy of belimumab on skin and mucous membrane lesions in systemic lupus erythematosus based on two published phase III trials.
Introduction
Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease affecting a broad variety of organs, including skin, joints, kidney, lungs and the heart. Skin lesions appear in 73-85% of patients with SLE and may occur at any stage of the disease. The disease can produce considerable morbidity resulting from e.g. its skin lesions (patients may suffer from disfiguring, painful scarring skin lesions, mucous membrane lesions) and therefore has a strong negative impact on quality of life.
In the last years, therapeutic advances have led to significant improvements in the treatment of SLE, but no medication has been specifically approved for skin lesions. The first-line treatment for severe skin manifestations is antimalarials, but not all patients respond to these agents. In 2011, belimumab was licensed for SLE based on two phase III studies (BLISS-52 and BLISS-76), which included 865 and 819 SLE patients, respectively. The data of both studies were combined, and Manzi et al. published a poster reporting the efficacy of belimumab on mucocutaneous (i.e., mucous membranes and skin) lesions by analyzing 7 of 18 mucocutaneous items of the “British Isles Lupus Assessment Group” (BILAG) score. The group demonstrated that treatment with antimalarials plus belimumab resulted in a higher improvement of the mucocutaneous lesions than treatment with antimalarials plus placebo.
Outcome
The data of the two phase III studies are the basis for the retrospective analysis, which will focus on the efficacy of belimumab in all 18 mucocutaneous items of the BILAG and in the 3 items of the “Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index” (SELENA-SLEDAI). Both scores were applied in the phase III trials, but only parts of the mucocutaneous data are analyzed. Furthermore, we will correlate the results with detailed characteristic demographic data of the 1684 included patients with SLE. We hypothesize that additive treatment with belimumab offers a safe and long-term treatment option for mucocutaneous lesions in patients with SLE. In addition to a publication of the planned analysis in a peer-reviewed journal, the results will be included in the German S2k Guidelines on Cutaneous Lupus Erythematosus (AWMF register number 013-060), which are currently under preparation.

Study Data Provided

[{ "PostingID": 1416, "Title": "GSK-HGS1006-C1056", "Description": "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 76-Week Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects with Systemic Lupus Erythematosus (SLE)" },{ "PostingID": 1417, "Title": "GSK-HGS1006-C1057", "Description": "A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, 52-Wk Study to Evaluate the Efficacy and Safety of Belimumab (HGS1006, LymphoStat-B™), a Fully Human Monoclonal Anti-BLyS Antibody, in Subjects With Systemic Lupus Erythematosus (SLE)" }]

Statistical Analysis Plan

Population:The primary population is the modified intent-to-treat (MITT) population defined as all subjects who are randomized and treated with at least one dose of study treatment. The MITT analysis will be performed according to the treatment that a subject was randomized to receive, regardless of the actual treatment received. Only those patients with mucocutaneous manifestations from BLISS-52 and BLISS-76 will be included in the analyses. The primary comparison will be between belimumab 10mg/kg and placebo.Baseline Characteristics:All demographic and baseline characteristics will be summarized by treatment group. Additionally, summaries of stratification factors at screening and baseline disease activity by treatment group will be provided.Primary Endpoints:The percentage of patients with improvement or no new occurrences in any mucocutaneous component of the SELENA-SLEDAI over 52 weeks of treatment will be summarized by treatment group. A logistic regression model will be constructed to assess the effect of treatment. Independent covariates in the model will include baseline SELENA-SLEDAI score (6-9 versus = 10), baseline proteinuria level (< 2 g/24 hour versus = 2 g/24 hour equivalent) and race (African descent or indigenous-American descent versus other).• Similar analyses will be conducted for percentage of patients with improvement or no worsening in individual manifestations within the mucocutaneous domain of the BILAG.Secondary Endpoints:The percentage of patients with new occurrences in any mucocutaneous component of the SELENA-SLEDAI and the percentage of patients with worsening in any individual manifestation within the mucocutaneous domain of the BILAG will be analyzed as described above for the primary endpoints. The SF36 scoring domains will be analyzed for quality of life improvement via analysis of covariance models.Exploratory Endpoints:Correlations and their associated 95% confidence intervals will be calculated between each measure of interest and each primary endpoint in order to assess the possibility of any relationship. For each measure that appears to correlate with improvement in mucocutaneous conditions, its ability to predict improvement in mucocutaneous measures (as measured by the primary endpoints) will be further evaluated via logistic regression models. Independent covariates in the models will include baseline SELENA-SLEDAI score (6-9 versus = 10), baseline proteinuria level (< 2 g/24 hour versus = 2 g/24 hour equivalent) and race (African descent or indigenous-American descent versus other). Other covariates of interest may also be included in the models. Odds ratios and their associated 95% confidence intervals will be presented.Safety:The number and percentage of subjects experiencing an adverse event including the System Organ Class skin and subcutaneous tissue disorders will be summarized by treatment group and preferred term.

Publication Citation

S2k guideline for treatment of cutaneous lupus erythematosus - guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV) - Kuhn - 2017 - Journal of the European Academy of Dermatology and Venereology - Wiley Online Library - https://onlinelibrary.wiley.com/doi/10.1111/jdv.14053