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Placebo Response in Randomised Controlled Trials of Systemic Therapies for Cutaneous Lupus Erythematosus: A
Stéphanie Légaré1, Sherry Lin1, Sarah Vahey1
1Indero (formerly Innovaderm Research), 3530 St-Laurent Blvd, Suite 300, Montreal, Quebec, H2X 2V1, Canada.
Background:
Lupus erythematosus is a heterogeneous autoimmune disease with manifestations ranging from skin-limited forms to severe systemic disease. Despite the high prevalence of skin symptoms among lupus participants, no therapies are currently approved specifically for cutaneous lupus erythematosus (CLE). An increasing number of clinical trials have evaluated systemic therapies in lupus participants with cutaneous manifestations; however, placebo response in CLE has never been systematically examined. Characterising the magnitude and predictors of placebo response is essential to optimising trial design and improving the interpretability of efficacy outcomes in this population with significant unmet medical needs.
Objective:
To characterise placebo response in randomised controlled trials (RCTs) of systemic therapies for CLE and explore clinical and design factors associated with increased placebo responses.
Methods:
A systematic literature review and meta-analysis were conducted on double-blind, randomised, placebo‑controlled trials published between 2005 and June 2024 that evaluated systemic therapies in CLE and reported outcomes using the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI‑A). Searches were performed in PubMed, Cochrane Library, and Scopus. The review was registered on the International Prospective Register of Systematic Reviews (PROSPERO). Risk of bias was evaluated using the Cochrane RoB2 tool. Random-effects meta-analyses were performed to estimate pooled placebo response rates (95% confidence intervals [CIs]), with further exploration of clinical and design factors associated with increased placebo responses through subgroup analyses, meta‑regression, and Pearson correlation analyses.
Results:
Overall, 33 RCTs, described in 43 publications and including 2382 placebo-treated participants, were included in this analysis. At the primary endpoint timepoint, the pooled proportion of placebo-treated participants (n = 424 in 14 trials) achieving ≥ 50% reduction in CLASI-A (CLASI‑A50) was 42% (95% CI, 35-50). The CLASI‑A50 placebo responses were 21% at Week 8, 33% at Week 24, and reached 46% at Week 52 for up to 8 trials (n = 150 to 278). Univariate analyses revealed higher placebo responses in studies initiated after 2016, those with follow‑up durations > 24 weeks, and those requiring stable background therapy. Study start year and primary endpoint timepoint were identified as the most influential predictors of placebo response in a meta-regression analysis. A positive correlation was also observed between the proportion of White participants and CLASI-A50 placebo responses.
Conclusions:
These findings suggest that limiting background therapy, shortening follow-up durations, and ensuring balanced racial representation should be further explored to reduce placebo responses in future CLE trials. Such strategies may improve signal detection and accelerate the development of effective systemic therapies for cutaneous lupus. PROSPERO record: CRD42024558334.
