Background Most clinical trials of new treatments for systemic lupus erythematosus (SLE) have shown weak discrimination between investigational agents and placebo when added to standard of care (SOC). Given that targeted biologics are unlikely to be effective in all patients, it is challenging for these experimental therapies to exceed the high response rates observed with SOC alone in placebo arms. The design of future SLE trials may be improved by considering strategies for reducing placebo response rates and obtaining a better understanding of the within-patient variability in disease activity during follow up.
Objectives The goal of this study was to evaluate longitudinal patterns of response in SLE patients who received placebo plus SOC in two completed 52-week clinical trials. Baseline characteristics discriminating early and persistent responders from non-responders to SOC were also examined to identify patient populations who may benefit most from experimental therapies and could be targeted for enrollment in future trials.
Methods Data was obtained from the Collective Data Analysis Initiative (CDAI) of the Lupus Foundation of America and included 147 patients from the placebo plus SOC arms of two randomized Phase II/III trials in moderately-to-severely active lupus patients without acute nephritis. A BILAG-based response was evaluated at weeks 12, 24, 36, 48, and 52. Both cross-sectional and longitudinal analyses of response patterns were performed. Clinical variables, including background medications and baseline factors associated with disease severity, that discriminated persistent responders from non-responders were identified using logistic regression.
Results The cross-sectional response rates ranged from 37% - 46% between 12 - 52 weeks for patients treated with placebo plus SOC, similar to the placebo response rates estimated in most non-nephritis lupus trials. The response rate decreased to 14.3% (95% CI: 8.6% - 19.9%) when the criterion was complete response, i.e., response at all visits between 12 - 52 weeks. Agreement between response status at 12 weeks and 36–52 weeks was low (kappa =0.15 - 0.25); furthermore only 31% of initial 12 week responders maintained response at all subsequent visits. Factors contributing to non-response to SOC at all visits included more severe disease, as suggested by more organ systems active at baseline, and low C3 levels at baseline. Less aggressive immunosuppression was also associated with non-response.
Conclusions An endpoint based on a sustained rather than cross-sectional response may reduce high placebo response rates in SLE trials that continue aggressive SOC and may improve discrimination between effective experimental treatments and SOC. Although there is increasing interest in conducting efficient 12 or 24 week early phase trials, the observed lack of stability in response to SOC over time highlights a potential weakness with shorter studies that use an endpoint of improvement. Our data also confirm earlier reports that the likelihood of response in the placebo group depends on the severity of disease and the aggressiveness of background treatments.
Disclosure of Interest M. Kim: None declared, J. Merrill: None declared, K. Kalunian Consultant for: Bristol-Myers Squibb, MedImmune, AstraZeneca, Merck Serono, UCB, and Genentech, B. Hahn Grant/research support from: Bristol-Myers Squibb, Consultant for: Eli Lilly, A. Roach: None declared, P. Izmirly: None declared