Session Type: Abstract Submissions (ACR)
Increases in background treatment in SLE trials lead to high placebo group responses in patients with moderate but not those with high disease activity (1-3). The optimal allowance of background medication increase to ensure patient safety and still enable data interpretability over a range of disease severity remains unknown. Since even moderate lupus activity leads to organ damage, disability and poor quality of life (4-6), a goal of the ADDRESS II trial of atacicept (inhibitor of B cell stimulators BLyS and APRIL) is to discriminate treatment effects on both moderate and high SLE disease activity within one trial.
This 24 week study examines atacicept (75 or 150 mg/wk) versus placebo for the reduction of SLE disease activity. Similar to the Phase III belimumab (BLISS) program, study drug is added to standard of care. Unlike the BLISS design, which allowed temporary unlimited background steroids and permanent increases in immune suppressant doses, after the Week 4 study visit ADDRESS II restricts the corticosteroid dose to ≤ the dose at the Screening visit and ≤30 mg prednisone (or equivalent), and immunosuppressives must be stable from 2 months before screening throughout the duration of the study. Additional treatment defines a non-responder.
The primary endpoint is similar to the BLISS trials as defined by the SRI (≥4 point reduction in SLEDAI-2K, <10% increase in PGA, no new BILAG A score and ≤1 new BILAG B score, at Week 24 compared to the Screening visit). A placebo response rate of 30% (lower than BLISS placebo rates due to more stringent background medication restriction) is predicted, enabling 80% power to detect a 20% absolute difference in proportion achieving an SRI response with 93 patients per arm and a 2-sided α=0.05 with a randomization ratio of 1:1:1. A steroid reduction endpoint, which includes a provision for lack of flare, will also be examined. Patients are stratified by level of disease activity (SLEDAI < 10 vs. ≥ 10), race, and use of mycophenolate at screening, enabling analysis of response in these subpopulations. A 2 year extension study will give all completer patients the option to receive active treatment (placebo patients will be switched to 150 mg atacicept), but the dose will be blinded, allowing longer term evaluation of responses.
Interpretation of SLE trials is hampered by confusing data in patients with moderate disease activity. The ADDRESS II study was designed to discern treatment impact in both severe and moderate disease patients, who represent a large, underserved population with poor quality of life and progressive damage despite high response rates to increased standard of care in trials.
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2. Thanou A. Nat Rev Rheumatol 2014;10:23–34
3. Van Vollenhoven R. Ann Rheum Dis 2012;71:1343–49
4. Urowitz MB. Arthritis Care Res 2012;64:132–7
5. Lim S. Arthritis Res Ther 2012;14(Suppl 3):A13
6. Abu-Shakra M. J Rheumatol 1999;26:306–9
J. T. Merrill,
S. D. Wax,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/approach-to-discriminate-treatment-impact-in-both-moderate-and-severe-sle-the-atacicept-phase-iib-trial-design/