A randomized phase 2 placebo-controlled trial of clobetasol solution for oral chronic graft-versus-host disease therapy

Chronic graft-versus-host disease (cGVHD) affects multiple organ systems and frequently the mouth. There is an unmet need for more effective topical therapy to adequately control cGVHD in the oral cavity. Clobetasol is a super-potent synthetic glucocorticoid formulated here as an oral solution in an aqueous base (clobetasol solution) to enhance mucosal coverage and steroid delivery. We conducted a randomized, double-blind, placebo-controlled phase 2 clinical trial to evaluate the safety and efficacy of clobetasol 0.05% solution at 28 days of clobetasol treatment (primary endpoint). Of the 35 of 40 randomized subjects who reached the day 28, 19% achieved a complete response (CR), 72% a partial response (PR), and 9% had stable disease (SD), resulting in an overall response rate (ORR) of 91%. During the 14-day placebo-controlled phase, greater improvement was measured in clinical disease and oral pain for clobetasol versus placebo. Although clobetasol solution was well-tolerated, day 28 cosyntropin testing demonstrated significant suppression of peak serum cortisol, indicating new adrenal insufficiency in 14 patients who were not already receiving supraphysiologic glucocorticoids. Paired oral mucosal biopsies from baseline and day 28 show reduction in the frequency of all T cells, including effector and proliferating T cells and a reduction in non-T cells with cytoplasmic IL-17, accompanied by reduced salivary IL-6 and CXCL10. These controlled study data demonstrate that 0.05% clobetasol oral rinse is clinically effective and induces measurable tissue-level immunologic changes in the treatment of oral GVHD, including among patients who failed clobetasol ointment. This trial was registered at www.clinicialtrials.gov as #NCT01557517.