A randomized, double-blind, placebo-controlled phase III study evaluating the preventive effect of diclofenac cream on capecitabine-related hand-foot syndrome: study protocol of J-SUPPORT2401/JORTC-SUP06 (J-DIRECT).

Background: Clinical evidence on preventive therapy for capecitabine-induced hand-foot syndrome (HFS) is limited, and moisturizing and avoiding local pressure are recommended in guidelines. Although the precise pathogenesis and mechanisms of HFS remain unclear, inflammatory reactions are thought to be involved. The preventive effects of topical diclofenac gel have been reported from India. However, the trial did not evaluate its preventive effect for the sole, and the HFS incidence in the control group was lower than that in previous reports. Therefore, this study aims to confirm the preventive effects of diclofenac sodium 0.1% cream for capecitabine-induced HFS.

Methods: This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Patients scheduled to receive capecitabine-containing chemotherapy are enrolled, and participants are prophylactically treated with topical diclofenac sodium 0.1% cream or placebo alongside standard preventive therapy. The primary endpoint is an incidence of grade 2 HFS within 3 months. The secondary endpoints include time to onset of HFS, incidences of dose reduction, schedule delay, discontinuation caused by capecitabine-induced HFS, dose intensity of capecitabine, an incidence of grade ≥ 2 peripheral sensory neuropathy, incidences of other capecitabine-related adverse events (nausea, vomiting, appetite loss, diarrhea, oral mucositis, pigmentation, abnormality of liver and renal functions, and neutropenia).

Discussion: If this study meets the primary endpoint, a new standard preventive therapy for HFS will be established. Moreover, the use of topical diclofenac cream alongside high-dose capecitabine may enhance chemotherapy efficacy.