AbstractImportanceSafe oral systemic treatments are needed to treat itch associated with atopic dermatitis (AD).ObjectiveTo examine the efficacy and safety of tradipitant, a neurokinin-1 receptor antagonist, in adults with mild to severe AD.Design, Setting, and ParticipantsEPIONE was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from July 09, 2018 to December 27, 2019 at 74 US centers. Patients were adults 18 years or older with worst itch rated ≥7 on the Worst Itch Numerical Rating Scale (WI-NRS) and ≥ 1% body surface area of AD involvement at screening.InterventionsPatients were randomly assigned (1:1) to twice-daily oral placebo or tradipitant (85 mg) for 8 weeks.Main Outcomes and MeasuresThe primary endpoint was mean improvement in WI-NRS (baseline to Week 8). Secondary endpoints included disease severity improvement measured by SCORing Atopic Dermatitis (SCORAD) index, the Eczema Area and Severity Index (EASI), and validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD™).Results341 patients (mean [SD]: age, 41.8 [15.0] years; sex, 243 [64.8%] female) were randomly assigned to placebo (n = 187) or tradipitant (n = 188). EPIONE did not meet its primary endpoint of reduction in pruritus (LS Mean difference (95% CI), −0.2 (−0.8 to 0.4), P = 0.567). However, robust antipruritic effect was observed in patients with mild lesion severity (rated 1 or 2 by the vIGA-AD at baseline, −1.6 (−2.9 to −0.3), P = 0.015). This result was confirmed by daily diary (−2.09 (−3.31 to −0.87), P = 0.001) and observed after one full day of treatment (−0.61 (−1.21 to −0.01), P = 0.0457). Treatment-emergent adverse events (TEAEs) were reported in 63 of 188 (33.5%) tradipitant patients and 43 of 187 (23.0%) placebo patients. TEAEs with > 2% incidence and twice that of placebo included diarrhea (VLY-686 = 5 (2.7%), PBO = 1 (0.5%)), fatigue (VLY-686 = 5 (2.7%), PBO = 0 (0.0%)), and worsening of AD (VLY-686 = 4 (2.1%), PBO = 1 (0.5%)).Conclusions and RelevanceDuring 8 weeks of treatment, tradipitant was well-tolerated for all study participants, but did not significantly improve worst itch in the overall study population. However, in patients with mild AD at baseline, tradipitant was observed to have a large and rapid antipruritic effect. These data support the role of neurokinin-1 antagonism and substance P signaling in chronic pruritus related to mild AD. If these findings replicate in the on-going phase 3 study, EPIONE2, tradipitant may represent a promising new oral therapy for these mild AD patients.Trial RegistrationClinicaltrials.gov: NCT03568331, https://clinicaltrials.gov/ct2/show/NCT03568331Key PointsQuestionIs tradipitant, a selective neurokinin-1 receptor antagonist, efficacious and safe for improving worst itch in patients with mild to severe atopic dermatitis (AD)?FindingsIn 375 mild to severe AD patients, tradipitant did not significantly improve worst itch. However, in a subgroup of 79 AD patients with mild lesion severity at baseline, tradipitant significantly improved worst itch and sleep during 8 weeks of treatment.MeaningThese data support the role of neurokinin-1 antagonism and substance P signaling in chronic pruritus related to mild AD, and further suggest tradipitant may represent a new oral systemic option for mild AD patients based on the well-tolerated safety profile and improvement in itch and sleep.
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