Study Design for an Open-Label, Efficacy-Assessor-Blinded, Phase 3 Study (START UP) to Compare the Safety and Efficacy of Upadacitinib to Dupilumab in Children From 2 to Less Than 12 Years of Age With Moderate-to-Severe Atopic Dermatitis

Introduction & Objectives While phase 3 studies established the safety and efficacy of upadacitinib (UPA), an oral JAK inhibitor, for treatment of atopic dermatitis (AD) in adults and adolescents,1-3 it is important to evaluate its safety, efficacy, and optimal dosing in the younger pediatric population. START UP is an ongoing open-label, efficacy-assessor-blinded, phase 3 study comparing UPA to dupilumab in children from 2 to < 12 years of age for the treatment of moderate to severe AD. Materials & Methods START UP (NCT06461897) is comprised of a 35-day screening period, an open-label treatment period (week 0 to 160; assessor-blinded up to week 16) and a follow-up period. Eligible patients are 2 to < 12 years of age with moderate to severe AD. In one cohort, patients with inadequate response (IR) to systemic therapy or intolerance of topical corticosteroids and/or topical calcineurin inhibitors or dupilumab-exposed patients without IR will be randomized 3:1:1 to receive an adult equivalent weight-based dose of UPA 15mg, an adult equivalent weight-based dose of UPA 7.5mg, or a label-indicated dose of dupilumab. In the second cohort, patients with IR or intolerance of dupilumab (dupilumab-IR) or for whom dupilumab is medically inadvisable will be treated with an adult equivalent weight-based dose of UPA 15mg. UPA will be administered as an oral solution twice a day (BID) or, for patients ≥ 30kg, as an oral tablet once daily (QD). Patients will be followed for 30 days after the last dose of UPA and for 12 weeks after the last dose of dupilumab. In countries other than the USA, the primary efficacy objective is to assess the proportion of patients achieving ≥75% improvement in Eczema Area and Severity Index (EASI-75) at week 16 in patients treated with UPA 15mg compared with those treated with dupilumab. In the USA and China, the primary, descriptive efficacy objective is to assess the proportion of patients achieving validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) 0 or 1 with a reduction from baseline of ≥ 2 points at week 16 in each treatment group, with dupilumab as the reference arm for UPA 15mg. From Week 20 to Week 40, patients not achieving EASI-75 will be eligible for dose escalation: those on UPA 7.5 mg may increase to UPA 15 mg, with further escalation to UPA 30 mg if EASI-75 is still not achieved; patients on UPA 15 mg may escalate directly to UPA 30 mg. At week 52, a dose reduction will be mandatory for patients who achieve EASI-90 with UPA 15mg or UPA 30mg. No dose changes will be permitted with dupilumab. Safety will be assessed throughout the study. Results Recruitment and follow-up for the START-UP study are ongoing. Conclusion The ongoing START UP study will compare the efficacy and safety of UPA to dupilumab in children aged 2 to < 12 years with moderate to severe AD, evaluate UPA in dupilumab-IR or dupilumab medically inadvisable patients, and assess dose optimization.