A Phase 3 Randomized, Placebo-Controlled, Double-Blind Study to Evaluate Upadacitinib in Combination with Topical Corticosteroids in Adolescent and Adult Subjects with Moderate to Severe Atopic Dermatitis

The primary objective of this Phase 3 randomized, placebo-controlled, double-blind study is to evaluate the **efficacy** and **safety** of upadacitinib in combination with topical corticosteroids for the treatment of adolescent and adult subjects with moderate to severe **atopic dermatitis** (AD) who are candidates for systemic therapy. This objective is clinically relevant as it aims to provide a potential therapeutic option for patients with moderate to severe AD, a condition that significantly impacts quality of life and may require systemic treatment when topical therapies are insufficient. Additionally, the study seeks to assess the long-term (10 years) efficacy and safety of upadacitinib for the same patient population, which is crucial for understanding the sustainability and potential risks of prolonged treatment.

The clinical trial involves a total of **1160 participants** diagnosed with **atopic dermatitis**. The study population comprises both male and female subjects aged between **12 and 75 years**. Participants are characterized by having active moderate to severe atopic dermatitis, as defined by EASI, IGA, BSA, and pruritus scores, and are candidates for systemic therapy or have recently required such treatment. The trial includes individuals who can tolerate topical corticosteroids for their dermatitis lesions. The selection process ensured a diverse representation of age and gender, with a focus on those who meet the specific health criteria related to the severity of their condition. The trial does not specify particular lifestyle considerations such as diet or physical activity, but it does include a vulnerable population, indicating a careful approach to participant selection and monitoring.

The clinical trial is designed to evaluate the efficacy and safety of **upadacitinib** in combination with topical corticosteroids for the treatment of moderate to severe **atopic dermatitis** in adolescents and adults. This is a Phase 3, randomized, double-blind, placebo-controlled study. The trial aims to assess both short-term and long-term outcomes, with an estimated duration extending until November 2030. Participants will be randomly assigned to receive either upadacitinib, a placebo, or a combination of upadacitinib with topical corticosteroids. The study will include several key visits: an initial screening visit to determine eligibility, multiple follow-up visits to monitor progress and safety, and a final end-of-study visit to assess overall outcomes.

Participants are expected to be involved in the study for a maximum treatment period of 524 days, with the possibility of early termination if they experience significant adverse effects or fail to adhere to the study protocol. The primary endpoints include the proportion of subjects achieving a validated Investigator's Global Assessment (vIGA) score of 0 or 1, and a 75% improvement in the Eczema Area and Severity Index (EASI 75) at Week 16. Secondary endpoints focus on improvements in pruritus and further reductions in EASI scores at various time points. The trial will include male and female subjects aged 12 to 75 years who have active moderate to severe atopic dermatitis and are candidates for systemic therapy. Participants must be able to tolerate topical corticosteroids. The study will exclude individuals who do not meet these criteria or who have conditions that could interfere with the trial's objectives.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Upadacitinib** is a key experimental medication in this study. It is administered in the form of a **modified-release tablet** and is taken orally. The trial includes two dosing regimens for upadacitinib: one with a maximum daily dose of 30 mg and another with a maximum daily dose of 15 mg. The total maximum dose for the 30 mg regimen is 110,040 mg over a treatment period of 524 days, while the 15 mg regimen has a total maximum dose of 55,020 mg over the same period. Upadacitinib functions as a Janus kinase (Jak) 1 inhibitor and is not a pediatric formulation.

**Hydrocortisone** is used as a non-experimental treatment in the trial. It is applied topically and is available in the pharmaceutical form coded as PHF00017MIG. The maximum daily dose is one application per day, with a total maximum of 21 applications over a treatment period of 3 days. Hydrocortisone is a chemical substance and is not formulated for pediatric use.

**Tacrolimus** is another non-experimental treatment, administered topically in the form coded as PHF00156MIG. It is applied once daily, with a total of 21 applications allowed over a 3-day treatment period. Tacrolimus is classified as a topical calcineurin inhibitor and is not a pediatric formulation.

The trial also includes a **placebo** for upadacitinib, which is a film-coated tablet. The placebo is used to maintain the double-blind nature of the study, ensuring unbiased results. The placebo does not contain any active substance and is not associated with a specific pharmaceutical form or dosing schedule.

**Fluocinolone acetonide** is administered topically in the form coded as PHF00024MIG. The dosing schedule allows for one application per day, with a total of 21 applications over a 3-day period. This chemical substance is not formulated for pediatric use.

**Pimecrolimus** is applied topically in the form coded as PHF00017MIG. It is administered once daily, with a total of 21 applications over a 3-day treatment period. Pimecrolimus is classified as a topical calcineurin inhibitor and is not a pediatric formulation.

**Triamcinolone** is another topical treatment used in the trial, available in the form coded as PHF00017MIG. It is applied once daily, with a total of 21 applications over a 3-day period. Triamcinolone is a chemical substance and is not formulated for pediatric use.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the proportion of subjects achieving a validated Investigator's Global Assessment (vIGA-AD) score of 0 or 1, with at least two grades of reduction from baseline at Week 16, and the proportion of subjects achieving at least a 75% improvement from baseline on the Eczema Area Severity Index (EASI 75) at Week 16. Secondary endpoints will evaluate additional measures of efficacy, such as the proportion of subjects achieving a reduction in the Worst Pruritus Numerical Rating Scale (NRS) by at least 4 points from baseline at Week 16, and the proportion of subjects achieving a 90% reduction in EASI (EASI 90) at Week 16. Other secondary endpoints include percent change from baseline in Worst Pruritus NRS and EASI score at Week 16, as well as various timepoints for achieving EASI 75, EASI 90, and EASI 100.

These efficacy parameters will be measured at specific timepoints, including Weeks 1, 2, 4, and 16, using validated scales and patient-reported outcomes. The trial will involve the use of topical corticosteroids in combination with **upadacitinib** for the treatment of moderate to severe atopic dermatitis. The trial aims to assess both the short-term and long-term efficacy and safety of this treatment regimen. Data collection and analysis will be conducted in accordance with the trial protocol to ensure the reliability and validity of the results.