Phase 3 Randomized, Double‑Blind, Placebo‑Controlled Study of Upadacitinib in Adolescents and Adults with Moderate to Severe Atopic Dermatitis

The primary objective of this study is to assess the **efficacy** and **safety** of upadacitinib in adolescent and adult subjects with moderate to severe **Atopic Dermatitis** who are candidates for systemic therapy. This is clinically relevant as it aims to provide a therapeutic option for patients with significant disease burden, potentially improving their quality of life and disease management.

Secondary objectives include:

• Evaluating the efficacy and safety of 15 mg and 30 mg upadacitinib for the treatment of adolescent and adult subjects with moderate to severe Atopic Dermatitis over a period of up to 260 weeks in subjects who have completed week 16.

The clinical trial involves a total of **538 participants** diagnosed with **moderate and severe atopic dermatitis**. The study population includes both male and female subjects aged between **12 and 75 years**. Participants were selected based on their active moderate to severe atopic dermatitis, as defined by EASI, IGA, BSA, and pruritus, and their candidacy for systemic therapy or recent requirement for such therapy. The trial population encompasses a diverse age range and includes individuals who are considered vulnerable. The selection criteria ensure that participants are representative of those who would typically require systemic treatment for atopic dermatitis. Lifestyle factors such as diet, physical activity, and habits were not specified by the sponsor.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the efficacy and safety of **upadacitinib** in adolescent and adult subjects with moderate to severe **atopic dermatitis**. The trial aims to assess the therapeutic potential of upadacitinib, a Janus kinase (Jak) 1 inhibitor, administered in the form of a modified-release tablet. The study involves two active treatment groups receiving upadacitinib at doses of 15 mg and 30 mg, respectively, and a placebo group. The trial is expected to span a duration of approximately 260 weeks, with the estimated recruitment start date being January 31, 2019, and the anticipated end date on December 3, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age (12-75 years), active moderate to severe atopic dermatitis, and candidacy for systemic therapy. Following successful screening, participants will be randomized into one of the treatment groups. The primary endpoint is 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 an improvement of at least 75% on the Eczema Area Severity Index (EASI 75) at the same time point.

Secondary endpoints include various measures of improvement in pruritus, eczema severity, and quality of life, assessed at multiple time points throughout the study. Follow-up visits will be conducted to monitor the participants' response to treatment and any adverse events. The end-of-study visit will conclude the trial, where final assessments will be made to evaluate the long-term efficacy and safety of the treatment.

Participant involvement is expected to last for the entire duration of the trial unless early termination is warranted. Conditions that may lead to early withdrawal include significant adverse reactions, non-compliance with study protocols, or withdrawal of consent. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **Upadacitinib**, a Janus kinase (Jak) 1 inhibitor, in the form of a **modified-release tablet**. The experimental medication is provided in two dosage strengths: 30 mg and 15 mg. The tablets are administered orally. The maximum daily dose for the 30 mg formulation is 30 mg, with a total maximum dose of 54,600 mg over a treatment period of 260 days. For the 15 mg formulation, the maximum daily dose is 15 mg, with a total maximum dose of 27,300 mg over the same treatment period. The medication is produced by AbbVie Deutschland GmbH & Co. KG and is not a paediatric formulation. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** group, which receives a placebo for Upadacitinib. The placebo is designed to match the experimental medication in appearance but does not contain the active substance. The placebo is administered in the same manner as the active drug, ensuring blinding of the study participants and investigators. The use of a placebo control allows for the assessment of the efficacy and safety of Upadacitinib in comparison to a non-active treatment. The placebo is not associated with any specific pharmaceutical form or active substance, and its administration is aligned with the trial's double-blind design.

The efficacy of **Upadacitinib** in the treatment of moderate to severe Atopic Dermatitis will be assessed through a series of 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 an improvement in the Worst Pruritus Numerical Rating Scale (NRS) by at least 4 points from baseline at Week 16, and the proportion of subjects achieving EASI 90 at Week 16. Other secondary endpoints include percent changes from baseline in Worst Pruritus NRS and EASI scores at Week 16, as well as improvements in patient-reported outcomes such as the Patient Oriented Eczema Measure (POEM) and the Dermatology Life Quality Index (DLQI).

These efficacy parameters will be measured at various timepoints, including Week 1, Week 2, and Week 16, using validated scales and patient-reported outcomes. The assessments will be conducted in a double-blind manner to ensure the reliability and validity of the results. The data collected will be analyzed to determine the overall efficacy of Upadacitinib in improving the symptoms and quality of life for patients with moderate to severe Atopic Dermatitis.