A Phase 3b/4 Randomized, Double-Blind, Double-Dummy, Active-Comparator Controlled Study, Comparing the Efficacy and Safety of Upadacitinib Versus Adalimumab in Subjects with Moderate to Severe Rheumatoid Arthritis on a stable background of MTX and who had an Inadequate Response or Intolerance to a Single TNF Inhibitor (SELECT- SWITCH)

The primary objective of this study is to evaluate the **efficacy** and **safety** of **upadacitinib** and **adalimumab** in adult subjects with moderate to severe **rheumatoid arthritis** who are on a stable background of methotrexate (MTX) and have shown an inadequate response or intolerance to a single tumor necrosis factor inhibitor (TNFi). This evaluation is clinically relevant as it aims to provide insights into alternative treatment options for patients who do not respond adequately to existing TNFi therapies, potentially improving patient outcomes and quality of life.

The clinical trial involves a total of **315 participants** diagnosed with **Rheumatoid Arthritis**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on their inadequate response or intolerance to a single TNF inhibitor, with a requirement of having been treated for at least three consecutive months prior to screening. The trial excludes vulnerable populations. All subjects must have been on a stable prescription of methotrexate (MTX) therapy for at least three consecutive months and are required to take a dietary supplement of folic acid or folinic acid throughout the study. The participants exhibit active rheumatoid arthritis, characterized by at least six swollen and six tender joints, and elevated high-sensitivity C-reactive protein (hsCRP) levels. The trial aims to evaluate the efficacy and safety of upadacitinib and adalimumab in this specific patient group.

The clinical trial is designed as a **randomized**, **double-blind**, **double-dummy**, active-comparator controlled study to evaluate the efficacy and safety of **upadacitinib** versus **adalimumab** in adult subjects with moderate to severe **rheumatoid arthritis**. Participants will be on a stable background of **methotrexate** (MTX) and must have had an inadequate response or intolerance to a single TNF inhibitor. The trial is expected to commence recruitment on October 1, 2023, and conclude by August 11, 2026, with a maximum treatment period of 48 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis duration, and previous treatment history. The primary endpoint is the achievement of DAS28-CRP ≤ 3.2 at Week 12, with secondary endpoints including the achievement of ACR50 and changes in DAS28-CRP, pain assessment, and HAQ-DI at the same time point. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse events. The end-of-study visit will assess the overall outcomes and safety of the interventions.

Participant involvement is expected to last up to 48 weeks, with conditions for early termination including significant adverse reactions or withdrawal of consent. The trial will utilize a double-dummy design to maintain blinding, with participants receiving either upadacitinib or adalimumab, along with corresponding placebos. The study aims to provide robust data on the comparative efficacy and safety of these treatments in the specified patient population.

The clinical trial involves the administration of several treatments to evaluate their efficacy and safety in subjects with moderate to severe **rheumatoid arthritis**. The primary experimental medication is **Upadacitinib**, a modified-release tablet with a maximum daily dose of 15 mg and a total maximum dose of 5040 mg over a 48-week period. The route of administration is oral. Upadacitinib is classified under the ATC code L04A, indicating its role as an immunosuppressant. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another key treatment in the study is **Adalimumab**, marketed as Humira, which is provided in a 40 mg solution for injection. This medication is administered subcutaneously, with a maximum daily dose of 40 mg and a total maximum dose of 960 mg over the same 48-week period. Adalimumab is a protein-based therapeutic agent, also classified under the ATC code L04AB04. The study includes multiple forms of Humira, including pre-filled syringes and pens, to accommodate different administration preferences.

The trial also incorporates a **placebo** control for both Upadacitinib and Adalimumab to ensure the validity of the study results. The Upadacitinib placebo is not specified in terms of pharmaceutical form or route of administration, while the Adalimumab placebo is similarly unspecified. These placebos are used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators are aware of the treatment allocations.

Additionally, participants will continue their stable background therapy with **Methotrexate** (MTX), an auxiliary treatment in the study. Methotrexate is administered either orally or intravenously, with a maximum daily dose of 25 mg and a total maximum dose of 1200 mg over the 48-week period. This standard-of-care therapy is included to provide a consistent treatment background for all participants, allowing for a more accurate assessment of the experimental treatments' efficacy and safety.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the achievement of DAS28-CRP ≤ 3.2 at Week 12. This will be calculated based on the values of TJC28, SJC28, PtGA, and **hsCRP**. Secondary endpoints include the achievement of ACR50 at Week 12, which is determined by a 50% or greater improvement in TJC68 and SJC66, along with at least three of the following measures: Patient's Assessment of Pain (past week, NRS), Patient's Global Assessment of Disease Activity (PtGA [past week, NRS]), Physician's Global Assessment of Disease Activity (PhGA [NRS]), HAQ-DI, or **hsCRP**. Additional secondary endpoints include the achievement of DAS28-CRP < 2.6 at Week 12, change from baseline in DAS28-CRP at Week 12, change from baseline in Patient's Assessment of Pain at Week 12, and change from baseline in HAQ-DI at Week 12.