A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to Placebo and to Adalimumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Who are on a Stable Background of Methotrexate (MTX) and Who Have an Inadequate Response to MTX (MTX-IR)

The primary objective of this Phase 3, randomized, double-blind study is to evaluate the **efficacy** of upadacitinib, administered once daily, compared to placebo and adalimumab, in the treatment of signs and symptoms of moderately to severely active **rheumatoid arthritis** in patients who are on a stable background of methotrexate and have an inadequate response to methotrexate. Additionally, the study aims to assess the efficacy of upadacitinib in preventing structural progression in these patients. The safety and tolerability of upadacitinib compared to placebo and adalimumab are also primary objectives. In the second period of the study, the long-term safety, tolerability, and efficacy of upadacitinib will be evaluated in subjects who have completed the first period. These objectives are clinically relevant as they address the need for effective treatment options for patients with rheumatoid arthritis who do not respond adequately to methotrexate, a common first-line therapy.

The clinical trial involves a total of **1032 participants** diagnosed with **rheumatoid arthritis**. The study population includes both male and female adults, aged 18 years and older, who have been diagnosed with rheumatoid arthritis for at least three months. Participants are required to have been on a stable prescription of methotrexate (MTX) for at least four weeks prior to the study, with a dosage ranging from 15 to 25 mg per week, or at least 10 mg per week for those intolerant to higher doses. All participants are advised to take a dietary supplement of folic acid or folinic acid throughout the study. The trial population was selected based on specific criteria, including having at least six swollen and tender joints and a high-sensitivity C-reactive protein (hsCRP) level of at least 5 mg/L at screening. Additionally, participants must have evidence of bone erosion or positive rheumatoid factor or anti-cyclic citrullinated peptide autoantibodies. The study allows for the inclusion of subjects with prior exposure to at most one biologic disease-modifying anti-rheumatic drug (bDMARD), excluding adalimumab, with a cap of 20% of the total study population. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy and safety across diverse patient groups.

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of **upadacitinib** compared to placebo and **adalimumab** in subjects with moderately to severely active **rheumatoid arthritis** who are on a stable background of methotrexate and have an inadequate response to it. The trial is structured in two periods, with the first focusing on comparing the efficacy of upadacitinib versus placebo and adalimumab, and the second evaluating the long-term safety, tolerability, and efficacy of upadacitinib. The trial is expected to last until September 2027, with recruitment having started in November 2015.

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 proportion of subjects achieving an ACR20 response or clinical remission at Week 12. Secondary endpoints include changes in Disease Activity Score, Health Assessment Questionnaire-Disability Index, and other measures of disease activity and quality of life at various time points. Follow-up visits will occur regularly to monitor progress and collect data on efficacy and safety outcomes. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any ongoing treatment needs are addressed.

Participant involvement is expected to last up to 520 weeks, depending on individual response and continuation criteria. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to adhere to study protocols. The trial aims to provide comprehensive data on the comparative effectiveness of upadacitinib, contributing to the understanding of treatment options for rheumatoid arthritis.

The clinical trial involves the administration of **Upadacitinib**, a modified-release tablet, as the experimental medication. Upadacitinib is a chemical substance provided by AbbVie Deutschland GmbH & Co. KG. The pharmaceutical form is a modified-release tablet, and the medication is administered orally. The maximum daily dose is 15 mg, with a total maximum dose of 54,600 mg over a treatment period of 520 days. The dosing schedule is once daily (QD), and participant compliance is monitored throughout the trial.

In addition to the experimental medication, the trial includes a comparator treatment with **Adalimumab**, marketed as Humira. Adalimumab is a protein-based substance also provided by AbbVie Deutschland GmbH & Co. KG. It is available as a solution for injection in pre-filled syringes. The administration route is subcutaneous injection, with a maximum daily dose of 40 mg and a total maximum dose of 10,440 mg over a treatment period of 520 days. The dosing schedule for Adalimumab is consistent with standard clinical practice for rheumatoid arthritis management.

The trial also includes a placebo group to evaluate the efficacy and safety of Upadacitinib compared to both placebo and Adalimumab. The placebo is administered in a manner consistent with the experimental and comparator treatments to maintain blinding and ensure the integrity of the study results. Compliance with the dosing schedule is monitored for all participants to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the proportion of subjects achieving an ACR20 response at Week 12 or achieving clinical remission based on DAS28 (CRP) at Week 12. Secondary endpoints include changes from baseline in Disease Activity Score (DAS)28 (C-reactive protein [CRP]) at Week 12, changes in mTSS at Week 26, and changes in HAQ-DI at Week 12. Additional secondary endpoints involve the ACR50 response rate at Week 12, changes in the Short Form 36 (SF-36) Physical Component Score (PCS) at Week 12, and the proportion of subjects achieving low disease activity (LDA) based on DAS28 [CRP] ≤ 3.2 at Week 12.

Other secondary endpoints include changes from baseline in morning stiffness, Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F), and Patient's Assessment of Pain at Week 12. The trial will also evaluate the ACR50 and ACR70 response rates at Week 12, and the proportion of subjects with no radiographic progression, defined as a change from baseline mTSS ≤ 0 at Week 26. These efficacy parameters will be measured and collected at specified timepoints, such as Week 12 and Week 26, using validated scales and laboratory tests. The analysis will focus on comparing the efficacy of **upadacitinib** versus placebo and versus **adalimumab** in subjects with moderately to severely active rheumatoid arthritis who are on a stable background of methotrexate and have an inadequate response to methotrexate.