A Phase 3 Randomized, Placebo-Controlled, Double-Blind Program to Evaluate Efficacy and Safety of Upadacitinib in Adult Subjects with Axial Spondyloarthritis Followed by a Remission-Withdrawal Period

The primary objective of this study is to evaluate the **efficacy** of upadacitinib compared with placebo in reducing signs and symptoms in adult subjects with active axial spondyloarthritis (axSpA), including those with biologic disease-modifying antirheumatic drug-inadequate response ankylosing spondylitis (bDMARD-IR AS) and non-radiographic axial spondyloarthritis (nr-axSpA). Additionally, the study aims to assess the safety and tolerability of upadacitinib in these patient populations. This is clinically relevant as axSpA is a chronic inflammatory disease that can lead to significant morbidity, and effective management is crucial for improving patient outcomes.

Secondary objectives include:

• Evaluating the safety and tolerability of upadacitinib in extended treatment for adult subjects with active axSpA, including bDMARD-IR AS and nr-axSpA, who have completed the double-blind period of the study.
• Assessing the maintenance of disease control after withdrawal of upadacitinib in subjects who achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) of less than 1.3 at Week 104 and less than 2.1 at Week 88.

The clinical trial involves a total of **418 participants** diagnosed with **Axial Spondyloarthritis** (axSpA), including both Ankylosing Spondylitis (AS) and non-radiographic axSpA (nr-axSpA). The study population comprises adult males and females, all of whom are at least 18 years of age. Participants were selected based on their clinical diagnosis and previous exposure to biologic disease-modifying antirheumatic drugs (bDMARDs), with specific criteria for prior treatment and disease activity levels. The trial includes individuals who have been exposed to one or two bDMARDs, with certain restrictions on the number of bDMARDs previously used. Participants are required to maintain stable background axSpA medications during the study's remission-withdrawal period. The trial population includes a vulnerable group, and both genders are represented. The selection process ensures that participants are suitable candidates for the study, with the ability to understand and adhere to protocol requirements. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** and safety of **Upadacitinib** in adult subjects with **axial spondyloarthritis**. This is a Phase 3, randomized, placebo-controlled, double-blind study. The trial includes two studies: Study 1 focuses on subjects with ankylosing spondylitis (AS) who meet the modified New York Criteria, and Study 2 targets subjects with non-radiographic axial spondyloarthritis (nr-axSpA) fulfilling the 2009 ASAS classification criteria. The trial is expected to conclude by May 31, 2025, with recruitment having started on April 14, 2020.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, clinical diagnosis, and previous treatment history. The primary endpoint for both studies is the ASAS 40 response at week 14. Secondary endpoints include changes from baseline in various disease activity scores and quality of life assessments. The trial involves a Remission-Withdrawal Period, during which subjects must maintain stable background medications and achieve specific disease activity scores to continue participation.

The expected duration of participant involvement is up to 263 days, with the possibility of early termination if the investigator deems the subject unsuitable for continued participation or if the subject develops a new medical condition that precludes further involvement. The study drug, Upadacitinib, is administered orally in a modified-release tablet form, with a maximum daily dose of 15 mg. Participants are required to adhere to all protocol requirements and provide informed consent prior to any study-specific procedures.

The clinical trial involves the administration of **Upadacitinib**, a **modified-release tablet** formulated for **oral use**. The active substance, known as ABT-494, is of chemical origin. The maximum daily dose of Upadacitinib is 15 mg, with a total maximum dose of 3945 mg over the course of the treatment period, which spans up to 263 days. The pharmaceutical form is designed to release the active ingredient gradually, ensuring a sustained therapeutic effect. The medication is provided by ABBVIE DEUTSCHLAND GMBH & CO. KG and is not a pediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** group, utilizing a product known as Upadacitinib matching placebo. This placebo is designed to mimic the appearance of the active medication but contains no active substance. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This allows for an unbiased assessment of the efficacy and safety of Upadacitinib in comparison to the placebo. The placebo administration follows the same schedule and route as the active medication, ensuring consistency across the study groups.

The efficacy of **Upadacitinib** in the treatment of adult subjects with active axial spondyloarthritis (axSpA) will be assessed through a Phase 3 randomized, placebo-controlled, double-blind clinical trial. The primary endpoint for both Study 1 and Study 2 is the ASAS 40 response at week 14. Secondary endpoints include changes from baseline in various disease activity and quality of life measures, such as the Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 response, and the Spondyloarthritis Research Consortium of Canada (SPARCC) score, among others.

These efficacy parameters will be measured at specified timepoints, including baseline and week 14, with additional assessments at week 52 for Study 2. The tools and instruments used for these assessments include validated scales such as the ASDAS, BASDAI, and SPARCC score. The trial will also evaluate changes in patient-reported outcomes, including assessments of total and nocturnal back pain, and quality of life indices like the Ankylosing Spondylitis Quality of Life (ASQoL) and ASAS Health Index (HI). The data collected will be analyzed to determine the efficacy of Upadacitinib in reducing the signs and symptoms of axSpA compared to placebo.