Phase 3 Evaluation of Upadacitinib Efficacy and Safety in Adults with Moderately to Severely Active Systemic Lupus Erythematosus

The primary objective of this study is to evaluate the **safety** and efficacy of upadacitinib compared with placebo in the treatment of signs and symptoms of **Systemic Lupus Erythematosus (SLE)** over a 52-week period in adults with moderately to severely active SLE. The primary efficacy objective is to demonstrate the superiority of upadacitinib compared to placebo with respect to the primary endpoint in adult subjects with moderately to severely active SLE despite background therapy. This is clinically relevant as it aims to provide a more effective treatment option for patients with SLE, potentially improving disease management and patient outcomes.

The secondary objectives include:

• Demonstrating the superiority of upadacitinib compared with placebo concerning secondary endpoints such as SLE disease activity, SLE flares, reduction of glucocorticoid dose, patient-reported outcomes, and damage in the replicate Phase 3 studies.
• Evaluating the long-term efficacy of upadacitinib in adults with moderately to severely active SLE and assessing whether the efficacy response observed in the initial studies can be maintained on a reduced upadacitinib dose in the long-term extension study.

The clinical trial involves a total of **770 participants** diagnosed with **Systemic Lupus Erythematosus (SLE)**. The study population comprises adult individuals aged 18 to 63 years, inclusive, who have been clinically diagnosed with SLE at least 24 weeks prior to screening. Both male and female subjects are included in the trial, and the population is characterized by moderately to severely active SLE despite background therapy. Participants were selected based on specific inclusion criteria, including a positive ANA titer, anti-dsDNA, or anti-Smith antibodies, and a clinical hSLEDAI score of 6 or higher. The trial also considers individuals on stable background treatment for at least 60 days prior to baseline, with certain medications allowed at specified dosages. The study does not exclude vulnerable populations, ensuring a comprehensive evaluation of the safety and efficacy of upadacitinib compared to placebo over a 52-week period.

The clinical trial is designed to evaluate the **safety** and **efficacy** of **upadacitinib** in adults with moderately to severely active **Systemic Lupus Erythematosus (SLE)**. This is a Phase III, randomized, double-blind, placebo-controlled study. The trial consists of two replicate studies, each lasting 52 weeks, and a long-term extension study. The primary objective is to demonstrate the superiority of upadacitinib over placebo in achieving a BICLA response at Week 52. Secondary endpoints include flare rate, achievement of SRI-4, LLDAS, and changes in various clinical scores at Week 52.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, clinical diagnosis of SLE, and stable background treatment. The baseline visit will follow, where clinical scores are reconfirmed. Subsequent visits will occur at regular intervals to monitor safety and efficacy outcomes, with the final visit at Week 52 marking the end of the study. The long-term extension study will focus on evaluating the long-term safety of upadacitinib.

The expected duration of participant involvement is up to 52 weeks for the initial studies, with the possibility of continued participation in the long-term extension. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The trial is estimated to conclude by October 31, 2027, with recruitment starting on October 1, 2023.

The clinical trial involves the evaluation of **Upadacitinib**, a **modified-release tablet** formulated for oral administration. Upadacitinib is a chemical substance developed by AbbVie Deutschland GmbH & Co. KG. The trial includes two dosing regimens: a maximum daily dose of 15 mg and a maximum daily dose of 30 mg. The treatment period for the 15 mg dose is up to 52 weeks, with a total maximum dose of 5460 mg, while the 30 mg dose can be administered for up to 104 weeks, with a total maximum dose of 21840 mg. The primary objective is to assess the safety and efficacy of Upadacitinib in adults with moderately to severely active systemic lupus erythematosus (SLE).

The study also includes a **placebo** group to serve as a comparator for Upadacitinib. The placebo is designed to mimic the pharmaceutical form of Upadacitinib, ensuring blinding in the trial. The placebo is administered orally, following the same schedule as the active treatment groups, to evaluate the efficacy of Upadacitinib against a non-active control. The placebo is essential for determining the true therapeutic effect of Upadacitinib by providing a baseline for comparison.

The efficacy of **Upadacitinib** in the treatment of moderately to severely active Systemic Lupus Erythematosus (SLE) will be assessed through a series of primary and secondary endpoints over a 52-week period. The primary efficacy endpoint for Study 1 and Study 2 is the achievement of a BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment) response at Week 52. This endpoint will also be evaluated at all other visits throughout the study duration. Secondary endpoints include the flare rate, defined by the SFI (Systemic Lupus Erythematosus Flare Index), achievement of SRI-4 (Systemic Lupus Erythematosus Responder Index-4), and LLDAS (Lupus Low Disease Activity State) at Week 52. Additional secondary endpoints involve the time to first flare per SFI, reduction in oral glucocorticoid dose, improvement in tender or swollen joints, reduction in CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) activity score, and changes from baseline in Lupus Pain NRS, FACIT-Fatigue v4, and SF-36v2® Health Survey Acute PCS at Week 52. These secondary endpoints, except for the flare rate, time to first flare, and glucocorticoid dose reduction, will also be assessed at all other visits collected during the study. Study 3, a long-term extension, focuses on evaluating the long-term safety of Upadacitinib and does not have primary or ranked secondary endpoints.