Evaluation of Upadacitinib and Prednisolone Combination Therapy in Patients with Giant Cell Arteritis: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of ABT-494, also known as **upadacitinib**, in combination with a corticosteroid taper regimen compared to placebo in combination with a corticosteroid taper regimen. This will be measured by the proportion of subjects in sustained remission at Week 52. Additionally, the study aims to assess the safety and tolerability of ABT-494 in subjects with **Giant Cell Arteritis** (GCA) during Period 1. This is clinically relevant as it seeks to determine the potential of ABT-494 to maintain remission in GCA, a condition characterized by inflammation of the blood vessels, which can lead to serious complications if not effectively managed.

Secondary objectives include evaluating the safety and efficacy of continuing versus withdrawing ABT-494 in maintaining remission in subjects who achieved remission in Period 1. This aspect of the study is crucial for understanding the long-term management of GCA and the role of ABT-494 in sustaining remission without continuous treatment.

The clinical trial involves a total of **198 participants** diagnosed with **Giant Cell Arteritis** (GCA). The study population includes both male and female subjects, all of whom are adults aged 50 years and older. Participants were selected based on specific criteria, including a history of elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) levels, and the presence of cranial symptoms or polymyalgia rheumatica (PMR) symptoms. Additionally, participants must have active GCA, either new onset or relapsing, within eight weeks of the study start, and must have been treated with prednisone or an equivalent corticosteroid. The trial includes individuals who are clinically stable and are receiving a daily dose of prednisone or prednisolone. Both genders are represented, and the study includes a vulnerable population. 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 combination with a corticosteroid taper regimen compared to placebo in subjects with **Giant Cell Arteritis** (GCA). This is a multicenter, randomized, double-blind, placebo-controlled study. The trial aims to assess the proportion of subjects achieving sustained remission at Week 52, alongside evaluating the safety and tolerability of upadacitinib. The trial is expected to run from February 1, 2019, to February 28, 2025, with a maximum treatment period of 104 weeks for upadacitinib and 52 weeks for prednisolone.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, history of elevated ESR or CRP, and active GCA. Following the screening, participants will be randomized to receive either upadacitinib or placebo, in combination with a corticosteroid taper regimen. The study includes regular follow-up visits to monitor the participants' health, adherence to the treatment regimen, and any adverse events. The end-of-study visit will assess the primary and secondary endpoints, including sustained remission and cumulative corticosteroid exposure.

The expected length of participant involvement is up to 104 weeks, depending on the treatment group. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that pose a risk to the participant's health. The trial's primary endpoint is the proportion of subjects achieving sustained remission at Week 52, defined by the absence of GCA signs and symptoms and adherence to the corticosteroid taper regimen. Secondary endpoints include the proportion of subjects in complete remission, time to first disease flare, and changes in quality of life measures.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **Upadacitinib**, a Janus Kinase (Jak-1) inhibitor, provided in a **modified-release tablet** form. Upadacitinib is administered orally with a maximum daily dose of 15 mg and a total dose of 10,920 mg over a treatment period of 104 weeks. The medication is manufactured by AbbVie Deutschland GmbH & Co. KG and is identified by the sponsor product code ABT-494. Participant compliance with the dosing schedule is monitored throughout the trial.

In addition to Upadacitinib, the trial includes the administration of **Prednisolone** in various dosages as part of a corticosteroid taper regimen. Prednisolone is provided in tablet form and is administered orally. The dosages include 1 mg, 5 mg, 10 mg, and 20 mg tablets, with a maximum daily dose corresponding to each tablet strength. The total dose for each strength is capped at 3,892 mg over a 52-week treatment period. Prednisolone is of chemical origin and is manufactured by MIBE GmbH Arzneimittel. The administration of Prednisolone is intended to be part of the standard-of-care therapy in the trial.

The trial also incorporates the use of placebos to maintain the double-blind nature of the study. Placebos corresponding to each Prednisolone dosage (1 mg, 5 mg, 10 mg, and 20 mg) and Upadacitinib are included. These placebos are indistinguishable from the active medications in appearance and are administered following the same schedule as their active counterparts. The use of placebos ensures that the effects of the experimental medication can be accurately assessed against a control group.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the proportion of subjects achieving sustained remission at Week 52. Sustained remission is defined by the absence of **Giant Cell Arteritis (GCA)** signs and symptoms from Week 12 through Week 52, along with adherence to the protocol-defined corticosteroid taper regimen.

Secondary endpoints include several measures: the proportion of subjects achieving sustained complete remission from Week 12 through Week 52, cumulative corticosteroid (CS) exposure, and time to first disease flare. A disease flare is characterized by a recurrence of GCA signs or symptoms or an erythrocyte sedimentation rate (ESR) measurement greater than 30 mm/hr attributable to GCA, necessitating an increase in CS dose. Additional secondary endpoints are the proportion of subjects experiencing at least one disease flare through Week 52, the proportion of subjects in complete remission at Week 52 and Week 24, and changes from baseline in the 36-item Short Form Quality of Life Questionnaire (SF-36) Physical Component Score (PCS) at Week 52.

Further assessments include the number of disease flares per subject during Period 1, changes from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at Week 52, and the Treatment Satisfaction Questionnaire for Medication (TSQM) patient global satisfaction subscale at Week 52. The rate of CS-related adverse events (AEs) will also be evaluated. These efficacy parameters will be measured and collected at specified timepoints, such as Week 12, Week 24, and Week 52, using validated scales and laboratory tests as appropriate.