Evaluation of Upadacitinib Efficacy and Safety in Adult and Adolescent Patients with Severe Alopecia Areata: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this Phase 3 randomized, placebo-controlled, double-blind study is to evaluate the **efficacy**, safety, and tolerability of **upadacitinib** in adult and adolescent subjects with severe **Alopecia Areata**. The study is structured into multiple periods:

• Double-blind Period (Baseline to Week 24): To assess the efficacy, safety, and tolerability of upadacitinib 15 mg once daily (QD) and 30 mg QD compared with placebo in treating signs and symptoms of severe Alopecia Areata in adult subjects, and in adolescents where permitted outside the United States and European Union.
• Blinded Extension Period (Week 24 to Week 52): To evaluate the continued efficacy, safety, and tolerability of upadacitinib 15 mg QD and 30 mg QD in extended treatment for adult subjects, and adolescents where permitted outside the US/EU.
• Rerandomized Blinded Extension Period (Week 52 to Week 160): To assess the long-term safety and efficacy of continuous upadacitinib 30 mg QD treatment, dose reduction to 15 mg QD in subjects achieving a sustained response, and dose escalation to 30 mg QD in subjects not achieving a desired response or losing response during the study.

The clinical trial involves a total of **990 participants** diagnosed with **Alopecia Areata**. The study population includes both male and female subjects, comprising adults under the age of 64 and adolescents aged 12 and above, where permitted outside the United States and European Union. Participants were selected based on a diagnosis of severe Alopecia Areata, characterized by a Severity of Alopecia Tool (SALT) score of 50 or greater, indicating significant scalp hair loss. The trial includes individuals who have experienced a current episode of Alopecia Areata for less than 8 years, with no spontaneous scalp hair regrowth over the past 6 months and no significant scalp hair loss over the past 3 months. The study population is considered vulnerable, and lifestyle factors such as diet and physical activity were not specified by the sponsor.

The clinical trial is designed to evaluate the **efficacy** and safety of **upadacitinib** in adult and adolescent subjects with severe **alopecia areata**. This is a Phase 3, randomized, placebo-controlled, double-blind study. The trial is structured into multiple periods, beginning with a double-blind period from baseline to Week 24, followed by a blinded extension period from Week 24 to Week 52, and a rerandomized blinded extension period extending to Week 160. The primary objective is to assess the efficacy, safety, and tolerability of upadacitinib 15 mg and 30 mg once daily compared to placebo. The primary endpoint is the achievement of a Severity of Alopecia Tool (SALT) score of ≤ 20 at Week 24, indicating less than or equal to 20% scalp hair loss.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis of severe alopecia areata, and SALT score. The inclusion criteria specify that eligible subjects must be adults under 64 years old or adolescents at least 12 years old, with a current episode of alopecia areata lasting less than 8 years. Follow-up visits will occur at regular intervals to monitor the participants' response to treatment and any adverse events. The end-of-study visit will conclude the trial, assessing the long-term safety and efficacy of the treatment.

The expected duration of participant involvement is up to 160 weeks, depending on the treatment 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 the study protocol. The trial is anticipated to start recruitment in February 2024 and is estimated to conclude by December 2027. Participants will receive either upadacitinib or a placebo, administered orally in the form of modified-release tablets. The study aims to provide comprehensive data on the long-term management of severe alopecia areata with upadacitinib.

The clinical trial involves the administration of **Upadacitinib**, a **modified-release tablet** formulated for **oral use**. The active substance, upadacitinib, is of chemical origin and is provided by AbbVie Deutschland GmbH & Co. KG. The trial includes two dosage regimens: 15 mg and 30 mg, administered once daily (QD). The maximum daily dose for the 15 mg regimen is 30 mg, with a total maximum dose of 33,600 mg over a treatment period of 160 days. For the 30 mg regimen, the maximum daily dose is 60 mg, with a total maximum dose of 67,200 mg over the same treatment period. The trial aims to evaluate the efficacy, safety, and tolerability of these dosages in subjects with severe **alopecia areata**.

In addition to the experimental medication, a **placebo** is utilized as a comparator treatment in the study. The placebo is designed to match the appearance of the upadacitinib tablets but does not contain the active substance. The placebo is administered in a similar manner to the active treatment, ensuring blinding and maintaining the integrity of the study design. The use of a placebo allows for a controlled assessment of the treatment's effects by providing a baseline for comparison.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. This monitoring is crucial for maintaining the validity of the trial results and for accurately assessing the treatment's efficacy and safety. The trial is conducted in a double-blind manner, meaning neither the participants nor the investigators are aware of the treatment assignments, further ensuring unbiased results.

The efficacy of **Upadacitinib** in the treatment of severe Alopecia Areata will be assessed through a series of primary and secondary endpoints. The primary endpoint is the achievement of a Severity of Alopecia Tool (SALT) score of ≤ 20 at Week 24, indicating less than or equal to 20% scalp hair loss. Secondary endpoints include the achievement of a SALT score ≤ 10 at Week 24, a SALT score ≤ 20 at Week 12, and a SALT score ≤ 20 at Week 4. Additional secondary endpoints involve the Clinician-Reported Outcome (ClinRO) measures for eyebrow and eyelash hair loss, with a score of 0 or 1 at Week 24 and a ≥ 2-point improvement from Baseline for subjects with a Baseline score ≥ 2.

Other secondary endpoints include the achievement of SALT 75 and SALT 90 at Week 24, percent change from Baseline in SALT score at Week 24, and the Patient Global Impression of Change for Alopecia Areata (PaGIC-AA) score of 1 "much better" or 2 "moderately better" at Week 24. Patient-Reported Outcomes (PRO) for Scalp Hair Assessment with a score of 0/1 and a ≥ 2-point improvement from Baseline at Week 24 among subjects with a Baseline score ≥ 3 will also be evaluated. Changes from Baseline in Skindex-16 AA Emotions and Functioning Domain scores, AASIS Interference and Symptoms Subscale scores, and the Hospital Anxiety and Depression Scale (HADS) scores will be assessed at Week 24. The efficacy assessments will be conducted at specified timepoints, including Weeks 4, 8, 12, and 24, using validated scales and patient-reported outcomes to ensure accurate and reliable data collection and analysis.