A Study to Evaluate the Safety and Effectiveness of Upadacitinib Tablets in Adult and Adolescent Participants With Severe Alopecia Areata

Study Overview
=================
Brief Summary
-----------------
Alopecia areata (AA) is a disease that happens when the immune system attacks hair follicles and causes hair loss. AA usually affects the head and face, but hair loss can happen on any part of the body. The purpose of this study is to assess how safe, effective, and tolerable upadacitinib is in adolescent and adult participants with severe AA. Upadacitinib is an approved drug being investigated for the treatment of AA. In Study 1 and Study 2 Period A, participants are placed in 1 of 3 groups, called treatment arms. Each group receives a different treatment. There is a 1 in 5 chance that participants will be assigned to placebo. In Study 1 and Study 2 Period B, participants originally randomized to upadacitinib dose group in Period A will continue their same treatment in Period B. Participants originally randomized to Placebo in Period A will either remain on placebo in Period B, or be randomized in 1 of 2 groups, based off of their Severity of Alopecia Tool (SALT) score. Participants who complete Study 1 or Study 2, can join Study 3 and may be re-randomized to receive 1 of 2 doses of upadacitinib for up to 108 weeks. Around 1500 participants with severe AA will be enrolled in the study at approximately 240 sites worldwide. Participants will receive oral tablets of either upadacitinib or placebo once daily for up to 160 weeks with the potential of being re-randomized into a different treatment group at Weeks 24 and 52. Participants will be followed up for up to 30 days after last study drug dose. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

Official Title
-----------------
A Phase 3 Randomized, Placebo-controlled, Double-blind Program to Evaluate Efficacy and Safety of Upadacitinib in Adult and Adolescent Subjects With Severe Alopecia Areata

Conditions
-----------------
Alopecia Areata

Intervention / Treatment
-----------------
* Drug: Upadacitinib
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult individuals < 64 years old at Baseline Visit. Where permitted outside United States (OUS), adolescent individuals who are at least 12 years old at Screening may participate. Diagnosis of severe AA with SALT score ≥ 50 scalp hair loss at Screening and Baseline. Severe AA with no spontaneous scalp hair regrowth over the past 6 months AND no significant scalp hair loss over the past 3 months. Current episode of AA of less than 8 years. Exclusion Criteria: Diagnosis of primarily diffuse type of AA. Diagnosis of other types of alopecia that would interfere with evaluation of AA, including but not limited to female pattern hair loss, male pattern hair loss (androgenetic alopecia) Stage III or greater based on Hamilton-Norwood classification, traction alopecia, lichen planopilaris (LPP), discoid lupus, frontal fibrosing alopecia (FFA), central centrifugal cicatricial alopecia (CCCA), folliculitis decalvans, trichotillomania, and telogen effluvium. Diagnosis of other types of inflammatory scalp, eyebrow, or eyelash disorders that would interfere with evaluation of AA, including but not limited to seborrheic dermatitis, scalp psoriasis, atopic dermatitis (AD), and tinea capitis.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 63 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study 1: Group 1 Upadacitinib Dose A<br>Participants will receive upadacitinib Dose A once daily for 52 weeks in Period A and Period B. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;|
| Experimental: Study 1: Group 2 Upadacitinib Dose B<br>Participants will receive upadacitinib Dose B once daily for 52 weeks in Period A and Period B. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;|
| Experimental: Study 1: Group 3 Placebo<br>Participants will receive matching placebo once daily for 24 weeks in Period A. | Drug: Placebo<br>* Oral Tablets<br>|
| Experimental: Study 1: Group 4 Upadacitinib Dose A<br>Participants initially randomized to placebo (Period A) with a SALT score > 20 at Week 24 will be re-randomized to receive upadacitinib Dose A once daily for 28 weeks in Period B. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;Drug: Placebo<br>* Oral Tablets<br>|
| Experimental: Study 1: Group 5 Upadacitinib Dose B<br>Participants initially randomized to placebo (Period A) with a SALT score > 20 at Week 24 will be re-randomized to receive upadacitinib Dose B once daily for 28 weeks in Period B. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;Drug: Placebo<br>* Oral Tablets<br>|
| Experimental: Study 1: Group 6 Placebo<br>Participants initially randomized to placebo with a SALT score ≤ 20 at Week 24 will continue on placebo through Week 52. | Drug: Placebo<br>* Oral Tablets<br>|
| Experimental: Study 2: Group 1 Upadacitinib Dose A<br>Participants will receive upadacitinib Dose A once daily for 52 weeks in Period A and Period B. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;|
| Experimental: Study 2: Group 2 Upadacitinib Dose B<br>Participants will receive upadacitinib Dose B once daily for 52 weeks in Period A and Period B. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;|
| Experimental: Study 2: Group 3 Placebo<br>Participants will receive matching placebo once daily for 24 weeks in Period A. | Drug: Placebo<br>* Oral Tablets<br>|
| Experimental: Study 2: Group 4 Upadacitinib Dose A<br>Participants initially randomized to placebo (Period A) with a SALT score > 20 at Week 24 will be re-randomized to receive upadacitinib Dose A once daily for 28 weeks in Period B. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;Drug: Placebo<br>* Oral Tablets<br>|
| Experimental: Study 2: Group 5 Upadacitinib Dose B<br>Participants initially randomized to placebo (Period A) with a SALT score > 20 at Week 24 will be re-randomized to receive upadacitinib Dose B once daily for 28 weeks in Period B. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;Drug: Placebo<br>* Oral Tablets<br>|
| Experimental: Study 2: Group 6 Placebo<br>Participants initially randomized to placebo with a SALT score ≤ 20 at Week 24 will continue on placebo through Week 52. | Drug: Placebo<br>* Oral Tablets<br>|
| Experimental: Study 3: Group 1 Upadacitinib Dose B (SALT > 20)<br>Participants receiving upadacitinib Dose A with a SALT score > 20 at Week 52 (end of Period B) of Study 1 or Study 2 will dose escalate to upadacitinib Dose B once daily for 108 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;|
| Experimental: Study 3: Group 2 Upadacitinib Dose A (SALT ≤ 20)<br>Participants receiving upadacitinib Dose A with a SALT score ≤ 20 at Week 52 (end of Period B) of Study 1 or Study 2 will remain on upadacitinib Dose A once daily for 108 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;|
| Experimental: Study 3: Group 3 Upadacitinib Dose B (Non-Sustained)<br>Participants who end Period B on upadacitinib Dose B with a with a SALT score > 20 at Week 40 or Week 52 of Study 1 or Study 2 will remain on upadacitinib Dose B once daily for 108 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;|
| Experimental: Study 3: Group 4 Upadacitinib Dose B (Sustained)<br>Participants who end Period B on upadacitinib Dose B with a with a SALT score ≤ 20 at Week 40 and Week 52 of Study 1 or Study 2 will be re-randomized to receive upadacitinib Dose B once daily for 108 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;|
| Experimental: Study 3: Group 5 Upadacitinib Dose A (Sustained)<br>Participants who end Period B on upadacitinib Dose B with a with a SALT score ≤ 20 at Week 40 and Week 52 of Study 1 or Study 2 will be re-randomized to receive upadacitinib Dose A once daily for 108 weeks. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: ABT-494;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with the Achievement of Severity of Alopecia Tool (SALT) Score <= 20 | The SALT is a global AA severity score based on the combination of extent and density of scalp hair loss. The score is determined by visually defining the amount of terminal hair loss in each of the 4 views of the scalp (left and right side each accounting for 18% of scalp area, the top for 40%, and the back for 24%) and adding these together with a maximum score of 100%. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with the Achievement of SALT Score <= 10 | The SALT is a global AA severity score based on the combination of extent and density of scalp hair loss. The score is determined by visually defining the amount of terminal hair loss in each of the 4 views of the scalp (left and right side each accounting for 18% of scalp area, the top for 40%, and the back for 24%) and adding these together with a maximum score of 100%. | Week 24 | 
| Percentage of Participants with the Achievement of SALT Score <= 20 | The SALT is a global AA severity score based on the combination of extent and density of scalp hair loss. The score is determined by visually defining the amount of terminal hair loss in each of the 4 views of the scalp (left and right side each accounting for 18% of scalp area, the top for 40%, and the back for 24%) and adding these together with a maximum score of 100%. | Up to Week 12 | 
| Percentage of Participants with the Achievement of Clinician-Reported Outcome (ClinRO) Measure for Eyebrow Hair Loss of 0 or 1 | The ClinRO for Eyebrow Hair Loss is a 4-point response scale where 0 = The eyebrows have full coverage and no areas of hair loss and 3 = No notable eyebrows. Responses should have a ≥ 2-point improvement from Baseline among participants with Baseline score ≥ 2. | Baseline to Week 24 | 
| Percentage of Participants with the Achievement of ClinRO Measure for Eyelash Hair Loss of 0 or 1 | The ClinRO for Eyebrow Hair Loss is a 4-point response scale where 0 = The eyelashes form a continuous line along the eyelids on both eyes and 3 = No notable eyelashes. Responses should have a ≥ 2-point improvement from Baseline among participants with Baseline score ≥ 2. | Baseline to Week 24 | 
| Percentage of Participants with the Achievement of SALT 75 | SALT 75 is defined as at least a 75% improvement [decrease] from Baseline in SALT score. | Baseline to Week 24 | 
| Percentage of Participants with the Achievement of SALT 90 | SALT 90 is defined as at least a 90% improvement [decrease] from Baseline in SALT score. | Baseline to Week 24 | 
| Percent Change from Baseline in SALT Score | The SALT is a global AA severity score based on the combination of extent and density of scalp hair loss. The score is determined by visually defining the amount of terminal hair loss in each of the 4 views of the scalp (left and right side each accounting for 18% of scalp area, the top for 40%, and the back for 24%) and adding these together with a maximum score of 100%. | Baseline to Week 24 | 
| Percentage of Participants with the Achievement of Patients' Global Impression of Change of Alopecia Areata (PaGIC-AA) Score of 1 Much Better or 2 Moderately Better | The PaGIC-AA is a single-item measure that asks participants to rate how their alopecia condition has changed overall since the start of the study using a 7-point scale. Responses range from much better to much worse. | Up to Week 24 | 
| Percentage of Participants with the Achievement of Patient-Reported Outcome (PRO) for Scalp Hair Assessment 0/1 with ≥ 2-Point Improvement (Reduction) | The PRO for Scalp Hair Assessment is single item, five-point, categorical response scale that asks respondents to look in the mirror and assess the total area of the scalp with missing hair. Response items range from No missing hair to Nearly all or all and includes percentage ranges for each category (0%, 1 to 20%, 21 to 49%, 50 to 94%, and 95 to 100%). Responses among participants with baseline score >=3. | Baseline to Week 24 | 
| Percentage of Participants with the Achievement of SALT Score 0 | The SALT is a global AA severity score based on the combination of extent and density of scalp hair loss. The score is determined by visually defining the amount of terminal hair loss in each of the 4 views of the scalp (left and right side each accounting for 18% of scalp area, the top for 40%, and the back for 24%) and adding these together with a maximum score of 100%. | Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Alopecia Areata, Upadacitinib, Rinvoq, ABT-494