A Study to Assess Treat-to-Target and Dosing Flexibility of Oral Upadacitinib Tablets in Adult Participants With Moderate to Severe Atopic Dermatitis

Study Overview
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Brief Summary
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Atopic dermatitis (AD) is a skin condition that may cause a rash and itching due to inflammation of the skin. Therapies spread over the skin may not be enough to control the AD in trial participants who require systemic anti-inflammatory treatment. This study evaluates the dosing flexibility of upadacitinib in adult participants with moderate to severe AD. Adverse events and change in the disease activity will be assessed. Upadacitinib is an approved drug for the treatment of moderate to severe/active immune-mediated inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and AD. The study is comprised of a 35-day Screening Period, a 12-week double-blind period and a 12-week single-blind period. During the double-blind period, participants are placed in 1 of 2 groups, called treatment arms and will be randomized in a 1:1 ratio to receive upadacitinib. At 12 weeks during the single blind period, participants will be blinded to the upadacitinib dose based on their EASI response and reassigned to in 1 of 4 arms. After the last study visit, there is a 30-day follow-up visit. Approximately 454 adult participants ages 18 to 64 with moderate to severe AD who are candidates for systemic therapy will be enrolled at up to 160 sites worldwide. The study is comprised of a 12-week double-blind period, followed by a 12-week single-blind period. Participants will receive upadacitinib oral tablets once daily for up to 24 weeks. There may be higher treatment burden for participants in this trial compared to their standard of care (due to study procedures). 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
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A Phase 3b/4 Randomized, Blinded, Treat-to-Target and Dose-Flexibility Study of Upadacitinib in Adult Subjects With Moderate to Severe Atopic Dermatitis

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: Upadacitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic atopic dermatitis (AD) with onset of symptoms at least 3 years prior to Baseline and participant meets Hanifin and Rajka criteria. Eczema Area and Severity Index (EASI) score >= 16, vIGA-AD score >= 3 and >= 10% Body Surface Area (BSA) of AD involvement at the Baseline Visit. Baseline weekly average of daily Worst Pruritus NRS >= 4. Candidate for systemic treatment defined as prior use of systemic treatment for AD, OR previous inadequate response to TCS, TCI or PDE-4 inhibitors, OR for whom topical treatments are otherwise medically inadvisable. Exclusion Criteria: Participants with current or past history of infection including: Two or more episodes of herpes zoster, or one or more episodes of disseminated herpes zoster; One or more episodes of disseminated herpes simplex (including eczema herpeticum); Human immunodeficiency virus (HIV) infection defined as confirmed positive anti-HIV antibody (HIV Ab) test; Active tuberculosis (TB) or meet TB exclusionary parameters (protocol specified requirements for TB testing); Japan only: Positive result of beta-D-glucan (screening for Pneumocystis jirovecii infection) or two consecutive indeterminate results of beta-D-glucan during the Screening Period; Active infection(s) requiring treatment with intravenous anti-infectives within 30 days, or oral/intramuscular anti-infectives within 14 days prior to the Baseline Visit; Chronic recurring infection and/or active viral infection that, based on the investigator's clinical assessment, makes the participant an unsuitable candidate for the study; COVID-19 infection: In participants who tested positive for COVID, at least 5 days must have passed since a COVID-19 positive test result for study entry of asymptomatic participants. Participants with mild/moderate COVID-19 infection can be enrolled if fever is resolved without use of antipyretics for 24 hours and other symptoms improved, or if 5 days have passed since the COVID-19 positive test result (whichever comes last). Participants may be rescreened if judged to be in good general health, as determined by the investigator based upon the medical history and physical examination. Evidence of Hepatitis B virus (HBV) or Hepatitis C virus (HCV). Any of the following medical diseases or disorders: Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting, and aorto-coronary bypass surgery; History of an organ transplant which requires continued immunosuppression; History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same class; History of gastrointestinal perforation (other than due to appendicitis or mechanical injury), diverticulitis, or significantly increased risk for gastrointestinal perforation per investigator judgment; Conditions that could interfere with drug absorption including but not limited to short bowel syndrome or gastric bypass surgery; participants with a history of gastric banding/segmentation are not excluded; History of malignancy except for successfully treated non-melanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-Blind Treatment Period Dose A<br>Participants will be administered updadacitinib Dose A once daily (QD) for 12 weeks. | Drug: Upadacitinib<br>* Oral tablet<br>* Other names: ABT-494;|
| Experimental: Double-Blind Treatment Period Dose B<br>Participants will be administered updadacitinib Dose B once daily (QD) for 12 weeks. | Drug: Upadacitinib<br>* Oral tablet<br>* Other names: ABT-494;|
| Experimental: Single-Blinded Treatment Period Arm A<br>Participants will be administered updadacitinib once daily (QD) for 12 weeks. | Drug: Upadacitinib<br>* Oral tablet<br>* Other names: ABT-494;|
| Experimental: Single-Blinded Treatment Period Arm B<br>Participants will be administered updadacitinib once daily (QD) for 12 weeks. | Drug: Upadacitinib<br>* Oral tablet<br>* Other names: ABT-494;|
| Experimental: Single-Blinded Treatment Period Arm C<br>Participants will be administered updadacitinib once daily (QD) for 12 weeks. | Drug: Upadacitinib<br>* Oral tablet<br>* Other names: ABT-494;|
| Experimental: Single-Blinded Treatment Period Arm D<br>Participants will be administered updadacitinib once daily (QD) for 12 weeks. | Drug: Upadacitinib<br>* Oral tablet<br>* Other names: ABT-494;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Eczema Area and Severity Index (EASI) 90 | EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving EASI 75 | EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. | Week 24 | 
| Percentage of Participants Achieving EASI 100 | EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. | Up to Week 24 | 
| Percentage of Participants Achieving EASI 75 | EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. | Week 12 | 
| Percentage of Participants Achieving EASI 90 | EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. | Week 12 | 
| Percentage of Participants Achieving EASI 100 | EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The total EASI score for each region is calculated by multiplying the severity score by the area score, with adjustment for the proportion of the body region to the whole body. The final EASI score is the sum of the 4 region scores and ranges from 0 to 72 where higher scores represent worse disease. | Week 12 | 
| Percentage of Participants Achieving EASI 90 and Worst Pruritus Numerical Rating Scale (NRS) of 0 or 1 | EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The final EASI score ranges from 0 to 72 where higher scores represent worse disease. Worst Pruritus NRS is a validated single self-reported item designed to measure peak pruritus, with '0' being 'no itch' and '10' being 'worst imaginable itch', over the previous 24 hours. | Week 12 | 
| Percentage of Participants Achieving EASI 90 and Worst Pruritus NRS of 0 or 1 | EASI is a tool used to measure the extent (area) and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the area score is recorded as the percentage of skin affected by eczema. For each region, the severity score is calculated as the sum of the intensity scores (scored as none [0], mild [1], moderate [2], or severe [3]) for redness (erythema, inflammation), thickness (induration, papulation, swelling - acute eczema), scratching (excoriation), and lichenification (lined skin, prurigo nodules - chronic eczema). The final EASI score ranges from 0 to 72 where higher scores represent worse disease. Worst Pruritus NRS is a validated single self-reported item designed to measure peak pruritus, with '0' being 'no itch' and '10' being 'worst imaginable itch', over the previous 24 hours. | Week 24 | 
| Percentage of Participants Achieving Validated Investigator Global Assessment for Atopic Dermatitis (vlGA-AD) of 0 or 1 | vIGA-AD is a validated assessment instrument used in clinical studies to rate the severity of AD globally. A 5-point scale is used to measure the severity of disease at the time of the investigator's evaluation of the participant ranging from 0 - Clear (no inflammatory signs of atopic dermatitis (no erythema, no induration/papulation, no lichenification, no oozing/crusting). Post-inflammatory hyperpigmentation and/or hypopigmentation may be present.) to 4 - Severe (marked erythema (deep or bright red), marked induration/papulation, and/or marked lichenification. | Up to Week 24 | 
| Percentage of Participants Achieving Improvement (reduction) in Worst Pruritus NRS of >= 4 | Worst Pruritus NRS is a validated single self-reported item designed to measure peak pruritus, with '0' being 'no itch' and '10' being 'worst imaginable itch', over the previous 24 hours. Higher score denoting worse itch. | Up to Week 24 | 
| Percentage of Participants Achieving Worst Pruritus NRS of 0 or 1 | Worst Pruritus NRS is a validated single self-reported item designed to measure peak pruritus, with '0' being 'no itch' and '10' being 'worst imaginable itch', over the previous 24 hours. Higher score denoting worse itch. | Up to Week 24 | 
| Percentage of Participants Achieving Improvement (reduction) in Dermatology Life Quality Index (DLQI) of >= 4 | DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on health-related quality of life (HRQoL). It consists of 10 questions assessing impact of skin diseases on different aspects of participant's QoL over the prior week. Each item is scored on a 4-point scale: 0 = not at all/not relevant; 1 = a little; 2 = a lot; and 3 = very much. Item scores (0 to 3) are added to provide a total score range of 0 to 30. Higher scores indicate greater impairment of HRQoL. | Up to Week 24 | 
| Percentage of Participants Achieving DLQI of 0 or 1 | DLQI is a 10-item, validated questionnaire used in clinical practice and clinical trials to assess the impact of AD disease symptoms and treatment on health-related quality of life (HRQoL). It consists of 10 questions assessing impact of skin diseases on different aspects of participant's QoL over the prior week. Each item is scored on a 4-point scale: 0 = not at all/not relevant; 1 = a little; 2 = a lot; and 3 = very much. Item scores (0 to 3) are added to provide a total score range of 0 to 30. Higher scores indicate greater impairment of HRQoL. | Up to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atopic Dermatitis (AD), Upadacitinib, RINVOQ