A Study to Evaluate ABT-494 (Upadacitinib) in Adults With Moderate to Severe Atopic Dermatitis

Study Overview
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Brief Summary
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The objective of this study was to evaluate the safety and efficacy of multiple doses of upadacitinib monotherapy versus placebo in the treatment of adults with moderate to severe atopic dermatitis (AD).

Detailed Description
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The study was to include a 16-week double-blind treatment period (Period 1) and a 72-week double-blind treatment period (Period 2) for a total of 88 weeks of treatment. Participants who met eligibility criteria were to be randomized in a 1:1:1:1 ratio to one of the four treatment groups. Participants who completed Period 1 were re-randomized at Week 16 into a 72-week double-blind, placebo-controlled treatment period (Period 2) in a 1:1 ratio: Group 1: Upadacitinib 7.5 mg once daily (QD) (Day 1 to Week 16) → upadacitinib 7.5 mg QD or placebo (Week 16 - and thereafter) Group 2: Upadacitinib 15 mg QD (Day 1 to Week 16) → upadacitinib 15 mg QD or placebo (Week 16 and thereafter) Group 3: Upadacitinib 30 mg QD (Day 1 to Week 16) → upadacitinib 30 mg QD or placebo (Week 16 - and thereafter) Group 4: Matching placebo (Day 1 to Week 16) → upadacitinib 30 mg QD or placebo (Week 16 and thereafter) In Period 1, discontinuation from study drug was mandatory for any participant with an Eczema Area and Severity Index (EASI) score worsening of 25% or more compared with their Baseline EASI score at any 2 consecutive scheduled study visits from Week 4 to Week 12. In Period 2, blinded rescue therapy with upadacitinib 30 mg QD was provided after the first instance of a < EASI 50 response starting at the Week 20 visit (4 weeks after re-randomization into Period 2) for the remainder of the study.

Official Title
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A Phase 2b Multicenter, Randomized, Placebo-Controlled, Double-Blind Dose-Ranging Study to Evaluate ABT-494 (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
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Atopic dermatitis with a diagnosis confirmed by a dermatologist (according to the Hanifin and Rajka criteria) and onset of symptoms at least 1 year prior to Baseline. Moderate to severe atopic dermatitis defined by an Eczema Area and Severity Index (EASI) ≥ 16, body surface area (BSA) ≥ 10% and an Investigators Global Assessment (IGA) score ≥ 3 at the Baseline visit. Documented history (within 1 year prior to the screening visit) of inadequate response to treatment with topical corticosteroids (TCS), or topical calcineurin inhibitors (TCI), or for whom topical treatments are otherwise medically inadvisable (e.g., because of important side effects or safety risks). Twice daily use of an additive-free, bland emollient for at least 7 days prior to Baseline. Exclusion Criteria: Prior exposure to any systemic or topical Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, ruxolitinib, and filgotinib). Treatment with topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), prescription moisturizers or moisturizers containing additives such as ceramide, hyaluronic acid, urea, or filaggrin within 10 days prior to the Baseline visit. Prior exposure to dupilumab or exposure to systemic therapies for AD including corticosteroids, methotrexate, cyclosporine, azathioprine, phosphodiesterase type 4 (PDE4)-inhibitors and mycophenolate mofetil within 4 weeks prior to Baseline. Prior exposure to any investigational systemic treatment within 30 days or 5 half-lives (whichever is longer) of the Baseline visit or is currently enrolled in another clinical study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants randomized to receive placebo once daily (QD) for 16 weeks in Period 1. At Week 16 participants were re-randomized to receive 30 mg upadacitinib or placebo once a day for 72 weeks in Period 2. | Drug: Upadacitinib<br>* Tablet for oral use<br>* Other names: ABT-494;Drug: Placebo<br>* Tablet<br>|
| Experimental: Upadacitinib 7.5 mg<br>Participants randomized to receive upadacitinib 7.5 mg QD for 16 weeks in Period 1. At Week 16 participants were re-randomized to receive 7.5 mg upadacitinib or placebo QD for 72 weeks in Period 2. | Drug: Upadacitinib<br>* Tablet for oral use<br>* Other names: ABT-494;Drug: Placebo<br>* Tablet<br>|
| Experimental: Upadacitinib 15 mg<br>Participants randomized to receive upadacitinib 15 mg QD for 16 weeks in Period 1. At Week 16 participants were re-randomized to receive 15 mg upadacitinib or placebo QD for 72 weeks in Period 2. | Drug: Upadacitinib<br>* Tablet for oral use<br>* Other names: ABT-494;Drug: Placebo<br>* Tablet<br>|
| Experimental: Upadacitinib 30 mg<br>Participants randomized to receive upadacitinib 30 mg QD for 16 weeks in Period 1. At Week 16 participants were re-randomized to receive 30 mg upadacitinib or placebo QD for 72 weeks in Period 2. | Drug: Upadacitinib<br>* Tablet for oral use<br>* Other names: ABT-494;Drug: Placebo<br>* Tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score at Week 16 | 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; a negative change from baseline indicates improvement. | Baseline and Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a 75% Reduction in EASI Score (EASI 75) at Week 16 | EASI is a tool to measure the extent and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the percentage of skin affected, and the severity of eczema (scored as none [0], mild [1], moderate [2], or severe [3]) for redness, thickness, scratching, and lichenification are assessed. The EASI score is the sum of the scores for each region and ranges from 0 to 72, where higher scores represent worse disease. An EASI 75 response is defined as participants with at least a 75% reduction (improvement) in EASI score relative to the Baseline value. Participants with missing values at Week 16 were counted as non-responders in this analysis (non-responder imputation). | Baseline and Week 16 | 
| Percentage of Participants Achieving an Investigator Global Assessment (IGA) of 0 or 1 at Week 16 | The Investigator's Global Assessment for Atopic Dermatitis (IGA) was scored on the following scale: 0: Clear (No inflammatory signs of atopic dermatitis) 1: Almost Clear (Just perceptible erythema and just perceptible papulation/infiltration) 2: Mild (Mild erythema and mild papulation/infiltration) 3: Moderate (Moderate erythema and moderate papulation/infiltration) 4: Severe (Severe erythema and severe papulation/infiltration with or without oozing/crusting) The percentage of participants with a score of 0 or 1 at Week 16 is reported. | Week 16 | 
| Percent Change From Baseline to Weeks 2, 8, and 16 in Pruritus Numerical Rating Scale (NRS) | Participants were asked to rate pruritus (itch) in the past 24 hours on a daily basis using a scale from 0 to 10, with 0 being no itch and 10 being the worst imaginable itch. The percent change from Baseline at each week was calculated from a rolling weekly average. | Baseline and Weeks 2, 8, and 16 | 
| Percent Change From Baseline in EASI Score at Week 8 | 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; a negative change from Baseline indicates improvement. | Baseline and Week 8 | 
| Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Weeks 8 and 16 | SCORAD is a clinical tool used to assess the extent and severity of eczema (SCORing Atopic Dermatitis). The extent is assessed using the rule of 9 to calculate the affected area (A) as a percentage of the whole body (0-100%). The intensity part of the SCORAD (B) consists of 6 items: erythema, oedema/papulation, excoriations, lichenification, oozing/crusts and dryness, each graded on a scale from 0 (none) to 3 (severe), for a total score of 0 to 18. Subjective items (C) include daily pruritus and sleeplessness, each scored on a visual analogue scale (VAS) from 0 to 10 (total score 0-20). SCORAD is calculated as A/5 + 7B/2 + C, and ranges from 0 to 103 (worst). A negative change from Baseline indicates improvement. | Baseline and Weeks 8 and 16 | 
| Percentage of Participants Who Achieved an EASI 75 Response at Week 8 | EASI is a tool to measure the extent and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the percentage of skin affected, and the severity of eczema (scored as none [0], mild [1], moderate [2], or severe [3]) for redness, thickness, scratching, and lichenification are assessed. The EASI score is the sum of the scores for each region and ranges from 0 to 72, where higher scores represent worse disease. An EASI 75 response is defined as participants with at least a 75% reduction (improvement) in EASI score relative to the Baseline value. Participants with missing values at Week 8 were counted as non-responders in this analysis (non-responder imputation). | Baseline and Week 8 | 
| Percentage of Participants Who Achieved an EASI 50 Response at Weeks 8 and 16 | EASI is a tool to measure the extent and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the percentage of skin affected, and the severity of eczema (scored as none [0], mild [1], moderate [2], or severe [3]) for redness, thickness, scratching, and lichenification are assessed. The EASI score is the sum of the scores for each region and ranges from 0 to 72, where higher scores represent worse disease. An EASI 50 response is defined as participants with at least a 50% reduction (improvement) in EASI score relative to the Baseline value. Participants with missing values at each time point were counted as non-responders in this analysis (non-responder imputation). | Baseline and Weeks 8 and 16 | 
| Percentage of Participants Who Achieved an EASI 90 Response at Weeks 8 and 16 | EASI is a tool to measure the extent and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the percentage of skin affected, and the severity of eczema (scored as none [0], mild [1], moderate [2], or severe [3]) for redness, thickness, scratching, and lichenification are assessed. The EASI score is the sum of the scores for each region and ranges from 0 to 72, where higher scores represent worse disease. An EASI 90 response is defined as participants with at least a 90% reduction (improvement) in EASI score relative to the Baseline value. Participants with missing values at each time point were counted as non-responders in this analysis (non-responder imputation). | Baseline and Weeks 8 and 16 | 
| Percentage of Participants Who Achieved a SCORAD 50 Response at Weeks 8 and 16 | SCORAD is a clinical tool used to assess the extent and severity of eczema (SCORing Atopic Dermatitis). The extent is assessed using the rule of 9 to calculate the affected area (A) as a percentage of the whole body (0-100%). The intensity part of the SCORAD (B) consists of 6 items: erythema, oedema/papulation, excoriations, lichenification, oozing/crusts and dryness, each graded on a scale from 0 (none) to 3 (severe), for a total score of 0 to 18. Subjective items (C) include daily pruritus and sleeplessness, each scored on a visual analogue scale (VAS) from 0 to 10 (total score 0-20). SCORAD is calculated as A/5 + 7B/2 + C, and ranges from 0 to 103 (worst). A SCORAD 50 response is defined as participants with at least a 50% reduction (improvement) in SCORAD score relative to the Baseline value. Participants with missing values were counted as non-responders in this analysis (non-responder imputation). | Baseline and Weeks 8 and 16 | 
| Percentage of Participants Who Achieved a SCORAD 75 Response at Weeks 8 and 16 | SCORAD is a clinical tool used to assess the extent and severity of eczema (SCORing Atopic Dermatitis). The extent is assessed using the rule of 9 to calculate the affected area (A) as a percentage of the whole body (0-100%). The intensity part of the SCORAD (B) consists of 6 items: erythema, oedema/papulation, excoriations, lichenification, oozing/crusts and dryness, each graded on a scale from 0 (none) to 3 (severe), for a total score of 0 to 18. Subjective items (C) include daily pruritus and sleeplessness, each scored on a visual analogue scale (VAS) from 0 to 10 (total score 0-20). SCORAD is calculated as A/5 + 7B/2 + C, and ranges from 0 to 103 (worst). A SCORAD 75 response is defined as participants with at least a 75% reduction (improvement) in SCORAD score relative to the Baseline value. Participants with missing values were counted as non-responders in this analysis (non-responder imputation). | Baseline and Weeks 8 and 16 | 
| Percentage of Participants Who Achieved a SCORAD 90 Response at Weeks 8 and 16 | SCORAD is a clinical tool used to assess the extent and severity of eczema (SCORing Atopic Dermatitis). The extent is assessed using the rule of 9 to calculate the affected area (A) as a percentage of the whole body (0-100%). The intensity part of the SCORAD (B) consists of 6 items: erythema, oedema/papulation, excoriations, lichenification, oozing/crusts and dryness, each graded on a scale from 0 (none) to 3 (severe), for a total score of 0 to 18. Subjective items (C) include daily pruritus and sleeplessness, each scored on a visual analogue scale (VAS) from 0 to 10 (total score 0-20). SCORAD is calculated as A/5 + 7B/2 + C, and ranges from 0 to 103 (worst). A SCORAD 90 response is defined as participants with at least a 90% reduction (improvement) in SCORAD score relative to the Baseline value. Participants with missing values were counted as non-responders in this analysis (non-responder imputation). | Baseline and Weeks 8 and 16 | 
| Percent Change From Re-randomization (Week 16) in EASI Score in Period 2 | 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; a negative change from Baseline indicates improvement. | Re-randomization (Week 16) and Weeks 20, 24, 32, 40, 52, 64, 76, and 88 | 
| Time to Loss of EASI 50 Response Relative to Baseline Among Participants Re-randomized as EASI 75 Responders at Week 16 | Time to loss of EASI 50 response in Period 2 relative to Baseline among those who were re-randomized as EASI 75 responders at Week 16. Time to loss of EASI 50 response was measured from Week 16 to the date of the first assessment in Period 2 where a participant's EASI score was higher than 50% of their Baseline score. Participants with no loss of response were censored at their last treatment visit or the start of rescue treatment, whichever occurred first. | From re-randomization at Week 16 until Week 88 | 
| Percentage of Participants With an EASI 75 Response in Period 2 in Participants Who Were Re-randomized as EASI 75 Non-responders at Week 16 | EASI is a tool to measure the extent and severity of atopic eczema based on assessments of the head/neck, trunk, upper limbs and lower limbs. For each region the percentage of skin affected, and the severity of eczema (scored as none [0], mild [1], moderate [2], or severe [3]) for redness, thickness, scratching, and lichenification are assessed. The EASI score is the sum of the scores for each region and ranges from 0 to 72, where higher scores represent worse disease. An EASI 75 response is defined as at least a 75% reduction (improvement) in EASI score relative to the Baseline value, and was analyzed in participants who were re-randomized at Week 16 and were EASI 75 non-responders at Week 16. | Weeks 20, 24, 32, 40, 52, 64, 76, and 88 | 
| Percentage of Participants Who Achieved a Dermatology Life Quality Index (DLQI) of 0 or 1 at Weeks 8 and 16 | The DLQI is a 10-item questionnaire that asks participants to evaluate the degree that psoriasis has affected their quality of life in the last week in the following 6 aspects: symptoms and feelings, daily activities, leisure, work or school activities, personal relationships and treatment related feelings. Participants answer the 10 questions on a scale from 0 (not at all) to 3 (very much). The DLQI is calculated by summing the scores of the 10 questions, resulting in a maximum of 30 and a minimum of 0 with higher scores indicating more impaired quality of life. A score of 0 or 1 means that the disease has no effect at all. Dermatology Life Quality Index outcomes were defined but are not reported because of an error in the programming of the electronic device used to administer the questionnaire that precluded determination of these outcomes. | Weeks 8 and 16 | 
| Change From Baseline in DLQI at Weeks 8 and 16 | The DLQI is a 10-item questionnaire that asks participants to evaluate the degree that psoriasis has affected their quality of life in the last week in the following 6 aspects: symptoms and feelings, daily activities, leisure, work or school activities, personal relationships and treatment related feelings. Participants answer the 10 questions on a scale from 0 (not at all) to 3 (very much). The DLQI is calculated by summing the scores of the 10 questions, resulting in a maximum of 30 and a minimum of 0 with higher scores indicating more impaired quality of life. A negative change from Baseline indicates improvement. Dermatology Life Quality Index outcomes were defined but are not reported because of an error in the programming of the electronic device used to administer the questionnaire that precluded determination of these outcomes. | Baseline and Weeks 8 and 16 | 
| Change From Baseline in Percentage of Body Surface Area (BSA) Affected by Atopic Dermatitis at Week 16 | Body surface area (BSA) affected by atopic dermatitis was assessed by the physician and is expressed as a percentage of the total BSA. For purposes of the estimation, the total surface of the participant's palm plus five digits was assumed to be approximately equivalent to 1% BSA. Last observation carried forward imputation was used. | Baseline and Week 16 | 
| Percentage of Participants With Reduction of ≥ 4 Points From Baseline in Pruritus NRS at Week 16 | Participants were asked to rate pruritus (itch) in the past 24 hours on a daily basis using a scale from 0 to 10, with 0 being no itch and 10 being the worst imaginable itch. The percentage of participants with reduction of ≥ 4 points from Baseline in pruritus NRS was assessed in participants with a baseline pruritus NRS of ≥ 4. Participants with missing values at Week 16 were counted as non-responders in this analysis (non-responder imputation). | Baseline and Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ABT-494, Atopic Dermatitis