Study of Abrocitinib Compared With Dupilumab in Adults With Moderate to Severe Atopic Dermatitis on Background Topical Therapy

Study Overview
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Brief Summary
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This is a randomized, double-blind, double-dummy, active-controlled, multi-center study to assess the efficacy and safety of abrocitinib 200 mg (2 x 100 mg tablets) administered orally QD compared with dupilumab 300 mg administered by subcutaneous injection every other week (as per label guidelines) in adult participants on background topical therapy, with moderate to severe AD. The treatment duration is 26 weeks. A total of approximately 600 participants will be enrolled from approximately 220 sites globally. Approximately 600 participants will be randomly assigned to study intervention. There are primary efficacy assessments at Week 2 and Week 4, and a key secondary efficacy assessment at Week 16. Efficacy and safety endpoints will be assessed throughout the entire study. Exploratory endpoints related to hand eczema efficacy will be assessed throughout the study.

Official Title
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A PHASE 3B RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, ACTIVE CONTROLLED MULTI-CENTER STUDY ASSESSING THE EFFICACY AND SAFETY OF ABROCITINIB COMPARED WITH DUPILUMAB IN ADULT PARTICIPANTS ON BACKGROUND TOPICAL THERAPY WITH MODERATE TO SEVERE ATOPIC DERMATITIS

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: Abrocitinib 200 mg
* Combination Product: Dupilumab 300 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Diagnosis of chronic atopic dermatitis (AD) for at least 6 months Moderate to severe AD (BSA at least 10%, IGA at least 3, EASI at least 16, and PP-NRS severity score at least 4) Recent history of inadequate response to treatment with medicated topical therapy for AD, or who have required systemic therapies for control of their disease Exclusion Criteria: Acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation Have increased risk of developing venous thromboembolism Unwilling to discontinue current AD medications prior to the study or require treatment with prohibited medications during the study Prior treatment with systemic JAK inhibitors or IL-4 or IL-13 antagonists including dupilumab, lebrikizumab or tralokinumab Other active non-AD inflammatory skin diseases or conditions affecting skin Medical history including thrombocytopenia, coagulopathy or platelet dysfunction, malignancies, current or history of certain infections, lymphoproliferative disorders and other medical conditions at the discretion of the investigator Pregnant or breastfeeding women, or women of childbearing potential who are unwilling to use contraception

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: Abrocitinib 200 mg plus placebo injection<br>Abrocitinib 200 mg daily through Week 26, plus placebo injections every other week through Week 24 | Drug: Abrocitinib 200 mg<br>* Abrocitinib 200 mg administered as two 100 mg tablets to be taken orally once daily for 26 weeks. Placebo injections will be administered every other week for 24 weeks.<br>|
| Active Comparator: Dupilumab 300 mg plus placebo tablets<br>Dupilumab 300 mg every other week (2 injections on Day 1) through Week 24, plus placebo tablets daily through Week 26 | Combination Product: Dupilumab 300 mg<br>* Dupilumab 300 mg administered as a single subcutaneous injection every other week for 24 weeks (2 injections on day 1). Placebo tablets will be administered daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Greater Than or Equal to (>=) 4 Points Improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) From Baseline at Week 2 | The severity of itch (pruritus) due to atopic dermatitis (AD) was assessed using the PP-NRS, a validated horizontal NRS. Participants were asked to assess their worst itching due to AD over the past 24 hours on an NRS with scale ranging from 0 to 10, where 0= no itch and 10= worst itch imaginable. Higher scores indicated worse itch. | Week 2 | 
| Percentage of Participants Achieving >= 90% Improvement From Baseline in Eczema Area and Severity Index (EASI-90) Response at Week 4 | EASI quantifies severity of AD based on severity of lesion clinical signs and percentage (%) of body surface area (BSA) affected. Severity of clinical signs of AD lesions (erythema, induration/papulation, excoriation and lichenification) were scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin)] and lower limbs [including buttocks]) on a 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based on % BSA with AD in body region: 0 (0%), 1 (>0 to <10%), 2 (10 to <30%), 3 (30 to <50%), 4 (50 to <70%), 5 (70 to <90%) and 6 (90 to 100%). Total EASI score =0.1*Ah*(Eh+Ih+Exh+Lh) + 0.2*Au*(Eu+Iu+ExU+Lu) + 0.3*At*(Et+It+Ext+Lt) + 0.4*Al*(El+Il+Exl+Ll); A = EASI area score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs. Total EASI score ranged from 0.0 to 72.0, with higher scores indicating greater severity of AD. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving EASI-90 Response at Week 16 | EASI quantifies severity of AD based on severity of lesion clinical signs and % of BSA affected. Severity of clinical signs of AD lesions (erythema, induration/papulation, excoriation and lichenification) were scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin)] and lower limbs [including buttocks]) on a 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based on % BSA with AD in body region: 0 (0%), 1 (>0 to <10%), 2 (10 to <30%), 3 (30 to <50%), 4 (50 to <70%), 5 (70 to <90%) and 6 (90 to 100%). Total EASI score =0.1*Ah*(Eh+Ih+Exh+Lh) + 0.2*Au*(Eu+Iu+ExU+Lu) + 0.3*At*(Et+It+Ext+Lt) + 0.4*Al*(El+Il+Exl+Ll); A = EASI area score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs. Total EASI score ranged from 0.0 to 72.0, with higher scores indicating greater severity of AD. | Week 16 | 
| Percentage of Participants Achieving EASI-90 Response at Weeks 2, 8, 12, 20 and 26 | EASI quantifies severity of AD based on severity of lesion clinical signs and % of BSA affected. Severity of clinical signs of AD lesions (erythema, induration/papulation, excoriation and lichenification) were scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin)] and lower limbs [including buttocks]) on a 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based on % BSA with AD in body region: 0 (0%), 1 (>0 to <10%), 2 (10 to <30%), 3 (30 to <50%), 4 (50 to <70%), 5 (70 to <90%) and 6 (90 to 100%). Total EASI score =0.1*Ah*(Eh+Ih+Exh+Lh) + 0.2*Au*(Eu+Iu+ExU+Lu) + 0.3*At*(Et+It+Ext+Lt) + 0.4*Al*(El+Il+Exl+Ll); A = EASI area score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs. Total EASI score ranged from 0.0 to 72.0, with higher scores indicating greater severity of AD. | Week 2, 8, 12, 20 and 26 | 
| Percentage of Participants Achieving >= 75% Improvement From Baseline in EASI (EASI-75) Response at Weeks 2, 4, 8, 12, 16, 20 and 26 | EASI quantifies severity of AD based on severity of lesion clinical signs and % of BSA affected. Severity of clinical signs of AD lesions (erythema, induration/papulation, excoriation and lichenification) were scored separately for each of 4 body regions (head and neck, upper limbs, trunk [including axillae and groin)] and lower limbs [including buttocks]) on a 4-point scale: 0= absent; 1= mild; 2= moderate; 3= severe. EASI area score was based on % BSA with AD in body region: 0 (0%), 1 (>0 to <10%), 2 (10 to <30%), 3 (30 to <50%), 4 (50 to <70%), 5 (70 to <90%) and 6 (90 to 100%). Total EASI score =0.1*Ah*(Eh+Ih+Exh+Lh) + 0.2*Au*(Eu+Iu+ExU+Lu) + 0.3*At*(Et+It+Ext+Lt) + 0.4*Al*(El+Il+Exl+Ll); A = EASI area score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs. Total EASI score ranged from 0.0 to 72.0, with higher scores indicating greater severity of AD. | Week 2, 4, 8, 12, 16, 20 and 26 | 
| Percentage of Participants Achieving Investigator's Global Assessment (IGA) Score of 'Clear' or 'Almost Clear' and >=2 Points Improvement From Baseline up to Week 26 | IGA assessed severity of AD on a 5 point scale (0 to 4, higher scores indicate more severity). Scores: 0= clear, except any residual discoloration (post-inflammatory hyperpigmentation and/or hypopigmentation); 1= almost clear, AD not fully cleared- light pink residual lesions (except post-inflammatory hyperpigmentation), just perceptible erythema, papulation/induration lichenification, excoriation, and no oozing/crusting; 2= mild AD with light red lesions, slight but definite erythema, papulation/induration, lichenification, excoriation and no oozing/crusting; 3= moderate AD with red lesions, moderate erythema, papulation/induration, lichenification, excoriation and slight oozing/crusting; 4= severe AD with deep dark red lesions, severe erythema, papulation/induration, lichenification, excoriation and moderate to severe oozing/crusting. | Week 2, 4, 8, 12, 16, 20 and 26 | 
| Percentage of Participants Achieving PP-NRS4 From Baseline at Days 2 to 15 | The severity of itch (pruritus) due to AD was assessed using the PP-NRS, a validated horizontal NRS. Participants were asked to assess their worst itching due to AD over the past 24 hours on an NRS with scale ranging from 0 to 10, where 0= no itch and 10= worst itch imaginable. Higher scores indicated worse itch. | Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 | 
| Percentage of Participants Achieving PP-NRS4 From Baseline at Week 4, 8, 12, 16, 20 and 26 | The severity of itch (pruritus) due to AD was assessed using the PP-NRS, a validated horizontal NRS. Participants were asked to assess their worst itching due to AD over the past 24 hours on an NRS with scale ranging from 0 to 10, where 0= no itch and 10= worst itch imaginable. Higher scores indicated worse itch. | Week 4, 8, 12, 16, 20 and 26 | 
| Time to Achieve >=4 Points Improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) | The severity of itch (pruritus) due to AD was assessed using the PP-NRS, a validated horizontal NRS. Participants were asked to assess their worst itching due to AD over the past 24 hours on an NRS with scale ranging from 0 to 10, where 0= no itch and 10= worst itch imaginable. Higher scores indicated worse itch. | Baseline (Day 1) up to Week 30 | 
| Percent Change From Baseline in the Percentage (%) Body Surface Area (BSA) Affected at Week 2, 4, 8, 12, 16, 20 and 26 | The extent (%) to which a body region was involved with AD was determined using handprint method. Number of handprints (size of participant's hand with fingers in a closed position) fitting in the affected area of a body region was estimated. Four body regions were evaluated: head and neck, upper limbs, trunk (including axillae and groin/genitals) and lower limbs (including buttocks). Total number of handprints were 10 for head and neck, 20 for upper limbs, 30 for trunk and 40 for lower limbs. Surface area of body region equivalent to 1 handprint: 1 handprint was equal to 10% for head and neck, 5% for upper limbs, 3.33% for trunk and 2.5% for lower limbs. Percent BSA for a body region was calculated as = total number of handprints in a body region * % surface area equivalent to 1 handprint. Overall % BSA for an individual was derived as sum of % BSA across all 4 body regions and ranged from 0 to 100%, with higher values representing greater severity of AD. | Baseline (Day 1), Week 2, 4, 8, 12, 16, 20 and 26 | 
| Percent Change From Baseline in the SCORing Atopic Dermatitis (SCORAD) Total Score at Week 2, 4, 8, 12, 16, 20 and 26 | SCORAD is a scoring index for AD which combined extent (A), severity (B) and subjective symptoms (C). For A, a rule of 9 was used to calculate BSA affected by AD as % of whole BSA for each body region- head and neck 9%; upper limbs 9% each; lower limbs 18% each; anterior trunk 18%; back 18%; genitals 1%. Score of each body region was added to determine A (range: 0-100). B: severity of each sign (erythema; edema/papulation; oozing/crusting; excoriation; skin thickening; dryness) was assessed as none (0), mild (1), moderate (2), severe (3); severity scores were added to give B (range: 0-18). C: pruritus and sleep loss, each of these 2 were scored by participant/caregiver using visual analog scale (VAS) where, 0=no itch/no sleep loss and 10=worst imaginable itch/sleep loss, higher scores=worse symptoms. Scores for itch and sleep loss were added to give 'C' (range: 0-20). SCORAD total score was calculated as: A/5+7*B/2+C; range (0-103); higher values=worse outcome. | Baseline (Day 1), Week 2, 4, 8, 12, 16, 20 and 26 | 
| Change From Baseline in Total Anxiety Score Measured Using the Hospital Anxiety and Depression Scale (HADS) at Week 12,16 and 26 | HADS was a validated 14-item questionnaire to assess states of anxiety and depression over the past week. HADS consisted of 2 subscales: HADS-Anxiety (HADS-A) scale and HADS-Depression (HADS-D) scale, each of which comprised of 7 items. Each item was rated on a 4-point scale, with scores ranging from 0 to 3, where higher scores indicated more anxiety/depression symptoms. HADS-A assessed state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks). HADS-A total score was calculated as the sum of all 7 items with score ranging from 0 (no presence of anxiety) to 21 (severe feeling of anxiety); higher score indicated greater severity of anxiety. | Baseline (Day 1), Week 12, 16 and 26 | 
| Change From Baseline in Total Depression Score Measured Using the HADS at Week 12,16 and 26 | HADS was a validated 14-item questionnaire to assess states of anxiety and depression over the past week. HADS consisted of 2 subscales: HADS-A scale and HADS-D scale, each of which comprised of 7 items. Each item was rated on a 4-point scale, with scores ranging from 0 to 3, where higher scores indicated more anxiety/depression symptoms. HADS-D assessed the state of lost interest and diminished pleasure response (lowering of hedonic tone). HADS-D: total score was calculated as the sum of all 7 items with score ranging from 0 (no presence of depression) to 21 (severe feeling of depression); higher score indicated greater severity of depression symptoms. | Baseline (Day 1), Week 12, 16 and 26 | 
| Change From Baseline in Dermatology Life Quality Index (DLQI) Total Score at Week 2, 12, 16, 20 and 26 | DLQI is a 10-item questionnaire that measured the impact of skin disease. Each question was evaluated on a 4-point scale (range 0 to 3) where, 0 = not at all, 1= a little, 2= a lot, 3= very much, where higher scores indicated more impact on quality of life. Scores from all 10 questions were added up to give DLQI total score, ranging from 0 (not at all) to 30 (very much). Higher scores indicated more impact on quality of life of participants. | Baseline (Day 1), Week 2, 12, 16, 20 and 26 | 
| Change From Baseline in EuroQol Quality of Life 5-Dimension 5-Level (EQ-5D-5L) Visual Analog Scale (VAS) Score at Week 12, 16 and 26 | The EQ-5D-5L is a self-reported health status questionnaire that consisted of six questions used to calculate a health utility score. There were two components to the EQ-5D-5L: a five-item health state profile that assessed mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a VAS that measured health state. EQ-5D VAS was used to record participant's rating for his/her current health-related quality of life state on a vertical VAS with scores ranging from 0 to 100, where 0 = worst imaginable health state and 100 = best imaginable health state. | Baseline (Day 1), Week 12, 16 and 26 | 
| Change From Baseline in Patient-Oriented Eczema Measure (POEM) Total Score at Week 12, 16 and 26 | POEM was a 7-item participant reported outcome measure used to assess the impact of AD (dryness, itching, flaking, cracking, sleep loss, bleeding and weeping) over the past week. Each item was scored as: no days=0, 1-2 days=1, 3-4 days=2, 5-6 days=3 and every day=4. The item scores were added to provide a total score ranging from 0 to 28, where higher score indicated greater severity. | Baseline (Day 1), Week 12, 16 and 26 | 
| Change From Baseline in Medical Outcomes Study - Sleep Scale (MOS-Sleep Scale) at Week 12, 16 and 26 | The MOS Sleep Scale is a 12-item measure that is segregated into subscales addressing seven sleep domains (i.e. sleep disturbance, snoring, short of breath or headache, adequacy of sleep, somnolence, sleep problems index I and sleep problems index II). An additional single item assessed quantity of sleep. Each of the sleep domains were scored on a range of 0 to 100, and higher scores indicated worse outcomes. The quantity of sleep scores ranged from 0 to 24 (number of hours slept). Change from baseline scores for each individual sleep domain and quantity of sleep are reported in this outcome measure. | Baseline (Day 1), Week 12, 16 and 26 | 
| Change From Baseline in Skin Pain NRS at Week 2, 12, 16, 20 and 26 | The skin pain NRS was a participant reported outcome where participants were asked to rate the worst skin pain in the past 24 hours on a 11-point scale from 0=no skin pain to 10=worst skin pain imaginable. Higher scores indicated worse pain. | Baseline (Day 1), Week 2, 12, 16, 20 and 26 | 
| Medicated Topical Background Therapy-free Days | Medicated topical background therapy-free days was defined as number of days where a participant maintained a response of EASI-90 or greater without the use of medicated topical background therapy. | Day 1 up to Week 26 | 
| Percentage of Participants Achieving >=4 Points Improvement From Baseline in DLQI at Week 2, 12, 16, 20 and 26 | DLQI was a 10-item questionnaire that measured the impact of skin disease. Each question was evaluated on a 4-point scale (range 0 to 3) where, 0 = not at all, 1= a little, 2= a lot, 3= very much, where higher scores indicated more impact on quality of life. Scores from all 10 questions were added up to give DLQI total score range from 0 (not at all) to 30 (very much). Higher scores indicated more impact on quality of life of participants. | Week 2, 12, 16, 20 and 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atopic dermatitis, atopic eczema, eczema, JAK, janus kinase