Study Evaluating the Mechanism of Action of PF-04965842 Monotherapy for Moderate-to-severe Atopic Dermatitis

Study Overview
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Brief Summary
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B7451037 is a randomized, double-blind, placebo-controlled, parallel-group, Phase 2a study to investigate the mechanism of action of PF-04965842 by correlating efficacy outcomes with changes from baseline in key skin and blood biomarkers in adult participants at least 18 years of age with moderate-to-severe atopic dermatitis. Participants will be screened within 28 days prior to the first dose of study intervention to confirm eligibility. A total of approximately 51 participants will be randomized in a 1:1:1 ratio to receive PF-04965842 200 mg once daily (QD), PF004965842 100 mg QD, or matching placebo QD for 12 weeks. At the end of the 12-week study treatment, qualified participants will have the option to enter the long-term extension study B7451015 (NCT03422822). Participants discontinuing early from this study will undergo a 4-week off-treatment follow-up period.

Official Title
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A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP, MULTI-CENTER STUDY TO INVESTIGATE THE MECHANISM OF ACTION OF ABROCITINIB MONOTHERAPY IN ADULT PARTICIPANTS WITH MODERATE-TO-SEVERE ATOPIC DERMATITIS

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: PF-04965842 200 mg
* Drug: PF-04965842 100 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of chronic moderate-to-severe atopic dermatitis (AD) for at least 1 year Recent history of inadequate response to medicated topical therapy for AD or required systemic therapy to control disease Moderate-to-severe AD defined as affected BSA at least 10%, IGA at least 3, EASI at least 16, Peak Pruritus NRS at least 4 Exclusion Criteria: A current or past medical history of conditions associated with thrombocytopenia, coagulopathy, or platelet dysfunction Currently have active forms of other inflammatory skin diseases, i.e. not AD, or have evidence of skin conditions (e.g. psoriasis, seborrheic dermatitis, lupus) at the time of Day 1 that would interfere with evaluation of AD or response to treatment Participants who have received prior treatment with any systemic JAK inhibitors Require treatment with prohibited concomitant medication(s) or have received a prohibited concomitant medication within specified time frames prior to the first dose of study medication, including topical treatments that could affect AD Pregnant or breastfeeding women or sexually-active 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: PF-04965842 200 mg<br> | Drug: PF-04965842 200 mg<br>* PF-04965842 200 mg administered as two tablets to be taken orally once daily for 12 weeks<br>|
| Experimental: PF-04965842 100 mg<br> | Drug: PF-04965842 100 mg<br>* PF-04965842 100 mg administered as two tablets to be taken orally once daily for 12 weeks<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo administered as two tablets to be taken orally once daily for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold-Change From Baseline in Atopic Dermatitis Biomarkers in Lesional and Non-lesional Skin at Week 12 | Mean fold-changes from baseline at Week 12 in the biomarkers for general inflammation (Matrix Metallopeptidase [MMP]12), hyperplasia (Keratin [KRT]16), Th2 immune response (C-C motif chemokine ligand [CCL]17, CCL18, CCL26), and Th22 immune response (S100 calcium binding protein A [S100A]8, S100A9, S100A12), in lesional (LS) and non-lesional (NL) skin tissues, respectively. Expression levels from RT-PCR are normalized to the housekeeping gene RPLP0 by negatively transforming the Ct values to -dCt. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold-Change From Baseline in Cellular (T-cell and Dendritic Cell) Inflammation Markers at Week 12 | Mean fold-changes from baseline in immunohistochemistry analysis in lesional skin endpoints at Week 12 are presented. Fold-changes are computed by obtaining the antilog of log2 fold-changes, retaining the sign for log2 fold-change. | Baseline, Week 12 | 
| Fold-Change From Baseline in Epidermal Hyperplasia Markers in Skin Biopsies and Skin Thickness at Week 12 | Mean fold-changes from baseline in hyperplasia markers in skin biopsies at Week 12 are presented. Fold-changes are computed by obtaining the antilog of log2 fold-changes, retaining the sign for log2 fold-change. | Baseline, Week 12 | 
| Fold-Change From Baseline in Blood Biomarkers for Inflammation and Immune Response at Week 12 | OLINK Proteomics Microassay was used to analyze biomarkers in serum to assess the effect of abrocitinib on the blood biomarkers. Mean fold-changes at Week 12 from baseline are listed. Baseline is defined as the last observation on or prior to day of first dose (Day 1). | Baseline, Week 12 | 
| Percent-Change From Baseline in T-cell Lymphocyte Subset Populations at Week 12 | Mean percent changes from baseline at Week 12 in T-cell lymphocyte subset populations (CD3+ T cells, CD4+ T cells, CD8+ T cells, NK cells, B cells) are presented. Baseline is defined as the last observation on or prior to day of first dose (Day 1). | Baseline, Week 12 | 
| Response Based on at Least 4 Points Improvement in the Severity of Peak Pruritus Numerical Rating Scale (NRS) From Baseline and Changes From Baseline in Immunohistochemistry (IHC) and Gene Expression Biomarkers in Lesional Skin | PP-NRS assesses the severity of itch (pruritus) due to AD. Participants were asked to assess their worst itching due to AD on an NRS anchored by the terms no itch (0) and worst itch imaginable (10). Participants who withdrew from the study were counted as non-responder. Spearman correlation coefficient was calculated to assess the relationship between PP-NRS CFB and fold CFB of IHC and gene expression biomarkers. | Baseline, Week 12 | 
| Percentage of Participants Achieving Investigator's Global Assessment (IGA) Response of 'Clear' or 'Almost Clear' and >=2 Points Improvement From Baseline at Week 2, 4, 8 and 12 | The IGA of AD is scored on a 5-point scale (0-4), reflecting a global consideration of the erythema, induration and scaling. The overall severity of AD was assessed according to the 5-point scale: 0=Clear, 1=Almost Clear, 2=Mild, 3=Moderate, and 4=Severe. Participants who withdrew from the study were counted as non-responder. | Baseline, Weeks 2, 4, 8, and 12 | 
| Percentage of Participants Achieving Eczema Area and Severity Index (EASI) Response ≥ 75% Improvement From Baseline Week 2, 4, 8 and 12 | The EASI quantifies the severity of AD based on both severity of lesion clinical signs and the percent of body surface area (BSA) affected. The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores representing greater severity of AD. Participants who withdrew from the study were counted as non-responder. | Baseline, Week 2, 4, 8, and 12 | 
| Percentage of Participants With >=4 Points at Baseline and Achieving >=4 Points Improvement From Baseline in Numeric Rating Scale for Severity of Pruritus (PP-NRS) at Weeks 2, 4, 8 and 12 | PP-NRS assesses the severity of itch (pruritus) due to AD. Participants were asked to assess their worst itching due to AD on an NRS anchored by the terms no itch (0) and worst itch imaginable (10). Higher scores indicated worse itch. Participants who withdrew from the study were counted as non-responder. | Baseline, Week 2, 4, 8, 12 | 
| Percentage of Participants Achieving EASI Response ≥ 90% Improvement From Baseline at Week 2, 4, 8 and 12 | The EASI quantifies the severity of AD based on both severity of lesion clinical signs and the percent of BSA affected. The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores representing greater severity of AD. Participants who withdrew from the study were counted as non-responder. | Baseline to Week 2, 4, 8 and 12 | 
| Percentage of Participants Achieving EASI Response ≥ 50% Improvement From Baseline at Week 2, 4, 8 and 12 | The EASI quantifies the severity of AD based on both severity of lesion clinical signs and the percent of BSA affected. The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores representing greater severity of AD. Participants who withdrew from the study were counted as non-responder. | Baseline to Week 2, 4, 8 and 12 | 
| Percent Change From Baseline in Percentage Body Surface Area (BSA) at Week 2, 4, 8 and 12 | BSA efficacy is derived from the sum of the BSA in handprints across 4 body regions assessed as part of the EASI assessment. Handprint refers to that of each individual participant for their own measurement. The BSA efficacy ranges from 0 to 100%, with higher values representing greater severity of AD. The percentage BSA ranges from 0 to 100, with higher scores representing greater severity of AD. Since the scalp, palms, and soles were excluded from the BSA (efficacy) assessment, the maximum possible percentage BSA was less than 100. | Baseline and Week 2, 4, 8 and 12 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. TEAEs were AEs that occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. | Baseline to 16 weeks | 
| Number of Participants With Serious Adverse Events (SAEs) | A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Treatment-related SAEs were determined by the investigator. | Baseline to 16 weeks | 
| Number of Participants Who Discontinued From the Study Due to TEAEs | An AE was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. TEAEs were AEs that occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. | Baseline to 16 weeks | 
| Number of Participants With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) | Laboratory tests included hematology (including coagulation panel), clinical chemistry, lipid profile panel, and routine urinalysis. LLN is lower limit of normal. ULN is upper limit of normal. | Baseline to 16 weeks | 

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