Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis: The JADE TEEN Randomized Clinical Trial (2024)

Study Design and Participants

JADE TEEN was a multicenter, international, phase 3, randomized, placebo-controlled, parallel-group study conducted between February 18, 2019, and April 8, 2020, in Australia, China, Czech Republic, Germany, Hungary, Italy, Japan, Latvia, Mexico, Poland, Spain, Taiwan, the UK, and the US (Supplement 1 and Supplement 2). Patients were screened within 28 days of the first dose followed by treatment with a study drug for 12 weeks. Eligible patients were aged 12 to 17 years with a body weight of 55 lb or greater (limit determined based on pharmaco*kinetic modeling) and a confirmed diagnosis of AD according to the diagnostic criteria of Hanifin and Rajka.¹⁵ Patients had moderate-to-severe AD (Investigator’s Global Assessment [IGA] score of ≥3; Eczema Area and Severity Index [EASI]¹⁶ score of ≥16; affected percentage of body surface area [BSA], ≥10; and Peak Pruritus Numerical Rating Scale [PP-NRS (used with permission of Regeneron Pharmaceuticals and Sanofi SA)] score of ≥4¹⁷) at baseline. Patients had a documented history of inadequate responses to treatment with medicated topical therapy for AD that was given for 4 consecutive weeks or longer within 6 months before screening, or had been treated with systemic therapy for AD within 6 months before screening or were candidates for systemic therapy for AD. Because JAK inhibition has the potential to increase the risk of varicella-zoster virus infection,¹⁸ prior documentation of varicella-zoster virus immunity was required for inclusion. Patients with substantial psychiatric conditions or with current or past medical history of conditions that were associated with thrombocytopenia, coagulopathy, platelet dysfunction, or disseminated herpes were excluded; those with a history of herpes labialis were allowed to participate. Patients were required to wash out prior AD treatments (eg, biologic therapies, including dupilumab, immunosuppressive drugs, and medicated topical therapies) before study initiation. Standardized regimens of nonmedicated topical emollients and medicated topical therapy were required during the study, as detailed in the eMethods in Supplement 3. Patients were permitted to use oral antihistamines.

The study was conducted in compliance with ethical principles from the Declaration of Helsinki and all International Council for Harmonisation Good Clinical Practice Guidelines. All local regulatory requirements were followed. This research was approved by institutional review boards or ethics committees at each study site. An independent data monitoring committee monitored patient safety. All patients or their legal guardian provided written informed consent.

Randomization and Masking

Patients were randomly assigned 1:1:1 to receive oral, once-daily abrocitinib, 200 mg or 100 mg, or placebo with medicated topical therapy for 12 weeks. Randomization was stratified by baseline disease severity (moderate vs severe) and administered via an interactive response technology system. Patients, investigators, and sponsors were masked to the study treatment.

Outcome Measures

Coprimary, multiplicity-controlled efficacy end points were the proportion of patients who achieved an IGA response (clear [0] or almost clear [1] and improvement of ≥2 grades from baseline) and/or EASI-75 response (≥75% improvement from baseline) at week 12. Key secondary, multiplicity-controlled efficacy end points were the proportion of patients who achieved an improvement of 4 points or more in PP-NRS score (PP-NRS4) from baseline at weeks 2, 4, and 12 and a change from baseline in Pruritus and Symptoms Assessment for AD (PSAAD)¹⁹ total score at week 12. The PP-NRS score was recorded daily from days 1 to 15 and at weeks 4, 8, and 12; daily PP-NRS values were used directly rather than averaged weekly. The PSAAD score was recorded daily. Both end points were recorded by patients using a handheld device. Secondary and other efficacy end points that were not controlled for multiplicity were the proportion of patients who achieved IGA and EASI-75 responses at weeks 2, 4, and 8 and PP-NRS4 response at week 8; time to achieve a PP-NRS4 response; proportion of patients who achieved an EASI-50 response (≥50% improvement from baseline), EASI-90 response (≥90% improvement from baseline), EASI-100 response (100% improvement from baseline), Scoring of AD index (SCORAD)–50 response (≥50% improvement from baseline), SCORAD-75 response (≥75% improvement from baseline); and change from baseline in SCORAD subjective assessments of itch and sleep loss at weeks 2, 4, 8, and 12.²⁰ Patient-reported outcomes included change from baseline at week 12 in the Children’s Dermatology Life Quality Index (CDLQI),²¹ Patient-Oriented Eczema Measure (POEM),²² and Dermatitis Family Impact (DFI).²³ Incidence of adverse events (AEs), serious AEs, and AEs that led to discontinuation were recorded. Vital signs, 12-lead electrocardiogram, serum chemistry/hematology, high-sensitivity C-reactive protein levels, and urinalysis were assessed at baseline and weeks 2, 4, 8, and 12. A lipid panel was conducted at baseline and weeks 4 and 12.

Statistical Analysis

Sample size calculation was based on the Fisher exact test for comparing 2 proportions (eMethods in Supplement 3). Familywise type 1 error rates for testing coprimary and key secondary end points were strictly controlled at 5% using a sequential, Bonferroni-based procedure (eMethods and eFigure 1 in Supplement 3). Testing of all other secondary end points was performed at a nominal 5% significance level and was not controlled for multiplicity. For all binary end points, patients who permanently discontinued the study were defined as nonresponders at all visits after discontinuation. Statistical analyses were conducted using SAS, version 9.4 (SAS Institute). Additional details of the statistical analyses are presented in the eMethods in Supplement 3.

Patients

In total, 273 patients completed JADE TEEN (Figure 1). The median (interquartile range) age was 15.0 (13.0-17.0) years (Table 1). A total of 160 (56.1%) were White, 94 (33.0%) were Asian, and 17 (6.0%) were Black. Seventy-six (26.7%) identified as Hispanic or Latino. Prior medication use is shown in Table 1. Most patients had moderate disease (175 [61.4%]) per their IGA score.

Efficacy

At week 12, IGA responses occurred in 43 (46.2%), 37 (41.6%), and 23 (24.5%) patients in the abrocitinib 200-mg, abrocitinib 100-mg, and placebo groups, respectively (eTable in Supplement 3; Figure 2A). Differences in IGA response rates at week 12 vs placebo for abrocitinib, 200 mg and 100 mg, were 20.6% (95% CI, 7.3%-33.9%; P < .05) and 16.7% (95% CI, 3.5%-29.9%; P < .05) (eTable in Supplement 3). At week 12, EASI-75 responses occurred in 67 (72.0%), 61 (68.5%), and 39 (41.5%) patients in the abrocitinib, 200 mg, 100 mg, and placebo groups, respectively (eTable in Supplement 3; Figure 2B). Differences in EASI-75 response rates vs placebo for abrocitinib, 200 mg and 100 mg, were 29.4% (95% CI, 16.3%-42.5%; P < .05) and 26.5% (95% CI, 13.1%-39.8%; P < .05) (eTable in Supplement 3). The proportion of patients who achieved IGA and EASI-75 responses was higher with abrocitinib treatment at each time assessed compared with placebo. Sensitivity analyses performed for coprimary end points using the per-protocol analysis set at week 12 (eMethods in Supplement 3) yielded similar results.

The proportions of patients who achieved EASI-50 and EASI-90 responses were higher for the abrocitinib groups than for placebo from weeks 2 to 12 (eTable and eFigure 2 in Supplement 3). The least-squares mean percentage change from baseline in EASI at week 12 was −80.6 (95% CI, −86.5 to −74.8), −77.3 (95% CI, −83.1 to −71.5), and −63.7 (95% CI, −69.5 to −57.9) in the abrocitinib 200-mg, abrocitinib 100-mg, and placebo groups, respectively.

The proportion of patients who achieved a PP-NRS4 response was significantly higher for the abrocitinib groups than placebo (eTable in Supplement 3; Figure 3A). Differences in PP-NRS scores between the abrocitinib groups vs placebo were observed within 2 days of dose 1 (Figure 3B). The median time to a PP-NRS4 response was 29.0 (95% CI, 15.0-61.0) days, 70.0 (95% CI, 30.0-85.0) days, and 90.0 (95% CI, 62.0-not evaluable) in the abrocitinib 200-mg, abrocitinib 100-mg, and placebo groups, respectively (Figure 3C). Decreases from baseline in PSAAD scores were greater for each abrocitinib group vs placebo at all times assessed (eTable and eFigure 3 in Supplement 2). For the proportion of patients who achieved SCORAD-50, SCORAD-75, and a SCORAD sleep loss visual analog scale score of less than 2, responses were higher for the abrocitinib groups than placebo (eTable and eFigure 4 in Supplement 3).

Patient-Reported Outcomes

From weeks 2 to 12, adolescents reported improvement in QoL, with greater improvements in CDLQI scores for the abrocitinib groups than placebo. Improvement in disease severity measured by POEM was greater for both abrocitinib doses compared with placebo from weeks 2 to 12. Caregivers of adolescents reported improvement in QoL, with greater improvements in DFI scores for abrocitinib groups than placebo (eTable and eFigure 5 in Supplement 3).

Safety

Overall, 59 (62.8%), 54 (56.8%), and 50 (52.1%) patients in the abrocitinib 200-mg, abrocitinib 100-mg, and placebo groups, respectively, experienced treatment-emergent adverse events (TEAEs; Table 2); of these, 2 (2.1%), 0, and 2 (2.1%), respectively, were severe. Most frequently reported TEAEs were nausea in the abrocitinib, 200 mg, group (17 [18.1%]), upper respiratory tract infection in the abrocitinib, 100 mg, group (9 [9.5%]), and upper respiratory tract infection in the placebo group (10 [10.4%]). The median (interquartile range) time to onset of nausea was 2.0 (1.0-5.0), 4.0 (1.0-25.0), and 1.0 (1.0-1.0) days in the abrocitinib 200-mg, abrocitinib 100-mg, and placebo groups, respectively; the median time to resolution was 13.0 (95% CI, 3.0-87.0), 23.0 (95% CI, 1.0-86.0), and 1.0 (95% CI, NE-NE) days. Most nausea TEAEs were mild; however, there were 2 severe cases in the abrocitinib, 200 mg, group.

Serious AEs were reported for 1 (1.1%) and 2 (2.1%) patients in the abrocitinib 200-mg and placebo groups, respectively. There were no reports of serious AEs in the abrocitinib, 100 mg, group (Table 2). One patient in the abrocitinib, 200 mg, group reported a serious AE of anxiety. One patient in the placebo group developed a serious AE of angioedema due to allergy; another experienced a serious AE of worsening of AD. These events did not result in dosing changes and were not considered treatment-related per investigators.

Two (2.1%), 1 (1.1%), and 2 (2.1%) patients in the abrocitinib 200-mg, abrocitinib 100-mg, and placebo groups, respectively, discontinued treatment because of experiencing AEs (Table 2). One patient in the abrocitinib, 200 mg, group developed headache, and another developed gastroesophageal reflux, nausea, and vomiting; all were considered related to treatment. One patient in the abrocitinib, 100 mg, group developed a gastrointestinal infection, which was not considered treatment related. One patient in the placebo group developed an upper respiratory tract infection, and another developed a wound abscess; neither was considered treatment related.

Regarding AEs of special interest, cutaneous herpes zoster was reported for 1 patient (1.1%) in the abrocitinib, 100 mg, group (Table 2). Herpes simplex was reported for 1 patient (1.1%) in the abrocitinib, 200 mg, group. Oral herpes was reported for 2 (2.1%) and 1 (1.1%) patients in the abrocitinib 200-mg and abrocitinib 100-mg groups, respectively. Eczema herpeticum was reported for 1 patient (1.1%) in the abrocitinib, 100 mg group. Conjunctivitis was reported for 1 patient (1.0%) in the placebo group. Acne was reported for 5 (5.3%), 3 (3.2%), and 1 (1.0%) patients in the abrocitinib 200-mg, abrocitinib 100-mg, and placebo groups, respectively. There were no cases of serious infection, venous thromboembolism, cancers, major adverse cardiovascular events, or deaths (Table 2).

There were modest increases in total cholesterol and high- and low-density lipoprotein cholesterol levels for both abrocitinib doses vs placebo that plateaued at week 4. Among the abrocitinib 200-mg, abrocitinib 100-mg, and placebo groups, elevated (>1.2 × upper limit of normal) low-density lipoprotein cholesterol levels occurred in 3 (3.2%), 2 (2.1%), and 2 (2.1%) patients, respectively.

Dose-related decreases in median platelet cell counts were observed in patients who were treated with abrocitinib, with a nadir at week 4 (median platelet count, 229 × 10³/μL and 246 × 10³/μL [to convert to × 10⁹/L, multiply by 1] in the 200 mg and 100 mg groups, respectively) and a return toward baseline values thereafter (eFigure 6 in Supplement 3). No patients discontinued participation because of changes in platelet cell counts or bleeding disorders. There were no clinically significant changes in hemoglobin levels or neutrophil or lymphocyte cell counts. One patient met prespecified discontinuation criteria for elevated aspartate aminotransferase levels. All other observed changes in clinical laboratory values, electrocardiographic measurements, and vital signs did not lead to study discontinuation.

Limitations

Limitations include the 12-week duration; studies are needed to address long-term efficacy and safety of abrocitinib in adolescents. This study was not powered to compare the 200-mg and 100-mg abrocitinib doses. Concomitant topical therapy may have reduced a potential dose-response effect between the 100-mg and 200-mg doses of abrocitinib.

Supplement 1.

Trial protocol

Supplement 2.

Statistical analysis plan

Supplement 3.

eMethods.

eTable. Summary of Efficacy End Points and Patient-Reported Outcomes

eFigure 1. Bonferroni-Based Procedure for Testing the Coprimary and Key Secondary End Points

eFigure 2. Proportions of Patients Who Achieved (A) EASI-50 and (B) EASI-90 Responses

eFigure 3. Change From Baseline in PSAAD Score

eFigure 4. SCORing Atopic Dermatitis Scale Outcomes

eFigure 5. Patient-Reported Outcomes

eFigure 6. Median Absolute Platelet Count

Supplement 4.

Data sharing statement

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