Search

BackgroundThe validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD™) is a standardized severity assessment for use in clinical trials and registries for atopic dermatitis (AD).ObjectivesTo investigate the reliability, validity, responsiveness and within-patient meaningful change of the vIGA-AD.MethodsData were analysed from adult patients with moderate-to-severe AD in the BREEZE-AD1 (N = 624 patients; NCT03334396), BREEZE-AD2 (N = 615; NCT03334422) and BREEZE-AD5 (N = 440; NCT03435081) phase III baricitinib clinical studies.ResultsAcross studies, test-retest reliability for stable patients showed moderate-to-good agreement [range of Kappa values for Patient Global Impression of Severity-Atopic Dermatitis (PGI-S-AD), 0·516-0·639; for Eczema Area and Severity Index (EASI), 0·658-0·778]. Moderate-to-large correlations between vIGA-AD and EASI or body surface area (range at baseline, 0·497-0·736; Week 16, 0·716-0·893) supported convergent validity. Known-groups validity was demonstrated vs. EASI and PGI-S-AD (vIGA-AD for severe vs. moderate EASI categories at baseline, P

BackgroundPatients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma.ObjectiveThe aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD.MethodsThis analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates.ResultsOf 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p

Abrocitinib, an oral, once-daily, Janus kinase (JAK) 1-selective inhibitor, is approved for the treatment of adults and adolescents with moderate-to-severe atopic dermatitis (AD). Abrocitinib has shown rapid and sustained efficacy in phase 3 trials and a consistent, manageable safety profile in long-term studies. Rapid itch relief and skin clearance are more likely to be achieved with a 200-mg daily dose of abrocitinib than with dupilumab. All oral JAK inhibitors are associated with adverse events of special interest and laboratory changes, and initial risk assessment and follow-up monitoring are important. Appropriate selection of patients and adequate monitoring are key for the safe use of JAK inhibitors. Here, we review the practical use of abrocitinib and discuss characteristics of patients who are candidates for abrocitinib therapy. In general, abrocitinib may be used in all appropriate patients with moderate-to-severe AD in need of systemic therapy, provided there are no contraindications, e.g., in patients with active serious systemic infections and those with severe hepatic impairment, as well as pregnant or breastfeeding women. For patients aged ≥ 65 years, current long-time or past long-time smokers, and those with risk factors for venous thromboembolism, major adverse cardiovascular events, or malignancies, a meticulous benefit–risk assessment is recommended, and it is advised to start with the 100-mg dose, when abrocitinib is the selected treatment option. [ABSTRACT FROM AUTHOR]

Background: Pediatric patients with moderate-to-severe atopic dermatitis (AD) often experience a high disease burden and have a high risk of persistent disease. Standard-of-care immunosuppressive systemic treatments have been used off-label for AD in pediatric patients despite concerns for suboptimal safety with continuous use and risk of relapse upon discontinuation. The biologic agent dupilumab is the first systemic treatment approved for moderate-to-severe AD in children as young as 6 months. Long-term safety and efficacy data in this patient population are needed to inform continuous AD management. Objectives: The purpose of this work was to determine the long-term safety and efficacy of dupilumab treatment up to 1 year in an open-label extension (OLE) study [LIBERTY AD PED-OLE (NCT02612454)] in children aged 6 months to 5 years with moderate-to-severe AD who previously participated in the 16-week, double-blind, phase 3 LIBERTY AD PRESCHOOL trial (NCT03346434 part B; parent study) and were subsequently enrolled in PED-OLE. Methods: In PED-OLE, patients received dupilumab every 4 weeks according to a weight-tiered regimen (body weight ≥ 5 kg to < 15 kg: 200 mg; ≥ 15 kg to < 30 kg: 300 mg). Results: Data for 142 patients were analyzed, 60 of whom had completed the 52-week visit at time of database lock. Mean age at baseline was 4.1 y [SD, 1.13; range, 1.0–5.9 years]. A majority (78.2%) of patients reported ≥ 1 treatment-emergent adverse event (TEAE), most of which were mild or moderate and transient. The most frequently reported TEAEs were nasopharyngitis (19.7%), cough (15.5%), and pyrexia (14.1%). One TEAE led to treatment discontinuation (severe urticaria, which resolved in 1 day). By week 52, 36.2% of patients had achieved an Investigator's Global Assessment score of 0/1 (clear/almost clear skin), and 96.6%, 79.3%, and 58.6% had at least 50%, 75%, or 90% improvement, respectively, in Eczema Area and Severity Index scores. Conclusions: Consistent with results seen in adults, adolescents, and older children (aged 6–11 years), treatment with dupilumab for up to 1 year in children aged 6 months to 5 years with inadequately controlled moderate-to-severe AD demonstrated an acceptable long-term safety profile and sustained efficacy. These results support the long-term continuous use of dupilumab in this patient population. Trial Registration: ClinicalTrials.gov Identifiers: NCT02612454 and NCT03346434 (part B). Plain Language Summary: Atopic dermatitis (AD) is a chronic inflammatory skin disease that often results in a high disease burden in young children and their families. Patients often need long-term treatment to control their disease symptoms, including itch and rash. Dupilumab treatment for 16 weeks has shown benefits in children aged 6 months to 5 years with moderate-to-severe AD, with an acceptable safety profile. As AD is likely to continue from childhood into adolescence and adulthood, there is a need for data supporting long-term use of dupilumab in young children. In this study, children who completed the 16-week study continued dupilumab treatment for up to 1 year, receiving 200 mg or 300 mg of dupilumab (depending on the child's bodyweight) every 4 weeks. Through the year of treatment, 78.2% of patients reported at least one side effect, most of which were mild or moderate. Only one patient interrupted treatment because of severe skin rash (hives), which was resolved in 1 day. At the end of the year, 36.2% of patients had clear or almost clear skin, and almost all (96.6%) achieved at least 50% improvement in their extent and severity of disease. Additionally, 79.3%, and 58.6% had at least 75% or 90% improvement in their extent and severity of disease. In summary, consistent with results seen in adults, adolescents, and older children, this study showed that 1-year dupilumab treatment provides continued benefits with an acceptable safety profile. These results support long-term continuous use of dupilumab in children aged 6 months to 5 years with moderate-to-severe AD. 5SqqskjZPmoHiNU8WnfbXp What is the long-term safety and efficacy profile in young children with moderate-to-severeatopic dermatitis treated with dupilumab? [ABSTRACT FROM AUTHOR]

Introduction: Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. Methods: This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). Results: Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week 16 (upadacitinib 15 mg, 47.1%; upadacitinib 30 mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1–2 weeks), increased through weeks 4–6, and were maintained through week 16. Conclusions: Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severe AD. Trial Registration: ClinicalTrials.gov identifiers, NCT03569293 and NCT03607422. Plain Language Summary: Atopic dermatitis, or eczema, is characterized by itchy, dry, inflamed skin. These symptoms often make it difficult for patients to get adequate sleep. Patients with atopic dermatitis may also experience anxiety, depression, reduced self-confidence, social isolation, disruption to daily activities like school and work, and decreased quality of life. Many atopic dermatitis symptoms, including itch and psychological impact, are difficult for doctors to assess. Thus, it is important to consider patients' descriptions of their symptoms and quality of life, particularly when assessing treatment benefit. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. We investigated how upadacitinib (15 mg or 30 mg) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis in the Measure Up 1 and 2 clinical trials impacts their symptoms and quality of life over a 16-week period. We compared changes in patient-reported itch, pain, sleep, daily activities, emotional state, mental health, and overall quality of life among patients in the clinical trials who received upadacitinib with those in the same studies who received a dummy (placebo) treatment. Upadacitinib improved patient-reported symptoms and quality of life early in the clinical trials, often within the first 1–2 weeks. The extent of the improvements increased through weeks 4–6 of treatment and lasted through week 16. Patients who received upadacitinib reported greater improvements in symptoms and quality of life than did patients who received placebo. Upadacitinib treatment resulted in rapid and lasting improvements in the well-being of patients with atopic dermatitis. [ABSTRACT FROM AUTHOR]

Background The Harmonising Outcome Measures for Eczema (HOME) initiative has agreed upon the Core Outcome Set (COS) for use in atopic dermatitis (AD) clinical trials, but additional guidance is needed to maximize its uptake. Objectives To provide answers to some of the commonly asked questions about using the HOME COS; to provide data to help with the interpretation of trial results; and to support sample size calculations for future trials. Methods and results We provide practical guidance on the use of the HOME COS for investigators planning clinical trials in patients with AD. It answers some of the common questions about using the HOME COS, how to access the outcome measurement instruments, what training/resources are needed to use them appropriately and clarifies when the COS is applicable. We also provide exemplar data to inform sample size calculations for eczema trials and encourage standardized data collection and reporting of the COS. Conclusions By encouraging adoption of the COS and facilitating consistent reporting of outcome data, it is hoped that the results of eczema trials will be more comprehensive and readily combined in meta-analyses and that patient care will subsequently be improved. [ABSTRACT FROM AUTHOR]

Introduction/Background Clinical trials of up to 52 weeks showed that tralokinumab, a monoclonal antibody that specifically neutralizes interleukin-13, was efficacious and well-tolerated as monotherapy and combination with TCS. Objectives Here, we evaluate the long-term safety of tralokinumab in an integrated analysis of seven phase 3 parent trials (PTs) (NCT03131648, NCT03160885, NCT03363854, NCT03562377, NCT03526861, NCT03761537, NCT04587453), and the ongoing, up to 5-year extension study (ECZTEND; NCT03587805). Methods Two datasets were analyzed: placebo-controlled (initial 16-week period of the PTs), and all-tralokinumab combining PTs with ECZTEND including patients from first dose until end of tralokinumab exposure or data cut-off (April 30th, 2022). In the all-tralokinumab dataset, periods on placebo were disregarded. Treatment-emergent adverse events (AEs) were recorded. AEs of special interest (AESIs) were predefined. Proportions of patients with events and incidence rates (IR) per 100 patient-years of exposure (PYE) were calculated. PYE was defined as time until first event or exposure end, whichever came first, and incidence was defined as first event. Results 2693 patients (≥12 years) received tralokinumab for up to 238.5 weeks (≈4.5 years) with a median exposure time of 76.5 weeks in the all-tralokinumab dataset. Median age at baseline was 33.0 years (min-max; 12-92). 10.4% of patients were 12-17 years. 2307 patients experienced an AE (IR=202.0), most (97.3%) of which were mild-to-moderate. Serious AEs (SAEs) were reported in 226 patients (IR=4.5); SAEs were considered possibly or probably related by the investigator in 50 patients (IR=0.9). No preferred term level SAEs were reported with an IR≥0.1. Discontinuation of treatment due to AEs was low (IR=2.8). AEs leading to drug withdrawal with an IR>0.1 were dermatitis atopic (IR=0.5) and injection site reaction (ISR) (IR=0.2). Frequently reported AEs in the all-tralokinumab dataset were consistent with the placebo-controlled dataset, including nasopharyngitis (IR=18.4), upper respiratory tract infection (IR=6.9), conjunctivitis (IR=5.0), ISR (IR=3.6), conjunctivitis allergic (IR=2.7), and injection site pain (IR=1.5). AESIs, including eye disorders, skin infections requiring systemic treatment, eczema herpeticum, and malignancies, were observed in the all-tralokinumab dataset at rates similar to or lower than the placebo-controlled dataset. Conclusion Long-term use of tralokinumab, for up to 4.5 years, was well-tolerated, and the pattern of AEs was consistent with the initial placebo-controlled treatment period with no new safety signals identified. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic, inflammatory, intensely pruritic skin disorder associated with significant patient burden. Interleukin (IL)‐13 is a cytokine that acts as a driver of immune dysregulation, skin‐barrier dysfunction, and microbiome dysbiosis that characterizes AD, and is consistently overexpressed in AD skin. Tralokinumab is a fully human immunoglobulin (Ig) G4 monoclonal antibody that binds specifically to IL‐13 with high affinity, thereby inhibiting subsequent downstream IL‐13 signaling. Three pivotal phase 3 clinical trials demonstrated that tralokinumab 300 mg every other week, as monotherapy or in combination with topical corticosteroids as needed, provides significant improvements in signs and symptoms of moderate‐to‐severe AD, as measured by Investigator's Global Assessment 0/1 (clear/almost clear) and Eczema Area and Severity Index‐75 at Week 16. Improvements were observed soon after tralokinumab initiation and were maintained over 52 weeks of therapy. Tralokinumab significantly improved patient‐reported outcomes such as itch and sleep, and demonstrated a safety profile comparable with placebo; conjunctivitis during tralokinumab therapy was generally mild. Similar results were observed in a phase 3 adolescent trial. The role of IL‐13 in the pathophysiology of AD justifies a targeted approach and a wealth of clinical data supports tralokinumab as a new therapeutic option for people with moderate‐to‐severe AD. [ABSTRACT FROM AUTHOR]

Introduction: Atopic dermatitis (AD) is heterogeneous in distribution pattern and clinical features. This analysis assessed the effect of dupilumab on the extent and severity of AD across various signs (erythema, edema/papulation, excoriation, lichenification) in different anatomical regions (head and neck, trunk, upper extremities, lower extremities) in patients aged 6 months to 5 years. Methods: In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo with concomitant low-potency topical corticosteroids (TCS) every 4 weeks for 16 weeks. Changes in AD signs across anatomical regions were assessed using unweighted Eczema Area and Severity Index (EASI) body region scores. Results: Overall, 162 patients were randomized to dupilumab (n = 83) or placebo (n = 79). A significant improvement in least squares mean EASI area score was seen by week 2 in all four anatomical regions (P < 0.0001 for dupilumab vs. placebo) and sustained throughout treatment. Least squares mean EASI sign scores in erythema, excoriations, and infiltration/papulation showed significant improvement by week 2 in all regions (P < 0.001), while lichenification showed significant improvement in all regions by week 4 (P < 0.001). Conclusion: Dupilumab use with concomitant low-potency TCS treatment resulted in rapid and consistent improvement in AD signs in all anatomical regions, in patients aged 6 months to 5 years with moderate-to-severe AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03346434 Part B. [ABSTRACT FROM AUTHOR]

Introduction/Background Lebrikizumab (LEB) is a novel monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) are identically designed Phase 3 trials that evaluated LEB as a monotherapy treatment for moderate-to-severe atopic dermatitis (AD). Many patients who met the protocol-defined response criteria at Week 16, defined as achieving ≥75% improvement in the Eczema Area and Severity Index (EASI 75) or an Investigator's Global Assessment of 0 or 1 (IGA 0/1) without use of rescue therapy, maintained a deep response up to Week 521. Deep response was defined as maintaining an IGA 0 (clear skin), a 100% improvement in the Eczema Area and Severity Index (EASI 100), or a Pruritus Numeric Rating Scale score of 0 or 1 (Pruritus NRS 0/1). Patients completing Week 52 were given the option to roll over into a long-term extension (LTE) study, ADjoin (NCT04392154), allowing the opportunity to analyze deep response for a longer period of time. This analysis supports the evolution of AD treatment goals toward maintaining higher efficacy thresholds for a longer duration. Objectives To present the long-term maintenance of LEB's depth of response for up to 104 weeks of treatment (52 weeks in the ADvocate studies and 52 weeks in the ADjoin study). Methods Patients entering ADjoin from ADvocate1 and ADvocate2 continued taking the same LEB dose as the parent study. Patients receiving placebo (LEB withdrawal) during the maintenance period of ADvocate1 and ADvocate2 transitioned to receive LEB every 2 weeks (Q2W) during ADjoin (data not included in this analysis). The proportion of patients achieving IGA and EASI responses were calculated from the LEB-treated patients who were IGA 0/1 or EASI 75 responders, respectively, at Week 16 in ADvocate1 and ADvocate2. The proportion of patients achieving a Pruritus NRS 0/1 response were calculated from the LEB patients who were per protocol responders at Week 16 of ADvocate1 and ADvocate2. Each patient's absolute Pruritus NRS score was calculated by averaging daily scores from the previous seven days with at least one nonmissing value. The weekly score was then rounded to the nearest integer. Consistent with common reporting practices for LTE studies, this post hoc analysis reports observed data which were analyzed regardless of rescue medication use or treatment discontinuation. Results From Week 52 to Week 104, the proportion of IGA 0 responders was maintained and slightly increased in patients treated with LEB Q2W (50.8% [N=59] to 52.3% [N=44]) and LEB every 4 weeks (Q4W; 43.5% [N=69] to 45.5% [N=55]). Greater improvements over the second year of treatment were seen in the proportion of EASI 100 responders treated with LEB Q2W (36.4% [N=88] to 39.7% [N=68]) and LEB Q4W (30.7% [N=101] to 41.3% [N=80]) as well as the proportion of Pruritus NRS 0/1 responders treated with LEB Q2W (46.3% [N=80] to 57.4% [N=61]) and Q4W (47.9% [N=94] to 55.4% [N=65]). Although rescue medication was allowed during ADjoin, a relatively low proportion of patients received ≥1 topical rescue medication in the LEB Q2W (9.8%) and LEB Q4W (15.2%) treatment arms. Conclusions These 2-year results demonstrate an extended maintenance of deep response in patients treated with LEB Q2W and LEB Q4W after responding to 16 weeks of LEB Q2W. Approximately 50% and 40% of LEB-treated patients sustained total skin clearance (IGA 0 and EASI 100, respectively) and more than 55% of LEB-treated patients reported no or minimal itch (Pruritus NRS 0/1). Maintenance treatment with LEB Q2W and LEB Q4W allows patients and providers to elevate their expected treatment goals in AD beyond EASI 75 and IGA 0/1 response. [ABSTRACT FROM AUTHOR]

Introduction/Background The SCORing Atopic Dermatitis (SCORAD) index is a validated clinician-reported measurement used to assess the extent and intensity of atopic dermatitis (AD). Multiple severity threshold bands have been published to translate the SCORAD's numeric scoring index into clinically meaningful categories, most of which were developed using small patient numbers in clinical practice. Further analyses using larger patient numbers from other clinical settings may provide additional insights into AD severity and outcomes. Objective To report an analysis of SCORAD severity bands using a large, pooled dataset of global, randomized, placebo-controlled clinical trials of dupilumab in adults with moderate-to-severe AD. Methods Data were collected during 2013–2016 from 5 double-blind, randomized, placebo-controlled trials of dupilumab in adults with moderate-to-severe AD (NCT01859988, NCT02277743, NCT02277769, NCT02260986, NCT02755649). Total SCORAD (range 0–103) data from all patients receiving dupilumab and placebo were pooled from all visits, excluding first visit. SCORAD values were anchored to the Investigator's Global Assessment (IGA) and designated into 5 severity categories: Clear, Almost Clear, Mild, Moderate, and Severe. Spearman's rank correlations were calculated between total SCORAD and IGA values. For each integer value of SCORAD, the following were calculated to determine potential threshold bands: means analyzed with spline regression (which accounts for potential non-linear relationships between anchor and outcome, and provides a broader range of potential thresholds); medians and modes; frequencies (where the threshold of the first severity band was set to 0 and each successive severity band was set at the value of the outcome measure where the maximum anchor frequency changes category); and results of previous analyses by Chopra et al. (Br J Dermatol. 2017;177:1316-21) and Kunz et al. (Dermatology. 1997;195:10-19), modified to incorporate 5 severity categories. Thresholds for body surface area (BSA, 0–100) and total SCORAD subscales (observed SCORAD [oSCORAD, 0–83], Pruritus Visual Analog [VAS, 0–10], and Sleep Loss VAS [0–10]) by medians were also evaluated. Goodness-of-fit and concordance between bands and anchors were assessed using R2 and quadratic weighted kappa (κ)-coefficients. Results Data from 31,367 visits from 2,822 adults with moderate-to-severe AD were used. The following banding thresholds were identified using the frequencies, medians, and modes: 0–4.9 (Clear), 5–17.9 (Almost Clear), 18–36.9 (Mild), 37–68.9 (Moderate), and 69–103 (Severe; R2: 0.997; κ: 0.831). Bands identified using the means were similar: 0–5.9 (Clear), 6–17.9 (Almost Clear), 18–36.9 (Mild), 37–77.9 (Moderate), 78–103 (Severe; R2: 0.999; κ: 0.815). Severity thresholds evaluated using modified results from Chopra et al. and Kunz et al. produced the following bands, respectively: 0–5.9 (Clear), 6–24.9 (Almost Clear), 25–49.9 (Mild), 50–77.9 (Moderate), and 78–103 (Severe; R2: 0.998; κ: 0.742); and 0–9.9 (Clear), 10–28.9 (Almost Clear), 29–39.9 (Mild), 40–77.9 (Moderate), and 78–103 (Severe; R2: 0.998; κ: 0.769). Analysis of BSA and SCORAD subscales by medians produced the following bands: BSA – 0–0.09 (Clear), 1–4.9 (Almost Clear), 5–22.9 (Mild), 23–79.9 (Moderate), and 80–100 (Severe); oSCORAD - 0–4.9 (Clear), 5–15.9 (Almost Clear), 16–31.9 (Mild), 32–58.9 (Moderate), and 59–83 (Severe); Pruritus VAS - 0–1.9 (None), 2–4.9 (Mild), 5–8.9 (Moderate/Severe), and 9–10 (Very Severe); and Sleep Loss VAS - 0–0.9 (None), 1–3.9 (Mild), 4–8.9 (Moderate), and 9–10 (Severe/Very Severe). Conclusions The SCORAD threshold bands developed in this anchor-based analysis utilized a large, global, diverse data set of adult patients with AD from clinical trials and used spline regressions as a novel methodology. These potential severity bands may enhance the understanding of AD severity and disease stratification. [ABSTRACT FROM AUTHOR]

Introduction/Background Seasonal trends in atopic dermatitis (AD)-related healthcare visits vary by geographical location and climate. Changes in temperature, moisture, and allergens contribute to disease fluctuation activities throughout the year. The global, placebo-controlled, 1-year LIBERTY AD CHRONOS study (NCT02260986) offers the opportunity to evaluate AD seasonality and the impact of dupilumab on moderate-to-severe AD in adults regardless of season. Objectives To identify seasonal trends in patient-reported AD severity and frequency of symptoms, and to report the effect of dupilumab treatment in adults with moderate-to-severe AD across seasons. Methods CHRONOS was a randomized, double-blind, phase 3 trial of adults with moderate-to-severe AD.1 Patients were treated with dupilumab 300 mg every week (qw), every two weeks (q2w), or placebo qw, all with concomitant topical corticosteroids (TCS). In this post hoc analysis, the proportion of patients per severity category of Patient-Oriented Eczema Measure (POEM) score (range 0–28) by month was compared between patients receiving dupilumab 300 mg q2w + TCS (n = 79) or placebo qw + TCS (n = 234) for 1 year across 10 countries in the Northern Hemisphere. Improvement in AD was determined as an increase in proportion of patients with mild and clear POEM scores (≤7). Meteorological seasons were defined as winter (December 1 – February 28/29), spring (March 1 – May 31), summer (June 1 – August 31), and fall (September 1 – November 30). Sensitivity analyses confirmed that season of enrollment was balanced across treatment arms and disease seasonality was independent of treatment length. P values are based on Chi-Square tests or Monte Carlo simulations of the Exact Test, based on sample size. All P values are nominal, and no adjustments have been made for multiple testing. Data are presented as observed. Results The proportion of patients in both treatment arms with mild and clear POEM scores (≤7) was lowest in spring months (March: 13% vs 24%; April: 10% vs 23%; May: 20% vs 44%; placebo vs dupilumab). The proportion of patients with mild and clear POEM scores was increased through summer (June: 21% vs 54%; July: 24% vs 58%; August: 29% vs 53%; placebo vs dupilumab) and fall (September: 27% vs 62%; October: 23% vs 58%; November: 21% vs 63%; placebo vs dupilumab), before beginning to decline in winter (December: 21% vs 56%; January: 16% vs 46%; February: 15% vs 41%; placebo vs dupilumab). Overall, POEM scores indicated significantly better outcomes for patients receiving dupilumab treatment vs placebo throughout the year (overall P < 0.01 for all 12 months). Conclusions Across the Northern Hemisphere, patient-reported disease severity in adults with moderate-to-severe AD was greatest in the spring months. Adults with moderate-to-severe AD receiving dupilumab treatment reported improvement in frequency of disease symptoms across all seasons compared to patients receiving placebo treatment. [ABSTRACT FROM AUTHOR]

Introduction Itch is the most bothersome symptom for patients with atopic dermatitis (AD), and has a significant negative impact on health-related quality of life. Rapid onset of pruritus relief with sustained efficacy is a key outcome for AD therapies. In ADORING 1 and 2, two identical pivotal phase 3, double-blind, vehicle-controlled trials, tapinarof cream 1% once daily (QD) demonstrated efficacy and was well tolerated in adults and children down to 2 years of age with AD. Objective Here, we evaluate time to onset of itch relief in the pivotal phase 3 trials. Methods In ADORING 1 and 2, patients with a Validated Investigator Global Assessment for Atopic DermatitisTM score of ≥3 (moderate or severe), an Eczema Area and Severity Index score of ≥6, and body surface area involvement of 5–35% were randomized 2:1 to tapinarof cream or vehicle QD for 8 weeks. Itch relief was assessed by changes in Peak Pruritus Numerical Rating Scale (PP-NRS) score, daily and by visit, from baseline through Week 8. PP-NRS considers itch over the past 24 hours; lower scores indicate less pruritus. Results 407 and 406 patients were randomized in ADORING 1 and 2. At baseline, mean PP-NRS scores were 6.7 and 6.8 in both trials, respectively. For daily evaluations of itch from baseline, greater reductions in mean PP-NRS scores for tapinarof versus vehicle were observed as early as Day 1, 24 hours after initial application in ADORING 1 (–1.2 vs –0.9), and Day 2 in ADORING 2 (–1.6 vs –1.4). Daily itch improvements continued through Week 8 in both trials. Statistically significant reductions in mean weekly PP-NRS scores occurred as early as Week 1 (earliest assessment) with tapinarof versus vehicle (–2.0 vs –1.2 [ P <0.0001]) and (–2.0 vs –1.3 [ P =0.0010]) in ADORING 1 and 2, respectively. Significantly greater reductions in mean PP-NRS scores with tapinarof versus vehicle were seen for all visits through Week 8 (–4.1 vs –2.6 and –4.1 vs –2.4 [both P<0.0001]). Conclusions Tapinarof cream 1% QD demonstrated rapid, significant, and clinically meaningful pruritus relief from 24 hours after initial application, with improvements increasing through Week 8 in both trials in adults and children down to 2 years with AD. [ABSTRACT FROM AUTHOR]

Introduction/Background Amlitelimab is a fully human, nondepleting anti-OX40 Ligand (OX40L) monoclonal antibody that blocks OX40L-OX40 interactions. In addition to an acceptable safety profile, phase 2a and 2b trials showed the clinical efficacy of amlitelimab in achieving lesional and symptomatic (pruritus) endpoints and demonstrating a continued durable response when patients with moderate-to-severe atopic dermatitis (AD) were withdrawn from amlitelimab during a 28-week period, suggesting the viability of extended interval dosing (every 12 weeks [Q12W]). Objectives Phase 3 clinical trials will determine the efficacy and safety of amlitelimab every four weeks (Q4W) and Q12W dosing in patients with moderate-to-severe AD with various treatment histories. Methods OCEANA phase 3 clinical trials (COAST 1, COAST 2, SHORE, AQUA, and ESTUARY) are multinational, multicenter, randomized, double-blind, parallel group, placebo-controlled trials evaluating efficacy and safety of subcutaneous amlitelimab with two different dosing regimens. Key inclusion criteria for COAST 1/2, SHORE, and AQUA include: adults and adolescents (≥12 years old) having AD ≥1 year with inadequate response to topical treatments (within 6 months before screening) and/or systemic treatment (within 12 months before screening), validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) baseline score of 3 or 4, Eczema Area and Severity Index (EASI) baseline score of ≥16, AD involvement of ≥10% of body surface area at baseline, and weekly average Peak Pruritus Numerical Rating Scale score of ≥4. COAST 1/2 are 24-week monotherapy studies, while SHORE is a 24-week study with background topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). AQUA is a 36-week study with background TCSs and TCIs that exclusively includes participants with an inadequate response to prior treatment with AD biologics or oral Janus kinase inhibitors. Primary endpoints for COAST 1/2, SHORE, and AQUA include vIGA-AD 0/1 and a reduction from baseline of ≥2 points (for US and US reference countries) and vIGA-AD 0/1 and EASI-75 (for Japan, EU, and EU reference countries). Adult patients ≥40 kg will be randomized to amlitelimab 250 mg Q4W + 500 mg loading dose (LD), amlitelimab 250 mg Q12W + 500 mg LD, or placebo; dose will be adjusted for patients <40 kg. Trials have a 2- to 4-week screening period. Primary endpoints will be evaluated at Week 24 for COAST 1/2 and SHORE and at Week 36 for AQUA, with expected enrollment of 420, 420, 496, and 249 patients in each study, respectively. Patients who have completed COAST 1/2 or SHORE can elect to enter the ESTUARY blinded extension study; patients completing AQUA can enter RIVER-AD, an open-label long-term study. Upon entering ESTUARY, clinical responders previously on 250 mg Q4W +LD will be randomized to 250 mg Q4W, 250 mg Q12W, or treatment withdrawal (placebo), while nonresponders will continue on 250 mg Q4W. Clinical responders previously on 250 mg Q12W +LD will be randomized to 250 mg Q12W or treatment withdrawal (placebo), while nonresponders will be randomized to 250 mg Q12W or 250 mg Q4W. Clinical responders previously on placebo will continue placebo, while nonresponders on placebo will receive amlitelimab 250 mg Q4W +LD. Participants not entering the ESTUARY or RIVER-AD trials will be included in a 16-week safety follow-up. ESTUARY and RIVER-AD will evaluate long-term safety and efficacy. Biopsies and blood samples will be collected at various timepoints in the OCEANA phase 3 trials. Results Enrollment for the OCEANA phase 3 trials began Q4 2023. COAST 1/2, SHORE, and AQUA trials are expected to be completed in 2026. Conclusions Results of the clinical trials should provide further evidence demonstrating the efficacy and safety of amlitelimab in treating moderate-to-severe AD using two different dosing regimens, including an extended dosing regimen, in patients with various treatment histories. [ABSTRACT FROM AUTHOR]

Background Formulating a topical medication that does not irritate the skin is an important factor contributing to patient treatment adherence and satisfaction. Many topical prescription products use penetration enhancers (including propylene glycol, polyethylene glycol, and ethanol) to overcome barrier properties of the skin. However, these excipients may irritate the skin causing tolerability reactions such as burning and stinging, which can reduce patient treatment adherence. Topical roflumilast is a highly potent (Kd∼0.7 nM) phosphodiesterase 4 inhibitor formulated as a water-based cream or foam that does not contain penetration enhancers or fragrances. Objective We present prospectively assessed investigator- and patient-rated local tolerability from Phase 3 trials of topical roflumilast for patients with psoriasis (DERMIS-1, DERMIS-2, ARRECTOR), seborrheic dermatitis (SD; STRATUM), and atopic dermatitis (AD; INTEGUMENT-1, INTEGUMENT-2). Methods Patients were randomized to apply topical roflumilast (DERMIS: 0.3% cream; ARRECTOR and STRATUM: 0.3% foam; INTEGUMENT: 0.15% cream) or vehicle once daily for 8 weeks (DERMIS, ARRECTOR, and STRATUM) or 4 weeks (INTEGUMENT). Investigators assessed local tolerability on an 8-point scale (0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) in the clinic before investigational product (IP) application. Patients reported local tolerability on a 4-point scale (0 [none: no sensation] to 3 [severe: hot, tingling/stinging sensation that has caused definite discomfort]) in the clinic 10-15 minutes after IP application. Tolerability was also assessed by reviewing documented adverse events. Results As assessed by investigators, ≥96.5% of patients in the roflumilast-treated groups had no evidence of irritation at the application site across all trials at all timepoints. Patient-rated local tolerability was favorable and improved with treatment: across all trials, 1% of roflumilast-treated patients reported a score of 3 (severe; defined as a "hot tingling/stinging sensation that has caused definite discomfort") after the first application (day 1) and <1% at each subsequent assessment. Rates of adverse events, including those at the application site, were low for all trials. Conclusions Roflumilast cream and foam formulations demonstrated favorable local tolerability based on investigator- and patient-rated assessments in patients with psoriasis, SD, and AD, including application to sensitive areas such as the face and intertriginous areas. [ABSTRACT FROM AUTHOR]

Background Lebrikizumab is a novel, high-affinity monoclonal antibody that selectively binds to interleukin (IL)-13. Objectives To evaluate the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) over 52 weeks of treatment in ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). Methods Patients who responded to lebrikizumab 250 mg every 2 weeks (Q2W) at the end of the 16-week induction period were re-randomized 2 : 2 : 1 to receive lebrikizumab Q2W, lebrikizumab 250 mg every 4 weeks (Q4W) or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. Response at week 16 was defined as achieving a 75% reduction in Eczema Area Severity Index (EASI 75) or an Investigator's Global Assessment (IGA) of 0 or 1, with a ≥ 2-point improvement and no rescue medication use. Multiple imputation was used to handle missing data. Intermittent use of topical therapy was permitted during the maintenance period. Results After 52 weeks, an IGA of 0 or 1 with a ≥ 2 point improvement was maintained by 71.2% of patients treated with lebrikizumab Q2W, 76.9% of patients treated with lebrikizumab Q4W and 47.9% of patients in the lebrikizumab withdrawal arm. EASI 75 was maintained by 78.4% of patients treated with lebrikizumab Q2W, 81.7% of patients treated with lebrikizumab Q4W and 66.4% of patients in the lebrikizumab withdrawal arm at week 52. Across treatment arms, proportions of patients using any rescue therapy were 14.0% (ADvocate1) and 16.4% (ADvocate2). During the combined induction and maintenance periods of ADvocate1 and ADvocate2, 63.0% of lebrikizumab-treated patients reported any treatment emergent adverse event, with most events (93.1%) being mild or moderate in severity. Conclusions After a 16-week induction period with lebrikizumab Q2W, lebrikizumab Q2W and Q4W maintained similar improvement of the signs and symptoms of moderate-to-severe AD, with a safety profile consistent with previously published data. [ABSTRACT FROM AUTHOR]

Background: Baricitinib demonstrated efficacy in treating adults with moderate‐to‐severe atopic dermatitis (AD) in Phase 3 clinical trials. Objective: To examine long‐term efficacy of baricitinib combined with topical corticosteroids (TCS) in adult patients from a Phase 3 study, BREEZE‐AD7 (NCT03733301), enrolled in ongoing extension study, BREEZE‐AD3 (NCT03334435). Methods: Upon BREEZE‐AD7 completion, responders or partial responders (RPR [vIGA‐AD™ ≤2]) receiving baricitinib 2‐mg or 4‐mg + TCS maintained their original treatment doses in BREEZE‐AD3. Nonresponders (NR; vIGA‐AD 3,4) receiving baricitinib 2‐mg were rerandomized 1:1 to baricitinib 2‐mg or 4‐mg; NR receiving baricitinib 4‐mg remained on same dose. Integrated data from all patients (RPR + NR = baricitinib 4‐mg intent‐to‐treat [ITT] cohort) receiving continuous baricitinib 4‐mg in BREEZE‐AD7 through BREEZE‐AD3 were analysed, along with baricitinib 4‐mg or 2‐mg RPR cohorts. Primary endpoint was proportion of patients with vIGA‐AD (0,1) at Weeks 16, 36 and 52 (Weeks 32, 52 and 68 of continuous therapy). Additional outcomes included improvement in EASI75 and Itch NRS (up to Week 32). Missing data were imputed by last observation carried forward. Results: In baricitinib 4‐mg ITT cohort (N = 102), proportions of patients achieving vIGA‐AD (0,1) at Week 32, Week 52, and Week 68 were 21.6%, 26.5% and 23.5%; EASI75 were 46.1%, 40.2% and 43.1%, respectively. Itch NRS ≥4‐point improvement (Itch ≥4) were 47.3% at Week 16 and 40.6% at Week 32. In baricitinib 4‐mg RPR cohort (N = 63), proportions of patients achieving vIGA‐AD (0,1) at Week 32, Week 52 and Week 68 were 31.7%, 33.3% 34.9%, respectively; EASI75 were 57.1%, 49.2% and 49.2%, respectively. Itch ≥4 were 53.6% at Week 16 and 46.4% at Week 32. Corresponding proportions for baricitinib 2‐mg RPR cohort (N = 53) for vIGA‐AD (0,1) were 39.6%, 45.3% and 30.2%; EASI75 were 77.4%, 69.8% and 58.5%, respectively. Itch ≥4 were 56.3% at Week 16 and 47.9% at Week 32. Conclusion: Baricitinib 4‐mg and 2‐mg combined with TCS maintained clinically meaningful sustained efficacy over 68 weeks of continuous treatment. [ABSTRACT FROM AUTHOR]

Baricitinib, a selective Janus kinase (JAK)1/JAK2 inhibitor, is approved for treatment of moderate-to-severe atopic dermatitis (AD) in adults. We report integrated baricitinib safety data in patients with up to 3.9-years exposure. Three datasets from the integrated AD clinical trial program were analyzed: placebo-controlled, 2-mg–4-mg extended, and All-bari. Data cutoffs were up to 21-December-2021 for long-term extension studies. Proportions of patients with events and incidence rates (IR)/100 patient years (PY) at risk were calculated. 2636 patients received baricitinib for 4628.4 PY. Discontinuation due to adverse events was low (IR = 3.4). IRs in All-bari were: serious adverse events, 5.2; infection, 67.2 (any infection), 6.7 (herpes simplex), 2.8 (herpes zoster), and 0.3 (opportunistic infections). Adverse events of special interest in All-bari included seven patients with positively adjudicated major adverse cardiovascular events (MACE) (IR = 0.15), three pulmonary emboli (PE) (IR = 0.06), 14 malignancies excluding nonmelanoma skin cancer (IR = 0.3), one gastrointestinal perforation (IR = 0.02), and four deaths (IR = 0.1). No deep vein thromboses (DVT) or tuberculosis were reported. In this analysis, baricitinib maintained a similar safety profile to earlier analyses with no new safety signals. Rates of MACE, DVT/PE, malignancies, and serious infections were within ranges of background rates in patients with AD. NCT02576938 (JAHG), NCT03334396 (JAHL; BREEZE-AD1), NCT03334422 (JAHM; BREEZE-AD2), NCT03334435 (JAHN; BREEZE-AD3), NCT03428100 (JAIN; BREEZE-AD4), NCT03435081 (JAIW; BREEZE-AD5), NCT03559270 (JAIX; BREEZE-AD6), NCT03733301 (JAIY; BREEZE-AD7) [ABSTRACT FROM AUTHOR]

Despite the need for improved eczema therapies and a rapid increase in available eczema clinical trials, participation remains low. The aim of this study was to identify factors associated with clinical trial awareness, interest, and barriers to enrolment and participation. An online survey, administered 1 May to 6 June 2020 to adults (≥18 years) with eczema in the USA, was analysed. Among 800 patients included, mean age was 49.4 years, most respondents were female (78.1%), White (75.4%), non-Hispanic (91.4%), and geographically living in an urban/suburban area (Rural-Urban Continuum Codes (RUCC) 1–3, 90.8%). Only 9.7% of respondents reported previous participation in clinical trials, while 57.1% had considered participation and 33.2% never considered participation. Higher satisfaction with current eczema therapy, clinical trial literacy, and confidence in finding eczema trial information were all associated with clinical trial awareness, interest, and successful participation. Younger age and having atopic dermatitis were associated with increased awareness, while female gender was a barrier to interest and successful participation. [ABSTRACT FROM AUTHOR]

Background: Ruxolitinib cream is a topical formulation of ruxolitinib, a Janus kinase (JAK) 1/JAK2 inhibitor. Objectives: To report timing and magnitude of effect of ruxolitinib cream on itch in patients with atopic dermatitis (AD), a highly pruritic inflammatory skin disease. Methods: Two phase 3 trials (TRuE‐AD1 [NCT03745638]/TRuE‐AD2 [NCT03745651]) enrolled patients aged ≥12 years with AD for ≥2 years, Investigator's Global Assessment score of 2 or 3, and 3%–20% affected body surface area. Patients (total N = 1249; median age, 32 years) were randomised (2:2:1) to twice daily 0.75% ruxolitinib cream, 1.5% ruxolitinib cream or vehicle cream for 8 weeks of double‐blinded treatment. Worst itch was measured using the numerical rating scale (NRS). Results: Significantly more patients who applied ruxolitinib cream (either strength) achieved a ≥2‐point itch reduction (NRS2) within approximately 12 h versus vehicle (0.75%/1.5% ruxolitinib cream, 16.3%/13.1%; vehicle, 6.9%; both P < 0.05), with further improvements through Week 8 (58.3%/65.1% vs 29.4%; both P < 0.0001). A ≥4‐point itch reduction (NRS4) was achieved by significantly more patients who applied 0.75%/1.5% ruxolitinib cream versus vehicle by Day 2 (8.9%/11.2% vs 2.1%; P < 0.005); higher rates were observed at Week 8 (41.5%/51.5% vs 15.8%; P < 0.0001). Median time for the 0.75%/1.5% ruxolitinib cream groups to achieve NRS4 from baseline was 15.0/13.0 days; this endpoint was not reached by the vehicle group. Conclusions: Ruxolitinib cream demonstrated rapid improvement in itch in patients with mild to moderate AD that was sustained for 8 weeks. Significantly more patients applying ruxolitinib cream achieved itch NRS2 within approximately 12 h and itch NRS4 by Day 2 versus vehicle. [ABSTRACT FROM AUTHOR]

Introduction: Three patient-reported outcome (PRO) questionnaires—Worst Pruritus Numerical Rating Scale (WP-NRS), Atopic Dermatitis Symptom Scale (ADerm-SS), and Atopic Dermatitis Impact Scale (ADerm-IS)—were developed to assess the symptoms and impacts of atopic dermatitis (AD). Severity strata for these PROs are needed to aid in their interpretation. Methods: Using data from a global, randomized, double-blind, placebo-controlled, phase 3 clinical trial (NCT03568318) of patients with moderate–severe AD (age ≥ 12 years), equipercentile linking analyses were conducted to define severity strata applying the Patient Global Impression of Severity as an anchor. Analyses were conducted separately for adults and adolescents, and then harmonized between the two age groups. Results: The sample included 769 adults and 113 adolescents. For the WP-NRS, 0 was associated with absent, 1–2 with minimal, 3 with mild, 4–7 with moderate, and 8–10 with severe. For the ADerm-SS Skin Pain, 0 was associated with absent, 1 with minimal, 2 with mild, 3–6 with moderate, and 7–10 with severe. For ADerm-SS 7-Item Total Symptom Score (TSS-7), 0–1 was associated with absent, 2–11 with minimal, 12–22 with mild, 23–47 with moderate, and 48–70 with severe. For ADerm-IS Sleep, 0 was associated with absent, 1–3 with minimal, 4–6 with mild, 7–20 with moderate, and 21–30 with severe. For ADerm-IS Daily Activities, 0 was associated with absent, 1–2 with minimal, 3–7 with mild, 8–25 with moderate, and 26–40 with severe. For ADerm-IS Emotional State, 0 was associated with absent, 1–2 with minimal, 3–8 with mild, 9–22 with moderate, and 23–30 with severe. Conclusions: These severity strata provide score interpretations of the WP-NRS, ADerm-SS, and ADerm-IS, translating these scores to simple and intuitive outcomes, which can inform clinical studies and clinical practice. Trial Registration Number: NCT03568318. [ABSTRACT FROM AUTHOR]

Introduction Roflumilast is a selective, highly potent phosphodiesterase 4 inhibitor under investigation as a nonsteroidal, once-daily cream for treatment of atopic dermatitis (AD). Methods We present pooled results from two identical phase 3 randomized controlled trials (INTEGUMENT-1: NCT04773587; INTEGUMENT-2: NCT04773600) of roflumilast cream 0.15%. Patients aged ≥6 years with mild to moderate AD were randomized 2:1 to apply roflumilast (n=884) or vehicle (n=453) cream once-daily for 4 weeks. The primary endpoint was validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) Success (Clear/Almost Clear vIGA-AD plus ≥2-grade improvement from baseline) at Week 4. Patient-reported outcomes (PROs) were evaluated using the Worst Itch-Numeric Rating Scale (WI-NRS), SCORing AD (SCORAD), Patient-Oriented Eczema Measure, Dermatology Life Quality Index/Children's Dermatology Life Quality Index, and the Dermatitis Family Impact questionnaire. Safety and tolerability were also evaluated. Results At Week 4, more roflumilast- than vehicle-treated patients achieved vIGA-AD Success (31.3% vs. 14.1%, P<0.0001), WI-NRS Success (≥4-point improvement on WI-NRS in patients aged ≥12 years with baseline WI-NRS ≥4; 31.9% vs. 16.6%, P<0.0001); and WI-NRS of 0/1 (in patients with baseline WI-NRS ≥2; 28.8% vs 18.5%, P=0.0087). At Week 4, roflumilast-treated patients improved more than vehicle-treated on the pruritus and sleep components of SCORAD (least squares mean percentage change −48.2% vs. −27.8%; [P<0.0001] and −47.9% vs. −22.9% [P<0.05], respectively). Differences favoring roflumilast were also seen for other secondary endpoints, including quality of life of the patient and family. Safety and local tolerability were favorable. Conclusion Once-daily, nonsteroidal roflumilast cream 0.15% improved PROs in patients with AD. [ABSTRACT FROM AUTHOR]

Background Roflumilast, a highly potent phosphodiesterase-4 inhibitor, is being investigated as a non-steroidal, once-daily cream for atopic dermatitis (AD). Methods INTEGUMENT-OLE (NCT04804605) was an open-label 52-week safety trial. Patients (N=658) with mild to moderate AD who completed a 4-week randomized vehicle-controlled phase 3 trial of roflumilast cream continued or switched to once-daily roflumilast cream 0.15% in this open-label extension trial. Starting at Week 4, patients achieving Validated Investigator Global Assessment for AD (vIGA-AD) score of 0 (Clear) switched to twice-weekly (BIW) maintenance dosing. The primary endpoint was safety; secondary endpoints included vIGA-AD, Worst Itch-Numeric Rating Scale (WI-NRS), and Eczema Area and Severity Index (EASI). "Disease control" was defined as duration of vIGA-AD=0/1 on BIW dosing following achievement of vIGA-AD=0. Results With cumulative treatment up to 56 weeks, 36.7% of patients reported treatment-emergent adverse events (AEs); most were mild to moderate in severity. Overall, 4.7% of patients had AEs deemed treatment-related and 3.0% discontinued due to AEs. The most common AEs (>2%) were COVID-19, upper respiratory tract infection, nasopharyngitis, and headache. At Week 52, 55.7%, 61.1%, and 53.6% of patients achieved vIGA-AD=0/1 (Clear/Almost Clear), ≥75% reduction in EASI, and ≥4-point reduction in WI-NRS (among patients aged ≥12 years with baseline WI-NRS ≥4), respectively. Of the 130 (19.8%) patients who achieved disease control, 50% maintained "disease control" for at least 281 days. Conclusion Treatment with roflumilast cream 0.15% demonstrated long-term safety in patients with AD consistent with parent trials and durable efficacy through 52 weeks, including patients who switched to BIW dosing. [ABSTRACT FROM AUTHOR]

Background: Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis.Methods: This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3-4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0-1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434.Findings: Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0-1 (23 [28%] vs three [4%], difference 24% [95% CI 13-34]; p<0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29-55]; p<0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation.Interpretation: Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults.Funding: Sanofi and Regeneron Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Introduction/Background Atopic dermatitis (AD) is a chronic, recurrent, inflammatory disease characterized by multiple skin manifestations and intense itching that can impact patient quality of life. The effect of upadacitinib (UPA) and dupilumab (DUP) was evaluated in a double-blind, double-dummy, head-to-head phase 3b clinical trial (Heads Up; NCT03738397) of adult patients (age: 18-75 years) with moderate-to-severe AD (Eczema Area and Severity Index [EASI] =16; body surface area =10%; validated Investigator Global Assessment of Atopic Dermatitis (vIGA-AD) =3 at screening and baseline; Worst Pruritus Numerical Rating Scale [WP-NRS] =4 at baseline) randomized 1:1 to UPA 30 mg orally once-daily (N=348) or DUP 300 mg subcutaneous injection every two weeks after a 600 mg loading dose (N=344). Objective The effects of UPA and DUP on skin clearance and itch improvement are reported here. Methods: Skin clearance was assessed by EASI, with response defined as an improvement =75% (EASI75), =90% (EASI90), and 100% (EASI100) from baseline. Itch intensity was assessed daily by WP-NRS up to week 16, then at study visits up to week 24. Weekly WP-NRS scores were analyzed as a 7-day rolling average up to week 16, then at study visits through week 24. Daily WP-NRS scores were analyzed day-to-day through day 28. Mean percent improvement and the proportion of patients achieving clinically meaningful improvement (=4-point improvement from baseline) were evaluated. The proportion of patients achieving a state of no/minimal itch (defined as WP-NRS score of 0/1) was evaluated as a posthoc analysis. Results: EASI75/90/100 response rates were significantly greater with UPA versus DUP at week 16 (UPA = 72.4%/61.6%/28.4%, DUP = 62.6%/40.3%/7.9%; P<0.01 for all comparisons), with greater EASI75 and EASI90 rates observed with UPA as early as week 1 (nominal P<0.05). Mean percent improvement in weekly WP-NRS was significantly greater with UPA versus DUP at week 16 (UPA = 67.8%, DUP= 49.6%; P<0.001), with greater improvement observed as early as week 1 (nominal P<0.001). Daily WP-NRS data showed a greater mean percent improvement with UPA versus DUP as early as day 2, the day after the first dose (UPA = 22.0%, DUP = 4.2%; nominal P<0.001). The proportion of patients that achieved clinically meaningful improvement in weekly WP-NRS was significantly greater with UPA versus DUP at week 16 (UPA = 56.1%, DUP = 36.4%; P<0.001), with greater proportions observed as early as week 1 (nominal P<0.001). Daily WP-NRS data showed a greater proportion of patients achieved clinically meaningful improvement with UPA versus DUP as early as day 2 (UPA = 15.3%, DUP = 3.4%; nominal P<0.001). The proportion of patients that achieved a state of no/minimal itch based on weekly WP-NRS was greater with UPA versus DUP at week 16 (UPA = 35.5%, DUP = 16.2%; nominal P<0.001) and at week 1 (nominal P<0.001). Conclusions: Skin clearance and itch improvement were consistently better with UPA compared with DUP in adult patients with moderate-to-severe AD, with greater improvements observed as early as week 1 for skin clearance and the day following treatment for itch improvement. [ABSTRACT FROM AUTHOR]

Introduction Itch is the most bothersome symptom for patients with atopic dermatitis (AD), with a significant negative impact on health-related quality of life. Rapid onset of pruritus relief with sustained efficacy is a key outcome for AD therapies. In a phase 2 trial in adults and adolescents with moderate to severe AD, tapinarof cream 1% once daily (QD) demonstrated efficacy versus vehicle and was well tolerated. Objective Here, we evaluate time to onset of itch relief in the pivotal phase 3 trials with tapinarof cream 1% QD in the treatment of adults and children down to 2 years of age with AD. Materials and Methods In ADORING 1 and 2, two identical, double-blind, vehicle-controlled trials, patients were randomized 2:1 to tapinarof cream 1% or vehicle QD for 8 weeks. Patients with a Validated Investigator Global Assessment for Atopic DermatitisTM score of ≥3, an Eczema Area and Severity Index score of ≥6, and body surface area involvement of 5-35% were included. Efficacy endpoints that evaluated itch relief were mean changes in Peak Pruritus-Numerical Rating Scale (PP-NRS) score (daily and by visit [Weeks 1, 2, 4, and 8]) from baseline through Week 8. The PP-NRS considers a person's worst itch over the past 24 hours, assessed on an 11-point scale (0 indicates "no itch" and 10 is "worst imaginable itch"). Daily PP-NRS scores were recorded in diaries. Patients aged ≥12 years self-completed the PP-NRS, while caregivers completed it for children aged <12 years. Results: 407 and 406 patients were randomized in ADORING 1 and 2. At baseline, mean (standard deviation [SD]) PP-NRS scores were 6.7 (2.4) and 6.8 (2.3) in both trials, respectively. For daily evaluations of itch from baseline, greater reductions in PP-NRS scores (mean [SD]) for tapinarof versus vehicle were observed as early as Day 1, 24 hours after initial application, in ADORING 1 (-1.2 [2.2] vs -0.9 [2.0]) and Day 2 in ADORING 2 (-1.6 [2.4] vs -1.4 [2.1]). Improvements in daily PP-NRS scores (mean [SD]) with tapinarof versus vehicle continued through the first 2 weeks (Day 14; -3.0 [2.8] vs -2.0 [2.4] and -2.9 [2.7] vs -1.8 [2.6]), and through Week 8 of both trials. There were statistically significant and clinically meaningful reductions in mean weekly PP-NRS scores as early as Week 1, the first assessment, for patients treated with tapinarof compared with vehicle (-2.0 vs -1.2 [P<0.0001]) and (-2.0 vs -1.3 [P=0.0010]), in ADORING 1 and 2, respectively. Significantly greater reductions in mean PP-NRS scores with tapinarof versus vehicle were seen for all visits through Week 8 (-4.1 vs -2.6 and -4.1 vs -2.4 [both P<0.0001]), for both trials. Conclusions: Tapinarof cream 1% QD demonstrated rapid, clinically meaningful, and significant onset of pruritus relief as early as 24 hours after initial application compared with vehicle. Improvements in itch with tapinarof cream increased through Week 8 in both trials in adults and children down to 2 years with AD. [ABSTRACT FROM AUTHOR]

Introduction/Background Tralokinumab, a monoclonal antibody that specifically neutralizes interleukin-13, is indicated for the treatment of patients (pts) with moderate-to-severe AD. Clinical trials of up to 52 weeks' duration, showed that tralokinumab was efficacious and well tolerated as monotherapy and in combination with topical therapy. Objectives: To evaluate the long-term safety of tralokinumab in an integrated analysis of seven phase 3 parent trials of up to 52 weeks' duration (NCT03131648, NCT03160885, NCT03363854, NCT03562377, NCT03526861, NCT03761537, NCT04587453), and the ongoing, up to 5-year extension study (ECZTEND; NCT03587805). Methods: Two datasets were analyzed: a placebo-controlled (PC) dataset from the initial 16-wk period of the parent trials and an all-tralokinumab (AT) dataset combining the parent trials with the subsequent ECZTEND trial including pts from first dose of tralokinumab until end of tralokinumab exposure or data cut-off (April 30th, 2022). Exposure was defined over the active treatment periods. For the AT dataset, periods on placebo were disregarded. All treatment-emergent adverse events (AEs) were recorded. AEs of special interest (AESIs) were predefined. Proportions of pts with events and incidence rates (IR) per 100 patient-years of exposure (PYE) were calculated. PYE was defined as the time until the first event or exposure end, whichever came first, and incidence was defined as the first event. Results: In total, 2693 pts (≥12 years) received tralokinumab for up to 238.5 weeks (≈4.5 years) with a median exposure time of 76.5 weeks in the AT dataset. Total exposure time was 5320.2 patient years. Median age at baseline was 33.0 years (min-max; 12-92). 10.4% of pts were 12-17 years. Overall, 2307 pts experienced an AE (IR=202.0), most (97.3%) of which were mild-to-moderate. Serious AEs (SAEs) were reported in 226 pts (IR=4.5); SAEs were considered possibly or probably related by the investigator in 50 pts (IR=0.9). No SAEs at the preferred term level were reported with an IR≥0.1. Discontinuation of treatment due to AEs was low (IR=2.8). AEs leading to drug withdrawal with an IR>0.1 were dermatitis atopic (IR=0.5) and injection site reaction (ISR) (IR=0.2). The most frequently reported AEs in the AT dataset were consistent with the PC dataset, including nasopharyngitis (IR=18.4), upper respiratory tract infection (IR=6.9), conjunctivitis (IR=5.0), ISR (IR=3.6), conjunctivitis allergic (IR=2.7), and injection site pain (IR=1.5). AESIs, including eye disorders, skin infections requiring systemic treatment, eczema herpeticum, and malignancies, were observed in the AT dataset at rates similar to or lower than reported in the PC dataset. Conclusions: Long-term use of tralokinumab, for up to 4.5 years, was well tolerated, and the pattern of AEs was consistent with the initial placebo-controlled treatment period and with no new safety signals identified. [ABSTRACT FROM AUTHOR]

Background Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, and dupilumab, an anti-interleukin 4 receptor a monoclonal antibody, have been approved for the treatment of patients with moderate-to-severe atopic dermatitis (AD). The efficacy of abrocitinib and dupilumab as monotherapy or in combination with medicated topical therapy has been demonstrated in multiple phase 3 clinical trials. As is the case with many therapies, some patients with AD may need to discontinue treatment with dupilumab (due to inadequate efficacy, intolerable side-effects, patient choice, or other reasons) and switch to other systemic therapies. Objective To evaluate the long-term treatment response in patients with moderate-to-severe AD who switched from dupilumab to abrocitinib, as it is valuable information for prescribers and patients to consider when making treatment decisions. Methods: The phase 3 JADE COMPARE trial (NCT03720470) evaluated the efficacy of abrocitinib (100 mg or 200 mg once daily) and dupilumab (300 mg every 2 weeks) versus placebo in combination with topical medicated therapy in patients with moderate-to-severe AD through week 16. After a wash-out period, dupilumab-treated patients from JADE COMPARE who enrolled in the ongoing long-term extension trial JADE EXTEND (NCT03422822; clinical data cutoff: Sept 25, 2021) were randomised to receive double-blinded treatment with abrocitinib 100 mg or 200 mg. This post hoc analysis evaluated the response to dupilumab through week 16 in JADE COMPARE and thereafter in JADE EXTEND following a switch to abrocitinib through week 104 of total treatment duration/week 84 of abrocitinib treatment. Assessments included Investigator's Global Assessment score of 0 (clear) or 1 (almost clear) with a =2-point improvement from baseline (IGA 0/1), =75% or =90% improvement from baseline in Eczema Area and Severity Index (EASI-75 or EASI-90), =4-point improvement from baseline in Peak Pruritus Numerical Rating Scale score (PP-NRS4; PP-NRS used with permission from Regeneron Pharmaceuticals, Inc., and Sanofi), and a PP-NRS score of 0 or 1 (PP-NRS 0/1). JADE EXTEND data are presented as observed; patients with missing data at a visit were excluded. Analyses included both dupilumab responders and non-responders. Results: Overall, 242 patients were treated with dupilumab in JADE COMPARE (mean age: 37 years; IGA score 4: 33%). Of those, 203 enrolled in JADE EXTEND and received abrocitinib 200 mg (n=73) or abrocitinib 100 mg (n=130). After 16 weeks of treatment with dupilumab in JADE COMPARE, the proportion of responders was 39% for IGA 0/1, 66% for EASI-75, 39% for EASI-90, 57% for PP-NRS4, and 24% for PP-NRS 0/1. As early as 2 weeks after switching to abrocitinib (200 mg/100 mg) in JADE EXTEND, the proportion of responders was observed to increase in a dose-dependent manner, respectively, for IGA 0/1 (61%; 51%), EASI-75 (90%; 85%), EASI-90 (60%; 54%), PP-NRS4 (81%; 72%), and PP-NRS 0/1 (47%; 37%). Long-term efficacy was observed out to week 84 (Figure). Conclusions: In patients with moderate-to-severe AD who received prior treatment with dupilumab, switching to abrocitinib resulted in dose-dependent increases in the proportion of responders as early as week 2 after treatment with abrocitinib. This efficacy continued to be observed long-term through week 84 of abrocitinib treatment. [ABSTRACT FROM AUTHOR]

Introduction Tapinarof cream 1% once daily (QD) demonstrated efficacy versus vehicle and was well tolerated in adults and Downloaded from https://academic.oup.com/bjd/article/190/Supplement_2/ii17/7601611 by Ebsco, Jnls Cust Serv on 12 February 2024 adolescents with moderate to severe atopic dermatitis (AD) in a previously reported phase 2 trial. Objective Here, we report pivotal phase 3 efficacy and safety results for tapinarof cream 1% QD in the treatment of adults and children down to 2 years of age with AD. Materials and Methods ADORING 1 and 2 were two identical phase 3, randomized, double-blind, vehicle-controlled trials. Eligibility criteria included a Validated Investigator Global Assessment for Atopic DermatitisTM (vIGA-ADTM) score of ≥3, Eczema Area and Severity Index (EASI) score of ≥6, and body surface area (BSA) involvement of 5-35%. Patients were randomized 2:1 to receive tapinarof cream 1% or vehicle cream QD for 8 weeks. The primary efficacy endpoint was vIGA-ADTM response, defined as a score of clear (0) or almost clear (1) and ≥2-grade improvement from baseline at Week 8. Secondary efficacy endpoints included ≥75% improvement in EASI score (EASI75) and proportion of patients (aged ≥12 years) with a baseline Peak Pruritus-Numerical Rating Scale (PP-NRS) score of ≥4 who achieved a ≥4-point reduction at Week 8. Adverse events (AEs) included rates of AEs of special interest (AESIs): contact dermatitis, follicular event, and headache. Results: 407 and 406 patients aged 2-81 years were randomized in ADORING 1 and 2, respectively. At baseline, 84.0-89.9% of patients had a vIGA-ADTM score of 3 (moderate), mean EASI score of 12.5-13.3, and mean BSA affected of 16.7-16.9% across trials. At Week 8, both the primary and all secondary efficacy endpoints were met with statistical significance in the tapinarof groups versus vehicle: vIGA-ADTM response rates were 45.4% vs 13.9% and 46.4% vs 18.0% (both P<0.0001); EASI75 response rates were 55.8% vs 22.9% and 59.1% vs 21.2% (both P<0.0001); and a ≥4-point reduction in PP-NRS was achieved by 55.8% vs 34.2% (P=0.0366) and 52.8% vs 24.1% (P=0.0015), in ADORING 1 and 2, respectively. AEs were mostly mild or moderate; the most frequent (≥5% in any group) were folliculitis, headache, and nasopharyngitis. Trial discontinuation rates due to AEs were lower with tapinarof versus vehicle (ADORING 1: 1.9% vs 3.6%; ADORING 2: 1.5% vs 3.0%, respectively). Rates of AESIs with tapinarof versus vehicle were: contact dermatitis 1.5% vs 2.2% and 1.1% vs 1.5%; follicular events 10.0% vs 0.7% and 8.9% vs 1.5%; and headache 7.0% vs 2.2% and 1.5% vs 0%, in each trial, respectively. Conclusions: Tapinarof cream 1% QD demonstrated statistically significant efficacy compared with vehicle for primary and secondary efficacy endpoints in adults and children down to 2 years of age with AD. Tapinarof was well tolerated, with no new safety or tolerability signals. AEs were mostly mild to moderate and led to low rates of trial discontinuation, demonstrating the predictable safety profile of tapinarof cream 1% QD. [ABSTRACT FROM AUTHOR]

Introduction Roflumilast cream 0.15% is a selective, highly potent phosphodiesterase 4 inhibitor under investigation as a non-steroidal, once-daily treatment for atopic dermatitis (AD). Objectives: Here, pooled results from two identical Phase 3 randomized controlled trials (INTEGUMENT-1: NCT04773587 and INTEGUMENT-2: NCT04773600) are presented. Methods: Patients with AD aged ≥6 years with baseline Eczema Area and Severity Index (EASI) score ≥5 and Validated Investigator Global Assessment-AD (vIGA-AD) score of Mild or Moderate were randomized 2:1 to apply roflumilast (n=884) or vehicle (n=453) once daily for 4 weeks. Results: A significantly greater percentage of roflumilast-versus vehicle-treated patients achieved the primary endpoint, vIGA-AD Success (Clear or Almost Clear vIGA-AD plus ≥2-grade improvement from baseline) at Week 4 (31.3% vs. 14.1%; P<0.0001). Significant differences favoring roflumilast were observed for multiple secondary endpoints at Week 4: percentage of patients achieving vIGA-AD of Clear or Almost Clear (41.1% vs. 21.4%; P<0.0001), percentage achieving 75% reduction in EASI (42.7% vs. 20.6%; P<0.0001), and percentage with baseline Worst Itch-Numeric Rating Scale ≥4 achieving a 4-point reduction (31.9% vs. 16.6%; P<0.0001). Improvement in itch was reported as early as 24 hours. Both groups had low incidences of treatment-emergent adverse events (TEAE), serious adverse events, and TEAEs leading to discontinuation. Local tolerability was favorable, with >90% of patients reporting no or mild sensation across both treatment groups at all timepoints. Conclusions: Once-daily roflumilast cream 0.15% provided improvement across multiple efficacy endpoints by Week 4 with favorable safety and tolerability in patients aged ≥6 years with AD in two Phase 3 trials. [ABSTRACT FROM AUTHOR]

Introduction Formulating a topical medication that does not irritate the skin is an important factor contributing to patient treatment adherence and satisfaction. Many topical prescription products use penetration enhancers (including propylene glycol, polyethylene glycol, and ethanol) to overcome barrier properties of the skin. However, these excipients may irritate the skin causing tolerability reactions such as burning and stinging, which can reduce patient treatment adherence. Topical roflumilast is a highly potent (Kd~0.7 nM) phosphodiesterase 4 inhibitor formulated as a water-based cream or foam that does not contain penetration enhancers or fragrances. Objectives: We present prospectively assessed investigator- and patient-rated local tolerability from Phase 3 trials of topical roflumilast for patients with psoriasis (DERMIS-1, DERMIS-2, ARRECTOR) seborrheic dermatitis (SD; STRATUM), and atopic dermatitis (AD; INTEGUMENT-1, INTEGUMENT-2). Methods: Patients were randomized to apply topical roflumilast (DERMIS: 0.3% cream; ARRECTOR and STRATUM: 0.3% foam; INTEGUMENT: 0.15% cream) or vehicle once daily for 8 weeks (DERMIS, ARRECTOR, and STRATUM) or 4 weeks (INTEGUMENT). Investigators assessed local tolerability on an 8-point scale (0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) in the clinic before investigational product (IP) application. Patients reported local tolerability on a 4-point scale (0 [none: no sensation] to 3 [severe: hot, tingling/stinging sensation that has caused definite discomfort]) in the clinic 10-15 minutes after IP application. Tolerability was also assessed by reviewing documented adverse events. Results: As assessed by investigators, =96.5% of patients in the roflumilast-treated groups had no evidence of irritation at the application site across all trials at all timepoints. Patient-rated local tolerability was favorable and improved with treatment: across all trials, 1% of roflumilast-treated patients reported a score of 3 (severe; defined as a "hot tingling/stinging sensation that has caused definite discomfort") after the first application (day 1) and <1% at each subsequent assessment. Rates of adverse events, including those at the application site, were low for all trials. Conclusions: Roflumilast cream and foam formulations demonstrated favorable local tolerability based on investigator- and patientrated assessments in patients with psoriasis, SD, and AD, including application to sensitive areas such as the face and intertriginous areas. [ABSTRACT FROM AUTHOR]

Introduction Lebrikizumab is a novel monoclonal antibody that binds with high affinity and slow off-rate to IL-13, thereby blocking the downstream effects of IL-13 with high potency. The efficacy and safety of lebrikizumab have been investigated in a number of Phase 3 trials including: ADvocate1 (NCT04146363), ADvocate2 (NCT04178967), ADhere (NCT04250337), and ADjoin (NCT04392154). Lebrikizumab (with or without TCS) was efficacious in providing clinically meaningful improvements in the signs and symptoms of AD through Week(W) 52 in adult and adolescent patients with moderate-to-severe AD. Objectives: We report the efficacy and safety of lebrikizumab (LEB) in the long-term extension study ADjoin (NCT04392154) following 104 weeks of continuous LEB treatment with and without TCS use. Methods: Patients in ADvocate1&2 who achieved either EASI 75 or IGA 0/1 (without rescue) at W16 were re-randomized 2:2:1 to LEB250mg Q2W, LEB250mg Q4W, or placebo (LEB withdrawal). Patients who completed W52 of ADvocate1&2 were able to enroll in ADjoin. Patients in ADhere who achieved either EASI 75 or IGA 0/1 (without rescue) at W16 were able to enroll into ADjoin and randomized 2:1 to LEB250mg Q2W or LEB250mg Q4W. Data are reported for patients originating from ADvocate1&2 and ADhere who received LEB250mg Q2W or Q4W in ADjoin. Efficacy outcomes were assessed based on all collected data (as observed analysis) up to 104W of LEB treatment. Safety was reported from ADjoin enrollment up to the data cut-off April 14, 2023. Results: At W104, IGA 0/1 was maintained by 38/44 (86.4%; Q2W) and 42/55 (76.4%; Q4W) patients from ADvocate1&2 and 26/31 (83.9%; Q2W) and 11/14 (78.6%; Q4W) patients from ADhere. EASI 75 was maintained by 65/68 (95.6%; Q2W) and 77/80 (96.3% Q4W) ADvocate1&2 patients and 39/41 (95.1%; Q2W) and 24/25 (96.0%; Q4W) ADhere patients at W104. In patients who achieved EASI 75 at W16, EASI 90 was achieved by 56/68 (82.4%; Q2W) and 66/80 (82.5%; Q4W) ADvocate1&2 patients and 35/41 (85.4%; Q2W) and 18/25 (72.0%; Q4W) ADhere patients at 104W.During ADjoin, 166/267 (62.2%) patients from the subpopulations of ADvocate1&2 and ADhere who received LEB Q2W or Q4W in ADjoin reported adverse events (AEs), most of which were mild (31.5%, n=84) or moderate (27.0%, n=72) in severity. Serious AEs were reported by 10 (3.8%) patients. There was one death in the ADhere Q2W arm. Six (2.3%) patients reported AEs leading to treatment discontinuation. The safety profile of LEB in ADjoin is consistent with that observed during ADvocate1&2 and ADhere. Conclusions: Efficacy outcomes were maintained long-term, over 2 years of continuous LEB treatment, in both LEB250mg Q2W and Q4W arms. The safety profile of LEB in ADjoin is consistent with previous LEB studies in patients with moderate-to-severe AD. [ABSTRACT FROM AUTHOR]

Baricitinib previously demonstrated improvements in itch and sleep disturbance versus placebo in adults with moderate-to-severe atopic dermatitis (AD). Examine if itch and sleep improvements are associated with better quality of life (QoL) and productivity in patients with AD. Data were drawn from BREEZE-AD5 (NCT03435081). Itch and sleep improvement at Week 16 were defined using ≥4-point improvements in the Itch Numeric Rating Scale and ≥1.5 decreases in the number of nighttime awakenings since baseline, respectively. Patients with and without improvements were compared on Dermatology Life Quality Index (DLQI) and Work Productivity and Activity Impairment-AD scores. Changes from baseline were analyzed using ANCOVA with last observation carried forward. Proportions were analyzed using logistic regression with non-responder imputation. Greater proportions of patients with versus without itch improvement indicated no impact of AD on QoL (37.7 vs. 1.8%). Patients with itch improvement had greater decreases in work time impaired (−29.3 vs. −5.6%). More patients with versus without sleep improvement reported no effect of AD on QoL (25.5 vs. 1.1%); patients with better sleep experienced larger reductions in work time spent impaired (−33.3 vs. −6.1%). Patients with AD who experienced itch and sleep improvement had significantly better QoL and productivity. [ABSTRACT FROM AUTHOR]

Core outcome sets are critically important outcomes that should be measured in clinical trials. Their absence in atopic dermatitis is a form of research waste and impedes combining evidence to inform patient care. Here, we articulate the rationale for core outcome sets in atopic dermatitis and review the work of the international Harmonising Outcome Measures for Eczema group from its inception in Munich, 2010. We describe core domain determination (what should be measured), to instrument selection (how domains should be measured), culminating in the complete core outcome measurement set in Tokyo, 2019. Using a "road map," Harmonising Outcome Measures for Eczema includes diverse research methods including Delphi and nominal group techniques informed by systematic reviews of properties of candidate instruments. The 4 domains and recommended instruments for including in all clinical trials of atopic dermatitis are patient symptoms, measured by Patient-Oriented Eczema Measure and peak Numerical Rating Scale 11 for itch intensity over 24 hours, clinical signs measured using the Eczema Area and Severity Index, quality of life measured by the Dermatology Life Quality Index series for adults, children, and infants, and long-term control measured by either Recap of atopic eczema or Atopic Dermatitis Control Tool. [ABSTRACT FROM AUTHOR]

Background: For adolescent patients (aged ≥ 12 to < 18 years) with uncontrolled moderate-to-severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo, with an acceptable safety profile. However, long-term data on the approved dose regimens of dupilumab in adolescents with AD are lacking. Objectives: This open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in adolescents with moderate-to-severe AD who had participated in dupilumab parent trials. Methods: Patients enrolled under the original study protocol received subcutaneous dupilumab according to a weight-based regimen (2 or 4 mg/kg every week). Following protocol amendment, patients were switched to subcutaneous dupilumab 300 mg every 4 weeks (q4w) irrespective of weight, and newly enrolled patients were started on dupilumab 300 mg q4w. Patients with an inadequate clinical response (Investigator's Global Assessment [IGA] score of 0/1 was not reached) to the q4w regimen could be uptitrated to the approved dupilumab dose regimens of 200 or 300 mg every 2 weeks (body weight < 60 or ≥ 60 kg, respectively). Patients whose IGA score of 0/1 was maintained continuously for a 12-week period after week 40 were discontinued from dupilumab, monitored for relapse, and re-initiated on dupilumab if required. Results: Data for 294 patients (mean age 14.7 years) were analyzed, 102 (34.7%) of whom had completed the 52-week visit at the database lock. The dupilumab long-term safety profile was comparable to that seen in adults and consistent with the known safety profile. Most treatment-emergent adverse events were mild/moderate. By week 52, 42.7% of patients had an IGA score of 0/1 (clear/almost clear), and 93.1%, 81.2%, and 56.4%, respectively, had at least a 50%, 75%, or 90% improvement in Eczema Area and Severity Index (EASI). Most (70.9%) patients required uptitration to the approved dupilumab dose regimen. The proportions of uptitrated patients with an IGA score of 0/1 or 75% improvement in EASI increased over time, reaching 35.7% and 51.9%, respectively, 48 weeks after the first uptitration visit. By week 52, 29.4% of patients had clear/almost clear skin sustained for 12 weeks and had stopped medication; 56.7% relapsed and were subsequently re-initiated on treatment, with a mean time to re-initiation of 17.5 (± standard deviation 17.3) weeks. Conclusions: Consistent with results seen with short-term treatment, long-term treatment with dupilumab showed an acceptable safety profile while providing incremental clinical benefit with continued treatment over time. The high proportion of patients who needed uptitration because of inadequate response to q4w dosing supports the q2w dose regimen as optimal for this age group. Finally, the majority of patients who stopped medication after having clear/almost clear skin sustained over 12 weeks experienced disease recurrence, suggesting the need for continued dupilumab dosing to maintain efficacy. Trial Registration: ClinicalTrials.gov Identifiers: NCT02612454, NCT02407756, NCT03054428, and NCT03050151. Infographic: EYru5bYjcUouUcQrkiC3DM Video abstract: What is the long-term safety and efficacy profile in adolescents with moderate-to-severe atopic dermatitis treated with the approved dupilumab dose regimen? (MP4 40,966 KB) Plain Language Summary: Atopic dermatitis, or eczema, is a common chronic skin disease that can cause intense and persistent itching and rashes. Atopic dermatitis remains a problem for many adolescent patients, even if they use a number of different treatments. Dupilumab is a newer treatment for atopic dermatitis. In short-term clinical studies, dupilumab improved the disease with acceptable safety. In this study, adolescents with moderate-to-severe atopic dermatitis who had completed one of the short-term studies continued dupilumab treatment for 1 year. The patients started treatment with dupilumab once every 4 weeks. But if their atopic dermatitis did not improve sufficiently, they were given dupilumab every 2 weeks. Through a year of treatment, there were no unexpected side effects. The side effects that did occur were mild or moderate in severity and in most cases did not lead to interruption of treatment. Almost half of the patients achieved skin that was clear or almost clear of atopic dermatitis during the study. But their atopic dermatitis often returned if they stopped being treated, and about half of them needed to start treatment again. Most patients needed to be treated every 2 weeks. The positive effects of dupilumab generally increased the longer patients were treated. [ABSTRACT FROM AUTHOR]

As atopic dermatitis (AD) is a chronic and potentially lifelong disease, it is important to determine the long-term safety of new treatments. Tralokinumab, which specifically targets interleukin-13, is approved in Europe, Canada and the United States for the treatment of adults with moderate-to-severe AD. During the initial 12–16 week placebo-controlled treatment period of Phase 2 and 3 trials, tralokinumab was well-tolerated with an overall frequency of adverse events (AEs) similar to the placebo. An ongoing open-label extension trial, ECZTEND (NCT03587805), is assessing the safety and efficacy of tralokinumab up to 5 years after parent trials (PT). To report an interim safety analysis of patients treated with tralokinumab for up to 42 months (≤ 1 year in PT and ≤ 2.5 years in the open-label extension ECZTEND), including AEs of special interest (AESI). In ECZTEND, moderate-to-severe AD patients who completed the previous tralokinumab PT received subcutaneous tralokinumab 300 mg every 2 weeks after a 600 mg loading dose; topical corticosteroid use was optional. All AEs were recorded, coded, and classified by severity, causality and outcome. AESIs were predefined in PT based on areas of safety interest for monoclonal antibodies in AD, including eye disorders (e.g. conjunctivitis), skin infections requiring systemic treatment, eczema herpeticum and malignancies diagnosed after dosing. Event rates are presented as the number of events (nE) per 100 patient-years of exposure (PYE). All AEs described were treatment-emergent AEs, defined as AEs reported after the first dosing of the study drug. As of 30 April 2021, the interim safety analysis included 1442 patients from the PT ECZTRA 1, 2, 3, 4, 5 and 7 who had received ≥1 dose of tralokinumab in ECZTEND, with 121.0 weeks mean exposure time on tralokinumab [median 131.5 weeks (IQR 83.4–161.8); min 0.0, max 186.4 weeks]. Total exposure time in ECZTEND was 2446.2 PYE. Overall, 1127 patients experienced an AE (198.7 nE/100 PYE), the majority of which were mild (132.6 nE/100 PYE). The most frequently reported AEs (≥5.0% of patients) were the same as in the PT, including viral upper respiratory tract infection (18.2 nE/100 PYE, mainly reported as the common cold), atopic dermatitis (17.9 nE/100 PYE), upper respiratory tract infection (5.8 nE/100 PYE), headache (4.4 nE/100 PYE) and conjunctivitis (3.8 nE/100 PYE). The rates of AEs were generally lower as compared to short-term rates in the PT. Most of the serious AEs (SAEs; 4.9 nE/100 PYE) were reported as single events without clustering on the type. No events of conjunctivitis AEs were SAEs, and only five patients discontinued due to conjunctivitis AEs. AESI eye disorders, skin infections requiring systemic treatment, eczema herpeticum and malignancies were observed at rates similar to or lower than reported in PT. Consistent safety was demonstrated during up to 42 months of tralokinumab treatment in patients with moderate-to-severe AD. Exposure-adjusted incidence rates of AESIs, including eczema herpeticum and skin infections requiring systemic treatment, were generally lower than rates reported during the short-term, placebo-controlled period up to week 16. Exposure-adjusted incidence rates of conjunctivitis were lower with long-term exposure, and only five patients discontinued due to conjunctivitis. This analysis supports the long-term benefit-risk profile of targeted IL-13 inhibition with tralokinumab for patients with moderate-to-severe AD. [ABSTRACT FROM AUTHOR]

Background: Pivotal phase III studies demonstrated that abrocitinib, an oral, once-daily, JAK1-selective inhibitor, is effective treatment for moderate-to-severe atopic dermatitis (AD) as monotherapy and in combination with topical therapy. Objective: The aim of this study was to evaluate the long-term safety of abrocitinib 200 mg and 100 mg in an integrated analysis of a phase IIb study, four phase III studies, and one long-term extension study. Methods: Two cohorts were analyzed: a placebo-controlled cohort from 12- to 16-week studies and an all-abrocitinib cohort including patients who received one or more abrocitinib doses. Adverse events (AEs) of interest and laboratory data are reported. Results: Total exposure in the all-abrocitinib cohort (n = 2856) was 1614 patient-years (PY); exposure was ≥ 24 weeks in 1248 patients and ≥ 48 weeks in 606 (maximum 108 weeks). In the placebo-controlled cohort (n = 1540), dose-related AEs (200 mg, 100 mg, placebo) were nausea (14.6%, 6.1%, 2.0%), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%). Platelet count was reduced transiently in a dose-dependent manner; 2/2718 patients (200-mg group) had confirmed platelet counts of < 50 × 103/mm3 at week 4. Incidence rates (IRs) were 2.33/100PY and 2.65/100 PY for serious infection, 4.34/100PY and 2.04/100PY for herpes zoster, and 11.83/100PY and 8.73/100PY for herpes simplex in the 200-mg and 100-mg groups, respectively. IRs for nonmelanoma skin cancer, other malignancies, and major adverse cardiovascular events were < 0.5/100PY for both doses. Five venous thromboembolism events occurred (IR 0.30/100PY), all in the 200-mg group. There were three deaths due to gastric carcinoma (diagnosed at day 43), sudden death, and COVID-19. Conclusion: Abrocitinib, with proper patient and dose selection, has a manageable tolerability and longer-term safety profile appropriate for long-term use in patients with moderate-to-severe AD. Trial Registries: ClinicalTrials.gov: NCT02780167, NCT03349060, NCT03575871, NCT03720470, NCT03627767, NCT03422822. [ABSTRACT FROM AUTHOR]

Introduction & Objectives: Upadacitinib (UPA) is an oral Janus kinase 1 (JAK1) inhibitor approved in multiple countries for the treatment of adolescents and adults with moderate-to-severe atopic dermatitis (AD). Here, we present the efficacy and safety of UPA administered over 140 weeks in an ongoing randomized, double-blinded, multicenter phase 3 study (Measure Up 1, NCT03569293). Materials & Methods: Patients (12-75 years) with moderate-to-severe AD were randomized 1:1:1 to receive UPA 15 mg (UPA15), UPA 30 mg (UPA30), or placebo (PBO) once daily at baseline. At week 16, PBO-treated patients were re-randomized 1:1 to receive UPA15 (PBO/UPA15) or UPA30 (PBO/UPA30) once daily. Co-primary endpoints were the proportion of patients achieving ≥75% reduction in EASI (EASI 75) from baseline and vIGA-AD of clear (0) or almost clear (1) with ≥2 grades of reduction from baseline (vIGA-AD 0/1) at week 16. A meaningful improvement in itch, defined as a ≥4-point reduction in Worst Pruritus Numeric Rating Scale (ΔWP-NRS≥4), was assessed among patients with baseline WP-NRS≥4. All efficacy endpoints were summarized using the Observed Cases (OC) approach, and no missing data imputation was applied. Safety was assessed by monitoring of serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and treatment-emergent adverse events of special interest (AESI), which were analysed as exposure-adjusted rates per 100 patient-years (PY). Results: Efficacy results were sustained up to week 140 since week 16. Proportions of patients in the UPA15 (205), UPA30 (206), PBO/UPA15 (91), and PBO/UPA30 (94) groups achieving EASI 75 at week 140 were 88.8% (182), 90.3% (186), 83.5% (76), and 89.4% (84), respectively, and for vIGA-AD 0/1 was 63.4% (130), 65.5% (135), 60.4% (55), and 75.5% (71), respectively. Proportions of patients achieving an improvement (reduction) in WP-NRS≥4 from baseline at week 140 were 68.0% (136), 70.5% (146), 71.3% (62), and 81.3% (74) respectively. Overall, the rates of AESIs were similar across treatment groups, which aligned with prior reports at earlier time points. Both UPA15 and UPA30 were well-tolerated in all patients, and no new safety signals were observed compared to the known safety profile of UPA. Data from two additional pivotal studies will be available at the time of presentation. Conclusion: In this interim analysis, sustained skin clearance and itch and a consistent safety profile were observed with UPA 15 mg and UPA 30 mg across 140 weeks in adolescent and adult patients with moderate-to-severe AD. [ABSTRACT FROM AUTHOR]

Background: Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis.Methods: In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060.Findings: Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p<0·0001). Of the patients with available data for the coprimary endpoints at week 12, compared with the placebo group, the proportion of patients who had achieved an EASI-75 response was significantly higher in the abrocitinib 100 mg group (62 [40%] of 156 patients vs nine [12%] of 76 patients; p<0·0001) and abrocitinib 200 mg group (96 [63%] of 153 patients vs nine [12%] of 76 patients; p<0·0001). Adverse events were reported in 108 (69%) of 156 patients in the abrocitinib 100 mg group, 120 (78%) of 154 patients in the abrocitinib 200 mg group, and 44 (57%) of 77 patients in the placebo group. Serious adverse events were reported in five (3%) of 156 patients in the abrocitinib 100 mg group, five (3%) of 154 patients in the abrocitinib 200 mg group, and three (4%) of 77 patients in the placebo group. No treatment-related deaths were reported.Interpretation: Monotherapy with oral abrocitinib once daily was effective and well tolerated in adolescents and adults with moderate-to-severe atopic dermatitis.Funding: Pfizer. [ABSTRACT FROM AUTHOR]

Missing data occur in clinical trials and have the potential to lead to biased results. Subsequently, the analytical methods for handling the missing data are important to evaluate. In atopic dermatitis (AD) trials, missing data are not handled consistently across studies. Lebrikizumab is a monoclonal antibody that binds with high affinity and slow off-rate to interleukin (IL)-13, thereby blocking the downstream effects of IL-13 with high potency. In ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), two randomized, double-blinded, placebo-controlled Phase 3 trials evaluating the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe AD, a combined nonresponder/multiple imputation (NRI/MI) approach, was applied on the primary and key secondary endpoints. This study aims to illustrate the NRI/MI method using individual patient examples and to present Week 16 study results from ADvocate1 and ADvocate2 with NRI/MI and single imputation methods, NRI and last-observation carried forward (LOCF). In the combined NRI/MI method, data from patients after initiating rescue medication or discontinuing treatment due to lack of efficacy were imputed with NRI, and missing data for other reasons were imputed with MI, which uses a statistical model based on all available patient data to impute missing values. The MI method considers each patient's trajectory and leverages information from other patients within the same treatment arm to impute the missing data. With NRI alone, the cause leading to the missing data is not considered and missing data for any reason are imputed as nonresponse. With LOCF, missing data are replaced with the last available measurement; LOCF assumes that the patient response would be stable over time and does not consider the reason for missing data. We determined the amount of missing data in ADvocate1 and ADvocate2, and we assessed patient-level imputed IGA scores to illustrate NRI/MI, NRI and LOCF. With these missing data handling methods, we evaluated the percentage of patients achieving the co-primary endpoints of ADvocate1 and ADvocate2: an Investigator's Global Assessment score of 0 or 1 [IGA (0,1); clear or almost clear] with ≥2-point improvement from baseline or 75% improvement in Eczema Area and Severity Index (EASI 75) at Week 16. With the NRI/MI method, most missing data at Week 16 were imputed with NRI (ADvocate1: 73%, ADvocate2: 82%) compared with MI (ADvocate1: 27%, ADvocate2: 18%). Example imputed IGA scores based on patient-level data will be presented to demonstrate the missing data handling methods. For NRI/MI, NRI and LOCF, respectively, the percentage of patients achieving IGA 0,1 were 12.7%, 11.3% and 12.8% for placebo in ADvocate1 and 10.8%, 9.6% and 11.0% for placebo in ADvocate2; 43.1%, 41.0% and 42.4% for lebrikizumab in ADvocate1 and 33.2%, 31.3% and 33.5% for lebrikizumab in ADvocate2. The percentage of patients achieving EASI 75 were 16.2%, 14.2% and 16.3% for placebo in ADvocate1 and 18.1%, 17.1% and 19.2% for placebo in ADvocate2; 58.8%, 56.5% and 60.1% for lebrikizumab in ADvocate1 and 52.1%, 50.2% and 55.5% for lebrikizumab in ADvocate2. When using the NRI/MI method, we determined most missing data in ADvocate1 and ADvocate2 were handled with NRI. This analysis suggests that the NRI/MI method may provide a realistic estimation of response rate in ADvocate1 and ADvocate2. [ABSTRACT FROM AUTHOR]

Lebrikizumab (LEB) is a novel, high-affinity monoclonal anti - body that selectively binds to interleukin (IL)-13. To evaluate the efficacy and safety of LEB monotherapy in patients with moderate-to-severe atopic dermatitis (AD) in two identical phase 3 trials ADvocate1 (ADv1) and ADvocate2 (ADv2). Patients who responded to LEB 250 mg every 2 weeks (LEB Q2W) at the end of the 16-week induction period were re-randomized in a 2 : 2 :1 ratio to receive LEB Q2W, LEB 250 mg every 4 weeks (LEB Q4W) or placebo (LEB withdrawal) for an additional 36 weeks. Response, at week 16, was defined as achieving an IGA (0, 1) with a ≥2-point improvement or EASI75 and no use of rescue medication. Efficacy outcomes reported at week 52 included IGA (0, 1), EASI 75, ≥4-point reduction in Pruritis Numeric Rating Scale (NRS), EASI 90 and DLQI ≥4-point. Safety analysis was conducted on all patients who received ≥1 dose of LEB. Patients maintained IGA (0, 1) in LEB Q2W (ADv1, 75.8%; ADv2, 64.6%), LEB Q4W (ADv1, 74.2%; ADv2, 80.6%) and LEB withdrawal (ADv1, 46.5%; ADv2, 49.8%). Maintenance of EASI75 was, in LEB Q2W (ADv1, 79.2%; ADv2, 77.4%), LEB Q4W (ADv1, 79.2%; ADv2, 84.7%) and LEB withdrawal (ADv1, 61.3%; ADv2, 72.0%). For Pruritus NRS ≥4-point improvement from baseline, patients-maintained improvement in the LEB Q2W (ADv1, 81.2%; ADv2, 90.3%), LEB Q4W (ADv1, 80.4%; ADv2, 88.1%) and LEB withdrawal (ADv1, 65.4%; ADv2, 67.6%). Maintenance of EASI90 was, in LEB Q2W (ADv1, 66.1%; ADv2, 61.5%), LEB Q4W (ADv1, 66.6%; ADv2, 67.4%) and LEB withdrawal (ADv1, 45.5%; ADv2, 36.9%). DLQI ≥4-point improvement from baseline was LEB Q2W (ADv1, 64.0%; ADv2, 59.0%), LEB Q4W (ADv1, 62.7%; ADv2, 73.0%) and LEB withdrawal (ADv1, 57.7%; ADv2, 45.5%). TEAEs were reported by 58.1% (ADv1) and 67.8% (ADv2) LEB-treated patients at week 52. Serious adverse events were reported by 3.3% of ADv1 patients and 2.7% of ADv2 patients. In ADv1 and ADv2, 2.3% and 3.9% of patients reported an adverse event leading to treatment discontinuation, respectively. Both LEB Q2W and LEB Q4W maintained improvement in all reported outcomes for the treatment of moderate-to-severe AD through 52 weeks. The safety profile was consistent with previously published data. [ABSTRACT FROM AUTHOR]

In the monotherapy phase 3 trial (ECZTRA 6, NCT03526861) in adolescents with moderate-to-severe atopic dermatitis (AD) treated with tralokinumab, IGA of clear/almost clear skin (IGA 0/1) at week 16 was a primary endpoint. IGA 0/1 can be a high standard to achieve for patients with moder - ate-to-severe AD and may not fully reflect achievement of other clinically meaningful parameters, such as improvement in signs, symptoms and/or quality-of-life (QoL). To assess the impact of tralokinumab (150 or 300 mg) vs. placebo on other clinically meaningful parameters at week 16 in the sub - set of patients who did not achieve IGA 0/1 at week 16 and/ or used rescue medication. Adolescents (12–17 years) were randomized to subcutaneous tralokinumab 150 or 300 mg, or placebo, every 2 weeks. Patients who did not achieve IGA 0/1 at week 16 and/or utilized rescue therapy were included in this post-hoc analysis. Non-responder imputation was used for patients who utilized rescue therapy or had missing data. Clinically meaningful responses were defined as EASI50, ≥ 3-point improvement in pruritus NRS, or ≥6-point improvement in CDLQI. At week 16, 78.6% and 82.5% of tralokinumab-treated patients (150 mg/300 mg) vs. 95.7% (placebo) exhibited IGA >1 and/or used rescue therapy. 36.4% (150 mg) and 52.5% (300 mg) of patients with IGA >1 in the tralokinumab arms, compared to 21.1% (placebo), achieved clinically meaningful responses in at least one measure: EASI-50, pruritus NRS, or CDLQI. Greater proportions of tralokinumab-treated patients (150/300 mg vs. placebo) achieved EASI-50 (31.2%/41.3% vs. 10.0%) and ≥3-point improvement in pruritus NRS (21.6%/22.8% vs. 8.0%). A greater proportion of tralokinumab 300 mg patients vs. placebo (35.2% vs. 15.0%) achieved ≥6-point improvement in CDLQI. Many tralokinumab-treated adolescents who did not achieve IGA 0/1 at week 16 and/or used rescue therapy still achieved clinically meaningful improvements in AD signs, symptoms, and/or QoL. [ABSTRACT FROM AUTHOR]

Background: Transepidermal water loss (TEWL) and surface capacitance measure skin barrier permeability and stratum corneum (SC) hydration, respectively, and are frequently utilized in atopic dermatitis clinical trials. Many barrier devices are costly and often used only in the academic setting. GPSkin is a low‐cost, patient‐operated device that measures both TEWL and SC hydration. This study aimed to test the reliability of GPSkin and assess its correlation with current industry standards. Materials and Methods: GPSkin was compared to the Biox AquaFlux (TEWL) and Courage‐Khazaka Corneometer (SC hydration). Participants with healthy skin (n = 50) collected measurements with GPSkin in Trial 1 without any device education and in Trial 2 with additional instruction. In Trial 2, the investigator also performed measurements with GPSkin. Spearman's coefficients (rs) were performed to assess device correlation. Intraclass correlation coefficients (ICC) were calculated to determine reliability. Results: Overall, GPSkin was moderately correlated with current industry device measurements for TEWL (Trial 1 rs:0.48; Trial 2 rs:0.40 participant, 0.34 investigator) and SC hydration (Trial 1 rs:0.63; Trial 2 rs:0.45). GPSkin demonstrated "good" test‐retest reliability for both TEWL (ICC: 0.89) and SC hydration (ICC: 0.85) measurements when participants were provided with some device education. There was no difference in reliability between participants provided with device education and investigators. Conclusion: Based on these findings, we concluded that GPSkin provides reasonably precise and reliable measurements of SC hydration and TEWL as compared to current devices. [ABSTRACT FROM AUTHOR]

The development of core outcome sets (COSs; ie, a minimum set of core outcomes that should be measured and reported in all trials or in clinical practice for a specific condition) in dermatology is increasing in pace. A total of 44 dermatology-related COS projects have been registered in the online Core Outcome Measures in Effectiveness Trials database (http://www.comet-initiative.org/studies/search) and include studies on 26 different skin diseases. With the increasing number of COSs in dermatology, care is needed to ensure the delivery of high-quality COSs that meet quality standards when using state-of-the-art methods. In 2015, the Cochrane Skin-Core Outcome Set Initiative (CS-COUSIN) was established. CS-COUSIN is an international, multidisciplinary working group aiming to improve the development and implementation of COSs in dermatology. CS-COUSIN has developed guidance on how to develop high-quality COSs for skin diseases and supports dermatology-specific COS initiatives. Currently, 17 COS development groups are affiliated with CS-COUSIN and following standardized COS development processes. To ensure successful uptake of COSs in dermatology, researchers, clinicians, systematic reviewers, guideline developers, and other stakeholders should use existing COSs in their work. [ABSTRACT FROM AUTHOR]

Abstract: Atopic dermatitis is the most common chronic skin disease, and it primarily affects children. Although atopic dermatitis (AD) has the highest effect on burden of skin disease, no high‐level studies have defined optimal therapy for severe disease. Corticosteroids have been used to treat AD since the 1950s and remain the only systemic medication with Food and Drug Administration approval for this indication in children, despite published guidelines of care that recommend against this option. Several clinical trials with level 1 evidence have supported the use of topical treatments for mild to moderate atopic dermatitis in adults and children, but these trials have had little consistency in protocol design. Consensus recommendations will help standardize clinical development and trial design for children. The Food and Drug Administration issues guidance documents for industry as a source for “the Agency's current thinking on a particular subject.” Although they are nonbinding, industry considers these documents to be the standard for clinical development and trial design. Our consensus group is the first to specifically address clinical trial design in this population. We developed a draft guidance document for industry, Developing Drugs for Treatment of Atopic Dermatitis in Children (≥3 months to <18 years of age). This draft guidance has been submitted to the Food and Drug Administration based on a provision in the Federal Register (Good Guidance Practices). [ABSTRACT FROM AUTHOR]

Roflumilast is a selective, highly potent phosphodie-sterase 4 inhibitor under investigation as a nonsteroidal, once-daily cream for treatment of atopic dermatitis (AD). INTEGUMENT-1 (n = 654; NCT04773587) and INTEGUMENT-2 (n = 683; NCT04773600) were identical phase 3 randomized controlled trials conducted in patients with AD aged ≥6 years with baseline Eczema Area and Severity Index (EASI) score ≥5 and Validated Investigator Global Assessment-AD (vIGA-AD) score of mild or moderate. Patients were randomized 2 : 1 to apply once-daily roflumilast cream 0.15% or vehicle for 4 weeks. The primary efficacy endpoint was vIGA-AD Success [defined as score of 0 (clear) or 1 (almost clear) with 2-grade improvement from baseline] at Week 4. Secondary endpoints included 75% improvement in EASI (EASI-75). At Week 4, significantly more roflumilast-treated than vehicle-treated patients achieved vIGA-AD Success (INTEGUMENT-1: 32.2% vs. 15.2%; P < 0.0001; INTEGUMENT-2: 28.9% vs. 12.0%; P < 0.0001) and EASI-75 (INTEGUMENT-1: 43.2% vs. 22.0%; P < 0.0001; INTEGUMENT-2: 42.0% vs. 19.7%; P < 0.0001). Incidence of treatment-emergent adverse events (AEs) was low in both arms, with most assessed as mild to moderate in severity. No AE occurred in more than 3.5% of patients in either arm with low rates of application site pain in both the roflumilast- and vehicle-treated patients (INTEGUMENT-1: 2.1% vs. 0.5%; INTEGUMENT-2: 0.9% vs. 0.9%). Local tolerability was favorable with >90% of roflumilast-treated patients reporting no or mild sensation across arms in both trials at any timepoint. Once-daily roflumilast cream 0.15% improved AD across multiple efficacy endpoints while demonstrating favorable safety and tolerability in two phase 3 trials. [ABSTRACT FROM AUTHOR]

Introduction: Patients with moderate-to-severe atopic dermatitis (AD) report a multidimensional disease burden that includes impaired health-related quality-of-life (HRQoL). Changes in overall health status and specific dimensions that contribute to HRQoL were evaluated in adults with moderate-to-severe AD who participated in phase 3 clinical trials of dupilumab, which is a fully human monoclonal antibody that inhibits signaling of cytokines IL-4 and IL-13. Methods: Two dupilumab phase 3 clinical trials of identical design included the 5-dimension 3-level EuroQol (EQ-5D) as a measure of HRQoL. EQ-5D data from the two trials were pooled in an analysis that, using analysis of covariance, compared subcutaneous dupilumab 300 mg once weekly (qw) or every 2 weeks (q2w) versus placebo for EQ-5D utility score change from baseline overall and for clinical responders. The proportions of patients who reported different levels of problems on the individual dimension of the EQ-5D were also compared by treatment group. Results: Patients ( n = 1379) were 57.9% male with a mean (SD) age of 38.3 (14.3) years; baseline EQ-5D utility scores ranged from 0.611 to 0.629 across treatment groups. EQ-5D least squares mean change from baseline at week 16 was 0.031 with placebo, and was significantly greater with dupilumab qw (0.207) and q2w (0.210) (both P < 0.0001), which exceeded the minimal clinically important difference and resulted in scores that approached population norms. Changes from baseline among patients who achieved AD clinical response were greater than changes among the total population. Improvements were driven by the individual EQ-5D dimensions with the greatest burden at baseline (i.e., pain/discomfort, anxiety/depression and usual activities). Conclusion: In adults with moderate-to-severe AD, dupilumab resulted in improvements in HRQoL that were statistically significant relative to placebo and were clinically meaningful. Funding: Sanofi and Regeneron Pharmaceuticals, Inc. Trial registration: ClinicalTrials.gov identifiers, NCT02277743 and NCT02277769, EudraCT Numbers 2014-001198-15 and 2014-002619-40. [ABSTRACT FROM AUTHOR]

Background: Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments.Methods: In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988.Findings: Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (-74% [SE 5·16]), 300 mg every 2 weeks (-68% [5·12]), 200 mg every 2 weeks (-65% [5·19]), 300 mg every 4 weeks (-64% [4·94]), 100 mg every 4 weeks (-45% [4·99]); placebo (-18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively).Interpretation: Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis.Funding: Sanofi and Regeneron Pharmaceuticals. INSET: Panel: Research in context.. [ABSTRACT FROM AUTHOR]

The lack of core outcome sets for atopic eczema (AE) is a major obstacle for advancing evidence-based treatment. The global Harmonising Outcome Measures for Eczema (HOME) initiative has already defined clinical signs, symptoms, quality of life, and long-term control of flares as core outcome domains for AE trials. This article deals with the standardization of measurement instruments to assess clinical signs of AE. To resolve the current lack of standardization of the assessment of clinical signs of AE, we followed a structured process of systematic reviews and international consensus sessions to identify 1 core outcome measurement instrument for assessment of clinical signs in all future AE trials. Systematic reviews indicated that from 16 different instruments identified to assess clinical signs of AE, only the Eczema Area and Severity Index (EASI) and the objective Scoring Atopic Dermatitis (SCORAD) index were identified as extensively validated. The EASI has adequate validity, responsiveness, internal consistency, and intraobserver reliability. The objective SCORAD index has adequate validity, responsiveness, and interobserver reliability but unclear intraobserver reliability to measure clinical signs of AE. In an international consensus study, patients, physicians, nurses, methodologists, and pharmaceutical industry representatives agreed that the EASI is the preferred core instrument to measure clinical signs in all future AE trials. All stakeholders involved in designing, reporting, and using clinical trials on AE are asked to comply with this consensus to enable better evidence-based decision making, clearer scientific communication, and improved patient care. [ABSTRACT FROM AUTHOR]

BACKGROUND Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Ra-interleukin-13Ral heterodimer receptor signaling complex. METHODS We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [218 years of age] and adolescents [12 to <18 years of age, weighing >40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed. RESULTS In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation. CONCLUSIONS In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocatel and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.) [ABSTRACT FROM AUTHOR]