Ustekinumab for the treatment of moderate‐to‐severe plaque psoriasis in paediatric patients (≥ 6 to < 12 years of age): efficacy, safety, pharmacokinetic and biomarker results from the open‐label CADMUS Jr study

Background Limited options are available for treatment of paediatric psoriasis. Objectives To evaluate the efficacy and safety of ustekinumab in paediatric patients with psoriasis (>= 6 to = 60 to 100 kg: 90 mg) administered by subcutaneous injection at weeks 0 and 4, then every 12 weeks through week 40. Study endpoints (all at week 12) included the proportions of patients achieving a Physician's Global Assessment score of cleared/minimal (PGA 0/1) and >= 75%/90% improvement in Psoriasis Area and Severity Index (PASI 75/90), and change in Children's Dermatology Life Quality Index (CDLQI). Serum ustekinumab concentrations, antidrug antibodies and cytokine levels were measured through week 52. Safety was evaluated through week 56. Results In total, 44 patients (median age 9 center dot 5 years) received at least one dose of ustekinumab. Three patients discontinued the study agent through week 40. At week 12, 77% of patients achieved PGA 0/1, 84% achieved PASI 75 and 64% achieved PASI 90 response. The mean change in CDLQI was -6 center dot 3. Trough serum ustekinumab concentrations reached steady state at weeks 28-52. The incidence of antidrug antibodies was 10% (n = 4). Mean serum concentrations of interleukin-17A/F and interleukin-22 were significantly reduced at weeks 12 and 52. Overall, 34 patients (77%) had at least one adverse event and three (7%) had a serious adverse event. Conclusions Ustekinumab effectively treated moderate-to-severe psoriasis in paediatric patients, and no new safety concerns were identified. What is already known about this topic? Ustekinumab is approved for use in adolescents (>= 12 to = 18 years) with moderate-to-severe psoriasis. What does this study add? Ustekinumab effectively treats moderate-to-severe psoriasis in paediatric patients (>= 6 to < 12 years of age), with no new safety concerns

Baseline Characteristics from UNITE: An Observational, International, Multicentre Registry to Evaluate Hidradenitis Suppurativa (Acne Inversa) in Clinical Practice

Background: Hidradenitis suppurativa (HS), also known as acne inversa, is a recurring, painful, chronic, and sometimes disfiguring inflammatory skin disease. Objectives: Our objective was to report the baseline clinical characteristics, natural history, and associated outcomes of patients with HS from the ongoing, prospective, non-interventional UNITE registry that is collecting data regarding the natural history and associated outcomes of HS. Methods: Patients with inflammatory HS lesions were enrolled, including adolescents (aged 12 to < 18 years) and adults (aged ≥ 18 years). None had participated in previous or current originator-adalimumab studies/registries. Patients received treatment consistent with site-specific, routine clinical practice. HS disease status was assessed by HS lesions and disease flare; treatment and outcomes data were collected at e

Optimization of placebo use in clinical trials with systemic treatments for atopic dermatitis: an International Eczema Council survey-based position statement.

Background: As novel systemic therapeutics for patients with atopic dermatitis (AD) are developed, ethical and methodological concerns regarding placebo-controlled-trials (PCT) have surfaced. Objective: To guide the design and implementation of PCT in AD, focusing on trials with systemic medications. Methods: A subgroup of the International Eczema Council (IEC) developed a consensus e-survey, which was disseminated to IEC members. Results: The response rate was 43/82 (52%). Consensus was reached on 24/27 statements and on 3/11 options from multiple-selection statements, including: performing monotherapy studies in proof-of-concept phases; avoiding concomitant topical corticosteroids or calcineurin inhibitors until a predefined timepoint as rescue (borderline consensus); selection of sites and assessors with recognized expertise in AD clinical trials; clear definition and identification of baseline disease severity; minimizing time and proportion of patients on placebo; using daily emollients with several options provided; instigating open-label extension studies for enrolment after a predefined timepoint; and including outcomes which set a higher bar for disease clearance. Conclusion: Conducting PCT in AD requires balancing several, sometimes opposing principles, including ethics, methodology, regulatory requirements and real-world needs. This paper can provide a framework for conducting PCT with systemic medications for patients with AD

Infections in children aged 6 months to 5 years treated with dupilumab in a placebo-controlled clinical trial of moderate-to-severe atopic dermatitis

Background: Patients with atopic dermatitis (AD), particularly infants and young children, are at greater risk of developing skin infections. In this study, we assessed infection rates in AD patients aged 6 months to 5 years treated with dupilumab. 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, every 4 weeks for 16 weeks. Exposure-adjusted infection rates were used to compare treatment groups. Results: The analysis included 162 patients, of whom 83 received dupilumab and 79 received placebo. Total infection rates were not significantly different between the dupilumab and placebo groups (rate ratio [RR] 0.75, 95% CI 0.48–1.19; p = 0.223). Non-herpetic adjudicated skin infections and bacterial infections were significantly less frequent with dupilumab versus placebo (non-herpetic skin infections: RR 0.46, 95% CI 0.21–0.99; p = 0.047; bacterial infections: RR 0.09, 95% CI 0.01–0.67; p = 0.019), and the number of patients using systemic anti-infective medication was significantly lower in the dupilumab group (RR 0.52, 95% CI 0.30–0.89; p = 0.019). There were no significant differences in the number of herpetic infections between the dupilumab and placebo groups (RR 1.17, 95% CI 0.31–4.35; p = 0.817). The number of patients with two or more infection events was significantly higher in the placebo group (RR 0.29, 95% CI 0.12–0.68; p = 0.004), and no severe or serious infections (including eczema herpeticum) were observed among patients receiving dupilumab. Conclusions: These data suggest that dupilumab treatment in infants and children younger than 6 years with AD does not increase overall risk of infections and is associated with a reduced risk of bacterial and non-herpetic skin infections compared with placebo, resulting in a reduced need for anti-infective medication. Trial Registration: The trial was registered with ClinicalTrials.gov with ID number NCT03346434 on November 17, 2017. Infographic: [Figure not available: see fulltext.

Laboratory safety from a randomized 16-week phase III study of dupilumab in children aged 6 months to 5 years with moderate-to-severe atopic dermatitis

Background and Objective: Previous studies of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents, and severe atopic dermatitis in children aged 6 to < 12 years demonstrate no clinically important changes in laboratory parameters. The objective of this study was to assess laboratory outcomes in children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis treated with dupilumab. Methods: In this randomized, placebo-controlled, phase III trial of dupilumab, 161 children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis were enrolled from 31 sites in Europe and North America and randomized 1:1 to receive subcutaneous placebo or dupilumab (5 kg to < 15 kg: 200 mg; 15 kg to < 30 kg: 300 mg) every 4 weeks plus topical corticosteroids for 16 weeks. Hematology, serum chemistry, and urinalysis assessments were analyzed on blood and urine samples collected at screening and weeks 4 and 16; descriptive statistics are provided. Results: No clinically meaningful changes in laboratory parameters were observed. While two cases of eosinophilia and one case each of neutropenia and leukocytosis were reported as treatment-emergent adverse events in the dupilumab plus topical corticosteroids group, these events were not associated with clinical symptoms and did not lead to treatment discontinuation or study withdrawal. Conclusions: These results suggest that routine laboratory monitoring of children aged 6 months to < 6 years treated with dupilumab plus topical corticosteroids is not required. Limitations of this study include short study duration, and exclusion of patients with abnormalities in laboratory test results at screening. Clinical Trial Registration: ClinicalTrials.gov: NCT03346434, part

Dupilumab demonstrates rapid and consistent improvement in extent and signs of atopic dermatitis across all anatomical regions in pediatric patients 6 years of age and older

Introduction In phase III trials in adolescents and children with atopic dermatitis (AD), dupilumab significantly decreased global disease severity. However, the effects of dupilumab on the extent and signs of AD across different anatomical regions were not reported. Here we characterize the efficacy of dupilumab in improving the extent and signs of AD across four different anatomical regions in children and adolescents. Methods A post hoc subset analysis was performed using data from two randomized, double-blind, placebo-controlled, international multicenter, phase III trials of dupilumab therapy in adolescents aged ≥ 12 to < 18 years with moderate-to-severe AD and children aged ≥ 6 to < 12 years with severe AD. Endpoints included mean percentage change in Eczema Area and Severity Index (EASI) signs (erythema, edema/papulation, excoriation, lichenification) and extent of AD (measured by percentage of body surface area [% BSA] involvement) from baseline to week 16 across four anatomical regions (head and neck, trunk, upper extremities, lower extremities). Results Dupilumab improved both the extent and severity of AD signs across the four anatomical regions. Improvements were shown to be similar across the four anatomical regions for % BSA involvement and for reduction in EASI signs. Improvements in all signs were seen early, within the first 4 weeks of treatment, and were sustained through week 16, across all regions. Conclusions In pediatric patients 6 years of age and older, treatment with dupilumab resulted in rapid and consistent improvement in the extent and signs of AD across all anatomical regions. ClinicalTrials.gov Identifiers LIBERTY AD ADOL (NCT03054428) and LIBERTY AD PEDS (NCT03345914)

Defining and measuring “eczema control”: An international qualitative study to explore the views of those living with and treating atopic eczema

Background Atopic eczema (also known as eczema) is a chronic, inflammatory skin condition that often afflicts patients’ health and wellbeing. The Harmonising Outcome Measures for Eczema (HOME) initiative recommends that “long-term control of eczema” is measured in all clinical trials 3 months or longer in duration. However, little has been published on what eczema control means to those living with or treating atopic eczema. Objectives To i) develop understanding of what eczema control means to patients, carers and clinicians and ii) explore the feasibility and acceptability of different ways of measuring eczema control in the long-term. Methods Online focus groups explored patients/carers experiences in the UK, USA, the Netherlands, France, Sweden and Japan, and an international online survey gathered views of clinicians. The Framework Method was used to analyse the focus groups and thematic analysis was used to analyse survey data. All findings were integrated into a theoretical framework to create overarching themes that cut across these diverse groups. Results Eight focus groups with patients (16 years+) and eight groups with carers of children took place (N=97). Sixty-two people took part in the survey. Eczema control was described as a multifaceted construct involving changes in disease activity, the treatment and management of the condition, and psychological, social and physical functioning. Patient /carer measurement allows personal accounts and frequent measurement, whilst clinician measurement was deemed less subjective. The burden on patients/carers and issues for analysing and interpreting data should be considered. Conclusions This study formed the basis of judging the content validity and feasibility of measurement instruments/methods to assess control of eczema in clinical trials. This online approach to an international qualitative study is an example of how core outcome set developers with limited resources can engage with multiple stakeholder groups on an international basis to inform consensus meeting discussions

Laboratory safety of dupilumab in patients aged 6–11 years with severe atopic dermatitis : results from a phase III clinical trial

Background Previous studies of dupilumab in adolescents and adults with moderate-to-severe atopic dermatitis (AD) showed no clinically meaningful adverse changes in laboratory parameters. Objective The aim of this study was to assess laboratory outcomes in children aged 6–11 years with severe AD in a randomized, placebo-controlled, phase III trial of dupilumab. Methods Children aged 6–11 years with severe AD were randomized 1:1:1 to 16 weeks of dupilumab 300 mg every 4 weeks, 100 or 200 mg every 2 weeks, or matching placebo, all with concomitant topical corticosteroids (TCS). Blood samples were collected at baseline and Weeks 4, 8, and 16; urine samples were collected at baseline and Weeks 4 and 16. Results Of 367 patients enrolled in the study, 362 were included in the safety analysis, 351 completed study treatment, and 4 withdrew due to treatment-emergent adverse events not related to laboratory abnormalities. Both dupilumab + TCS groups showed overall trends toward increases in mean blood levels of eosinophils and alkaline phosphatase, and decreases in mean blood levels of platelets, neutrophils, and lactate dehydrogenase levels, without corresponding mean changes in the placebo + TCS group. None of these changes were associated with symptoms or clinically meaningful adverse outcomes, and none led to treatment modification. No clinically significant changes or trends were observed for other measured laboratory parameters. Conclusion There were no clinically meaningful adverse changes in routine laboratory parameters attributable to treatment with dupilumab + TCS. Changes in platelet counts and lactate dehydrogenase levels likely reflect reduced inflammation. These results confirm similar findings in adults and adolescents, and suggest that there is no need for routine laboratory monitoring of children aged 6–11 years treated with dupilumab + TCS for severe AD. Trial Registration ClinicalTrials.gov Identifier: NCT03345914

A phase 2, open‐label study of single‐dose dupilumab in children aged 6 months to <6 years with severe uncontrolled atopic dermatitis: pharmacokinetics, safety and efficacy

Background Dupilumab has demonstrated efficacy and acceptable safety in adults and children (aged 6–17 years) with moderate-to-severe atopic dermatitis (AD), but effective systemic therapy with a favorable risk–benefit profile in younger children remains a significant unmet need. Objectives To determine the pharmacokinetics, safety and efficacy of single-dose dupilumab in children with severe AD aged ≥6 months to <6 years. Methods This open-label, multicenter, phase 2, sequential, two-age cohort, two-dose level study (LIBERTY AD PRE-SCHOOL; NCT03346434) included an initial cohort of older children aged ≥2 to <6 years, followed by a younger cohort aged ≥6 months to <2 years. Pharmacokinetic sampling, safety monitoring and efficacy assessments were performed during the 4-week period after a single subcutaneous injection of dupilumab, in two sequential dosing groups (3 mg/kg, then 6 mg/kg). The use of standardized, low-to-medium potency topical corticosteroids was allowed. Results Forty patients were enrolled (20/age cohort, 10/dose level within a cohort) between December 20, 2017 and July 22, 2019. Within each age cohort, pharmacokinetic exposures after a single injection of dupilumab increased in a greater than dose-proportional manner. At week 3, treatment with 3 and 6 mg/kg dupilumab reduced scores of mean Eczema Area and Severity Index by −44.6% and −49.7% (older cohort) and −42.7% and −38.8% (younger cohort), and mean Peak Pruritus NRS scores by −22.9% and −44.7% (older cohort) and −11.1% and −18.2% (younger cohort), respectively. At week 4, improvements in most efficacy outcomes diminished in both age groups, particularly with the lower dose. The safety profile was comparable to that seen in adults, adolescents and children. Conclusions Single-dose dupilumab was generally well tolerated and substantially reduced clinical signs/symptoms of AD. Slightly better responses were seen in older than younger children. The pharmacokinetics of dupilumab were non-linear, consistent with previous studies in adults and adolescents