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Figure 1.  Participant Flow
Participant Flow

One participant was randomized in error and found to be ineligible later; therefore, this participant was not offered any treatment and was excluded from the study and intention-to-treat analysis.

Figure 2.  Atopic Dermatitis Severity and Quality of Life in Participants During the 24-Week Treatment and 48-Week Follow-up Periods
Atopic Dermatitis Severity and Quality of Life in Participants During the 24-Week Treatment and 48-Week Follow-up Periods

CDLQI/DLQI indicates Children’s Dermatology Life Quality Index/Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; and SCORAD, Scoring Atopic Dermatitis.

Figure 3.  Proportion of Patients Using Potent Topical Corticosteroids During the 24-Week Treatment and 48-Week Follow-up Periods
Proportion of Patients Using Potent Topical Corticosteroids During the 24-Week Treatment and 48-Week Follow-up Periods
Table 1.  Baseline Characteristics of Trial Participants
Baseline Characteristics of Trial Participants
Table 2.  Change in Eczema Severity Scores From Baseline to Week 24
Change in Eczema Severity Scores From Baseline to Week 24
1.
Odhiambo  JA, Williams  HC, Clayton  TO, Robertson  CF, Asher  MI; ISAAC Phase Three Study Group.  Global variations in prevalence of eczema symptoms in children from ISAAC phase three.  J Allergy Clin Immunol. 2009;124(6):1251-1258.e23. doi:10.1016/j.jaci.2009.10.009PubMedGoogle ScholarCrossref
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Proudfoot  LE, Powell  AM, Ayis  S,  et al; European Dermato-Epidemiology Network (EDEN).  The European Treatment of Severe Atopic Eczema in Children Taskforce (TREAT) survey  [published correction appears in Br J Dermatol. 2013;169(5):1171].  Br J Dermatol. 2013;169(4):901-909. doi:10.1111/bjd.12505PubMedGoogle ScholarCrossref
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Klubal  R, Osterhoff  B, Wang  B, Kinet  J-P, Maurer  D, Stingl  G.  The high-affinity receptor for IgE is the predominant IgE-binding structure in lesional skin of atopic dermatitis patients.  J Invest Dermatol. 1997;108(3):336-342. doi:10.1111/1523-1747.ep12286482PubMedGoogle ScholarCrossref
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Maurer  D, Ebner  C, Reininger  B,  et al.  The high affinity IgE receptor (Fc epsilon RI) mediates IgE-dependent allergen presentation.  J Immunol. 1995;154(12):6285-6290.PubMedGoogle Scholar
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Werfel  T.  The role of leukocytes, keratinocytes, and allergen-specific IgE in the development of atopic dermatitis.  J Invest Dermatol. 2009;129(8):1878-1891. doi:10.1038/jid.2009.71PubMedGoogle ScholarCrossref
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Bieber  T.  Atopic dermatitis.  N Engl J Med. 2008;358(14):1483-1494. doi:10.1056/NEJMra074081PubMedGoogle ScholarCrossref
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Novartis Pharmaceuticals UK Ltd. Xolair 150 mg solution for injection in pre-filled syringe. https://www.medicines.org.uk/emc/product/4725/smpc. Accessed October 25, 2019.
8.
Chan  S, Cornelius  V, Chen  T,  et al.  Atopic Dermatitis Anti-IgE Paediatric Trial (ADAPT): the role of anti-IgE in severe paediatric eczema: study protocol for a randomised controlled trial.  Trials. 2017;18(1):136. doi:10.1186/s13063-017-1809-7PubMedGoogle ScholarCrossref
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Silverberg  JI, Simpson  EL.  Associations of childhood eczema severity: a US population-based study.  Dermatitis. 2014;25(3):107-114. doi:10.1097/DER.0000000000000034PubMedGoogle ScholarCrossref
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Altman  DG, Bland  JM.  Treatment allocation by minimisation.  BMJ. 2005;330(7495):843. doi:10.1136/bmj.330.7495.843PubMedGoogle ScholarCrossref
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Chen  T, Chan  S, Lack  G, Cro  S, Cornelius  VR.  The role of anti-IgE (omalizumab/Xolair) in the management of severe recalcitrant paediatric atopic eczema (ADAPT): statistical analysis plan.  Trials. 2017;18(1):231. doi:10.1186/s13063-017-1976-6PubMedGoogle ScholarCrossref
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Schram  ME, Spuls  PI, Leeflang  MM, Lindeboom  R, Bos  JD, Schmitt  J.  EASI, (objective) SCORAD and POEM for atopic eczema: responsiveness and minimal clinically important difference.  Allergy. 2012;67(1):99-106. doi:10.1111/j.1398-9995.2011.02719.xPubMedGoogle ScholarCrossref
13.
Heil  PM, Maurer  D, Klein  B, Hultsch  T, Stingl  G.  Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course—a randomized, placebo-controlled and double blind pilot study.  J Dtsch Dermatol Ges. 2010;8(12):990-998. doi:10.1111/j.1610-0387.2010.07497.xPubMedGoogle Scholar
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Iyengar  SR, Hoyte  EG, Loza  A,  et al.  Immunologic effects of omalizumab in children with severe refractory atopic dermatitis: a randomized, placebo-controlled clinical trial.  Int Arch Allergy Immunol. 2013;162(1):89-93. doi:10.1159/000350486PubMedGoogle ScholarCrossref
15.
Lieberman  PL, Jones  I, Rajwanshi  R, Rosén  K, Umetsu  DT.  Anaphylaxis associated with omalizumab administration: risk factors and patient characteristics.  J Allergy Clin Immunol. 2017;140(6):1734-1736.e4. doi:10.1016/j.jaci.2017.07.013PubMedGoogle ScholarCrossref
16.
Kaufman  BP, Guttman-Yassky  E, Alexis  AF.  Atopic dermatitis in diverse racial and ethnic groups—variations in epidemiology, genetics, clinical presentation and treatment.  Exp Dermatol. 2018;27(4):340-357. doi:10.1111/exd.13514PubMedGoogle ScholarCrossref
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Lawrence  MG, Woodfolk  JA, Schuyler  AJ, Stillman  LC, Chapman  MD, Platts-Mills  TA.  Half-life of IgE in serum and skin: consequences for anti-IgE therapy in patients with allergic disease.  J Allergy Clin Immunol. 2017;139(2):422-428.e4. doi:10.1016/j.jaci.2016.04.056PubMedGoogle ScholarCrossref
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Humbert  M, Beasley  R, Ayres  J,  et al.  Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE.  Allergy. 2005;60(3):309-316. doi:10.1111/j.1398-9995.2004.00772.xPubMedGoogle ScholarCrossref
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Maurer  M, Rosén  K, Hsieh  H-J,  et al.  Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria.  N Engl J Med. 2013;368(10):924-935. doi:10.1056/NEJMoa1215372PubMedGoogle ScholarCrossref
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Tsabouri  S, Tseretopoulou  X, Priftis  K, Ntzani  EE.  Omalizumab for the treatment of inadequately controlled allergic rhinitis: a systematic review and meta-analysis of randomized clinical trials.  J Allergy Clin Immunol Pract. 2014;2(3):332-340.e1. doi:10.1016/j.jaip.2014.02.001PubMedGoogle ScholarCrossref
21.
Sampson  HA, Leung  DY, Burks  AW,  et al.  A phase II, randomized, double-blind, parallel-group, placebo-controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy.  J Allergy Clin Immunol. 2011;127(5):1309-1310.e1. doi:10.1016/j.jaci.2011.01.051PubMedGoogle ScholarCrossref
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    Original Investigation
    November 25, 2019

    Treatment Effect of Omalizumab on Severe Pediatric Atopic Dermatitis: The ADAPT Randomized Clinical Trial

    Author Affiliations
    • 1Children’s Allergy, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
    • 2King’s College London, School of Life Course Sciences & School of Immunology & Microbial Sciences, King’s Health Partners, London, United Kingdom
    • 3Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, United Kingdom
    • 4UCL Great Ormond Street Institute of Child Health, London, United Kingdom
    JAMA Pediatr. 2020;174(1):29-37. doi:10.1001/jamapediatrics.2019.4476
    Key Points

    Question  Is omalizumab (anti-IgE medication) effective in the treatment of severe pediatric atopic dermatitis?

    Findings  In this randomized clinical trial of 62 children with severe atopic dermatitis, significant reduction in eczema severity was observed in the omalizumab group, compared with placebo after adjustment for baseline objective Scoring Atopic Dermatitis index, age, and IgE level. This improvement occurred in the context of markedly potent topical corticosteroid sparing in the omalizumab group.

    Meaning  This trial presents evidence that anti-IgE therapy may have a role in managing severe pediatric atopic dermatitis.

    Abstract

    Importance  Systemic treatments for severe childhood atopic dermatitis have limited evidence and/or are unlicensed. Despite the efficacy of anti-IgE medication (omalizumab) in the treatment of atopy, no large randomized studies in childhood atopic dermatitis have been published.

    Objective  To determine the effectiveness of omalizumab in treating severe atopic dermatitis in children.

    Design, Setting, and Participants  The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) was a 24-week single-center, double-blind, placebo-controlled randomized clinical trial with a 24-week follow-up. Conducted from November 20, 2014, to August 31, 2017, at Guy’s and St Thomas’ Hospital NHS Foundation Trust and King’s College London in the United Kingdom, this trial recruited participants after a screening visit. Eligible participants (n = 62) were aged 4 to 19 years and had severe eczema (with objective Scoring Atopic Dermatitis [SCORAD] index >40) that was unresponsive to optimum therapy. Statistical analysis was conducted using the intention-to-treat principle.

    Interventions  Subcutaneous omalizumab or placebo for 24 weeks. The drug manufacturer’s dosing tables were used to determine the dosage based on total IgE (30-1500 IU/mL) and body weight (in kilograms) at randomization.

    Main Outcomes and Measures  Objective SCORAD index after 24 weeks of treatment.

    Results  In total, 62 children (mean [SD] age, 10.3 [4.2] years; 32 (52%) were male) were randomized to either omalizumab (n = 30) or placebo (n = 32). Five participants withdrew from treatment (4 [13%] from the placebo group, and 1 [3%] from the omalizumab group). Follow-up attendance was 97% at week 24 and 98% at week 48. After adjustment for baseline objective SCORAD index, age, and IgE level, the mean difference in objective SCORAD index improvement between groups at week 24 was −6.9 (95% CI, −12.2 to −1.5; P = .01), significantly favoring omalizumab therapy and reflecting the results in other assessments of atopic dermatitis severity. Improved quality-of-life scores were seen in the omalizumab group, as measured by the Children's Dermatology Life Quality Index/Dermatology Life Quality Index (−3.5; 95% CI, −6.4 to −0.5) and Pediatric Allergic Disease Quality of Life Questionnaire score (−0.5; 95% CI, −0.9 to −0.0). Improvements in disease severity occurred despite lower potent topical corticosteroid use in the omalizumab group compared with the placebo group (median [interquartile range (IQR)] percentage of body surface area covered, 16% [10%-46%] vs 31% [14%-55%]; median [IQR] number of days of use, 109 [34-164] days vs 161 [82-171] days).

    Conclusions and Relevance  This randomized clinical trial found that omalizumab significantly reduced atopic dermatitis severity and improved quality of life in a pediatric population with atopy and severe eczema despite highly elevated total IgE levels at baseline. The result was associated with a potent topical corticosteroid sparing effect and may suggest that omalizumab is a treatment option for difficult-to-manage severe eczema in children with atopy.

    Trial Registration  ClinicalTrials.gov identifier: NCT02300701

    Introduction

    Atopic dermatitis is one of the most common dermatoses, affecting 7.7% of children aged 6 to 7 years and 7.3% of adolescents aged 13 to 14 years worldwide.1 In more severe cases of atopic dermatitis, systemic immunosuppressants (including cyclosporine, azathioprine sodium, and methotrexate sodium) have been used. However, published evidence in childhood is limited; most drugs are unlicensed and potentially have serious adverse effects, whereas other biological agents remain unlicensed for treatment of atopic dermatitis in children.2

    Genetics, environmental factors, and immunological system interact in the complex pathophysiological mechanism of atopic dermatitis. Higher IgE levels are associated with more severe disease, and atopic dermatitis lesions have been found to bear sizeable numbers of IgE-bearing cells. They bind the high-affinity receptors, the main IgE-binding structure in eczematous skin.3 The high-affinity receptor–bound, allergen-specific IgE presents allergen more effectively to primed T cells,4 leading to T-cell activation and cutaneous inflammation. Release of IgE-mediated histamine from cutaneous mast cells may also aggravate eczema through the itch-scratch cycle.5 Atopic dermatitis may become less allergen-driven and more autoreactive with age.

    This randomized clinical trial targeted the pediatric atopic population, for whom IgE involvement may be more relevant.6 Omalizumab (Xolair; Novartis) is designed to bind human IgE, limiting mast cell degranulation and inflammatory mediator release.7 Licensed for use in children from age 6 years, omalizumab is well tolerated in children with severe asthma. We hypothesized that anti-IgE medication would reduce IgE levels in children with severe eczema, alleviating symptoms.

    Methods
    Study Design and Participants

    The Atopic Dermatitis Anti-IgE Pediatric Trial (ADAPT) was a single-center, double-blind, parallel-group, placebo-controlled randomized clinical trial that compared anti-IgE medication (omalizumab) with placebo to treat severe eczema in children with atopy. It was carried out from November 20, 2014, to August 31, 2017, at Guy’s and St Thomas’ Hospital NHS Foundation Trust and King’s College London in the United Kingdom. Ethical approval was granted by the London Westminster NHS Research Ethics Committee. All participants provided written informed consent. The Consolidated Standards of Reporting Trials (CONSORT) reporting guideline was followed.

    The trial protocol is included in Supplement 1. In brief, eligible participants were aged 4 to 19 years and had severe eczema (according to the objective Scoring Atopic Dermatitis [SCORAD] index; score range, 0-103, with scores >40 considered severe) that was unresponsive to optimal topical or systemic therapy, with evidence of atopic disease.8 Given that race/ethnicity has been reported to be associated with eczema and eczema severity,9 parents or caregivers were asked to classify the child participants by race/ethnicity according to investigator-specified groups. Before randomization, a minimum washout period was stipulated if the participant had stopped using a systemic immunosuppressant or UV therapy. Similarly, if immunosuppression or UV therapy was ongoing during the trial, it was stabilized for the same stipulated period before randomization, and treatment was continued during the course of the intervention.

    Randomization and Masking

    A secure web-based randomization system randomized participants 1:1 to receive either omalizumab or placebo (Figure 1). The sequence was computer generated by the UK Clinical Research Collaboration–registered King’s College London Clinical Trials Unit. Participants were randomized using minimization, which minimized the imbalance across groups according to the characteristics of participants already randomized.10 Minimization factors were IgE level (≤1500 or >1500 IU/mL; to convert to milligrams per liter, multiply by 0.0024) and age (<10 or ≥10 years).

    Participants, caregivers, and staff involved in outcome assessments and the investigators were masked to the treatment assignment until data analysis was complete. Randomization details were electronically delivered to independent pharmacists. A separate unblinded group of clinical staff collected and returned used vials of medication to the pharmacy and also prepared and administered the intervention in a closed treatment room separate from the main clinical area.

    Procedures

    Each participant commenced 24 weeks of treatment at their baseline visit, with an additional 24 weeks of follow-up. Novartis supplied the omalizumab as 150-mg, single-use vials containing powder for reconstitution and the placebo, which was comparable to the omalizumab in appearance, with matching excipients. The manufacturer’s dosing tables were used to determine the dose based on total IgE level (30-1500 IU/mL) and body weight (in kilograms) at randomization. The dose closest to the child’s weight and IgE level was administered subcutaneously. Participants with total IgE levels greater than 1500 IU/mL received the maximum dose for their weight based on the manufacturer’s dosing tables.

    Skin prick tests (SPTs) to a panel of allergens were performed at baseline and at week 24. The SPT is an assessment of the allergic response to specific foods or aeroallergens.

    Statistical Analysis

    The estimated sample size was 62 participants. Thirty-one participants per group provided 90% power to detect a difference in an objective SCORAD index change of 13.5 points between treatment groups, assuming an SD of 15, a 2-sided significance level of 5%, and 90% power and 15% dropout (eAppendixes 1 and 2 in Supplement 2). Other outcomes are listed in the eAppendix 2 in Supplement 2.

    Analysis was conducted using the intention-to-treat principle. All eligible participants were analyzed in the group to which they were randomized. For the primary outcome, a linear mixed-effects model with a group × time interaction estimated the mean between-group treatment difference in objective SCORAD index at week 24 with 95% CI and corresponding P value after adjustment for the baseline objective SCORAD index (which is equivalent to the mean between-group difference in change in objective SCORAD index at week 24), IgE level (≤1500 or >1500 IU/mL), and age (<10 or ≥10 years). Participant-level random intercepts were used to account for repeated-measures correlation. The model assumed that missing data were missing at random given the observed data. Preplanned sensitivity analyses for the primary outcome were performed (eAppendix 3 in Supplement 2). P values were 2-sided, and the statistical significance level was set at 5%.

    Secondary outcome analyses conducted at week 24 used linear regression models for continuous outcomes. Binary outcomes were analyzed with logistic regression models. Zero-inflated Poisson regression models were used to analyze counts. Secondary outcomes are reported in eFigures 1 to 4 in Supplement 2. All regression analyses included adjustments for the minimization variables (IgE level and age) as covariates and for continuous outcomes, the outcomes measured at baseline.

    Adverse events were tabulated by type. Poisson regression models estimated nonserious body system class event rates between groups. A volcano plot identified events with the strongest signal of between-group differences. The full statistical analysis plan is published elsewhere.11 All statistical analyses were conducted using Stata, version 15.1 (StataCorp LLC).

    Results

    In total, 30 participants were randomized to omalizumab and 32 were randomized to placebo. The mean (SD) age of the participants was 10.3 (4.2) years, and 32 (52%) were male. Participants were recruited between November 20, 2014, and October 6, 2016. They attended a screening visit, and randomization to the omalizumab or placebo group took place at a mean (range) of 4.1 (1.3-19.9) weeks later, during their baseline visit. Four participants (13%) withdrew from the placebo group (1 because of pruritus, 2 declined further injections, and 1 had travel-related issues), and the investigators discontinued treatment for 1 participant (3%) in the omalizumab group (because of a potential adverse reaction). All other participants achieved 100% treatment adherence. Follow-up attendance was 97% at week 24 and 98% at week 48 (Figure 1).

    The median (interquartile range [IQR]) baseline total IgE level was 8373 (4556-18506) IU/mL. The mean (SD) eczema severity at baseline measured by the objective SCORAD index was 54.9 (8.6). The mean (SD) total (combined objective and subjective) SCORAD index was 69.3 (9.9), and the mean (SD) EASI (Eczema Area and Severity Index) score was 44.5 (10.6). The EASI is a validated scoring system, ranging from 0 to 72, that grades the severity of the physical signs of atopic dermatitis (erythema, edema, excoriation, and lichenification) and the extent of the severity.

    The baseline characteristics of patients in the omalizumab and placebo groups were generally well matched. No clinically important imbalances were found between groups demographically (mean [SD] age, 10.2 [0.1] vs 10.4 [4.3] years; male, 13 [43%] vs 19 [59%]; and white race/ethnicity, 10 [33%] vs 10 [31%]), in the severity of their eczema (mean [SD] EASI score, 45.5 [10.1] vs 43.5 [11.1]; mean [SD] POEM [Patient-Oriented Eczema Measure] score, 20.7 [4.6] vs 22.2 [3.9]), and in the use of potent topical corticosteroids (22 [73%] vs 25 [78%]) (Table 1 and eTables 1 and 2 in Supplement 2). The POEM is a tool used for monitoring atopic eczema severity as experienced by the patient. A POEM score of 0 to 2 indicates eczema that is clear or almost clear; 3 to 7, mild; 8 to 16, moderate; 17 to 24, severe; and 25 to 28, very severe.

    Eczema Severity at Weeks 24 and 48

    The adjusted mean treatment group difference (ie, the difference between the change in objective SCORAD index in each group) at week 24 was −6.9 (95% CI, −12.2 to −1.5; P = .01), which was statistically significantly in favor of omalizumab (Table 2 and Figure 2). The minimum clinically important difference of 8.5 was contained well within the 95% CI of −1.5 to −12.2 (eAppendix 4 in Supplement 2). The results of multiple sensitivity analyses for the objective SCORAD index were consistent with those of the primary analysis, in which the treatment effect ranged from −5.6 (95% CI, −10.9 to −0.2) to −7.2 (95% CI, −12.6 to −1.8) (eTables 3-5 in Supplement 2).

    Improvements were observed in favor of treatment with omalizumab for other atopic dermatitis severity scores at week 24 (Table 2 and Figure 2). The adjusted mean treatment group difference for the EASI was −6.7 (95% CI, −13.2 to −0.1). The adjusted mean treatment group difference for the total SCORAD index was −8.3 (95% CI, −15.1 to −1.1). The adjusted mean treatment group difference for the POEM score for treatment with omalizumab vs placebo was −1.1 (95% CI, −4.6 to 2.4) (eFigure 1 in Supplement 2).12

    Another assessment was made at week 48 to assess whether the benefits persisted beyond the 24-week treatment period. The difference in the objective SCORAD index remained, albeit to a lesser extent (−2.8; 95% CI, −8.6 to 3.0) (Figure 2).

    Potent Topical Corticosteroid Use

    Of a total 168 days (24 weeks), potent topical corticosteroids were used for a median (IQR) of 161 (82-171) days in the placebo group and 109 (34-164) days in the omalizumab group (Figure 3). The median number of days of use was thus 48% higher in the placebo group. Some visits fell just outside the 24-week time frame, and assessments were made up to 171 days in 1 case.

    The median (IQR) percentage of body surface area over which potent topical corticosteroids was used was 31% (14%-55%) in the placebo group and 16% (10%-46%) in the omalizumab group across 24 weeks, representing a 102% greater body surface area coverage in the placebo group.

    These effects persisted through week 48, 24 weeks after cessation of therapy. The median (IQR) number of days of potent topical corticosteroid use across 48 weeks was 55% higher in the placebo group. Of a total 336 days (48 weeks), the median (IQR) number of days of use was 291 (111-336) days in the placebo group and 188 (49-299) days in the omalizumab group. Thus, the median body surface area coverage across 48 weeks was 77% greater in the placebo group:32% compared with 18% in the omalizumab group.

    The median (IQR) weight of potent topical corticosteroids used was 76% higher in the placebo group compared with the omalizumab group at both week 24 (102 [55-209] g vs 58 [14-125] g) and week 48 (144 [65-260] g vs 82 [27-181] g).

    Systemic Treatment Burden

    The systemic treatment burden (ie, requirement of additional treatment because of treatment failure; in this case, ≥2 courses of rescue therapy with oral prednisolone and/or alternative systemic immunosuppression by week 30) was experienced by 1 participant (3%) in the omalizumab group and 5 participants (16%) in the placebo group.

    Treatment failure was defined as persistent severe eczema despite 2 courses of rescue therapy with oral prednisolone initiated after the first 12 weeks. Participation of 1 patient in the omalizumab group was discontinued by investigators after the third dose at week 4 because of a serious potential adverse reaction (anaphylaxis). That participant was the only one in the omalizumab group (3%) and also the only one who went on to receive systemic immunosuppression. Three treatment failures (10%) occurred in the placebo group and the only one (3%) in the omalizumab group who went on to receive systemic immunosuppression. In contrast, in the placebo group, 3 participants (10%) experienced treatment failures and 4 participants (13%), comprising 2 of the 3 with treatment failures and 2 others, started systemic immunosuppression therapy within 30 weeks.

    Quality of Life

    Improvement in quality of life (QOL) at week 24 (as measured by the Children’s Dermatology Life Quality Index/Dermatology Life Quality Index [CDLQI/DLQI]) was statistically significantly in favor of omalizumab, with an adjusted mean treatment group difference of −3.5 (95% CI, −6.4 to −0.5) and a minimum clinically important difference of 3.3 for the CDLQI/DLQI (Figure 2). An improvement in favor of the omalizumab group was also seen in the Pediatric Allergic Disease Quality of Life Questionnaire (PADQLQ) score, a multisystem QOL assessment, with an adjusted mean treatment group difference of −0.5 (95% CI, −0.9 to −0.0) and a minimum clinically important difference of 0.33 (eFigure 2 in Supplement 2). These effects on both CDLQI/DLQI and PADQLQ persisted to a lesser extent to week 48, 24 weeks after treatment stopped (Figure 2 and eFigure 2 in Supplement 2).

    Skin Prick Test Results and Specific IgE Level

    The omalizumab group showed a statistically significant 44% decrease in positive SPT number from baseline to week 24 compared with the placebo group (adjusted incidence rate ratio, 0.56; 95% CI, 0.40-0.78).

    Post hoc analysis identified that the therapeutic response increased with the number of positive baseline SPT results. The mean improvement in objective SCORAD index at week 24 for each additional positive baseline SPT result in the omalizumab group was −1.7 (95% CI, −3.1 to −0.28) (eFigures 3 and 4 in Supplement 2).

    A greater treatment effect was observed when the baseline total IgE level was lower. The mean increase in objective SCORAD index at week 24 for a 1000-IU/mL increase in baseline IgE level in the omalizumab group was 0.3 (95% CI, −0.2 to 0.7).

    Infections, Exacerbations, and Safety

    The numbers of participants with 1 or more infective episodes of atopic dermatitis (6 [20%] in the omalizumab group vs 8 [25%] in the placebo group) and atopic dermatitis exacerbation (5 [17%] in the omalizumab group vs 6 [19%] in the placebo group) were low. No important differences were noted (eTable 6 in Supplement 2).

    Seven serious adverse events occurred in 6 patients in each group (20% in omalizumab and 19% in placebo) (eTable 7 in Supplement 2). One was a serious potential adverse reaction in the omalizumab group. The participant, who had a preexisting history of idiopathic anaphylaxis and weekly allergic reactions, reported experiencing anaphylaxis 10 hours after the third treatment injection. The participant was withdrawn from treatment by trial investigators, who remained blinded to treatment randomization. The participant reported 2 more episodes of unexplained anaphylaxis during the study period; both reactions occurred 21 weeks after treatment had ceased.

    Few respiratory and dermatological nonserious events were reported in the omalizumab group (eTables 8 and 9 and eFigure 5 in Supplement 2). Respiratory events occurred in 15 participants (50%) in the omalizumab group and 25 (78%) in the placebo group (relative risk, 0.64; 95% CI, 0.43-0.96). Dermatological events occurred in 23 participants (77%) in the omalizumab group and 31 (97%) in the placebo group (relative risk, 0.79; 95% CI, 0.64-0.98).

    Discussion

    This randomized clinical trial found that treatment with omalizumab improved atopic dermatitis severity and QOL in children with severe atopy and severe eczema despite high baseline total IgE levels and marked potent topical corticosteroid sparing.

    At week 24, the mean between-group treatment difference in objective SCORAD index after adjustment for baseline objective SCORAD index, age, and IgE level was significantly in favor of omalizumab at −6.9. Differences were also significantly in favor of omalizumab for the total SCORAD index and EASI as well as the QOL assessments CDLQI/DLQI and PADQLQ.

    To our knowledge, this is the largest trial of omalizumab for atopic dermatitis and the first to demonstrate a positive clinical outcome. It is also the first, compared with previous studies, to target a larger cohort of children and to use higher doses of omalizumab, which are now licensed. Positive outcomes were seen despite the existence of high baseline total IgE levels, which were more than 5 times the level that the maximum omalizumab dose was designed to treat, and markedly reduced use of potent topical corticosteroids in the omalizumab group.

    Two previous randomized clinical trials did not demonstrate treatment response with omalizumab.13,14 However, one was an adult study and one treated only 4 children with omalizumab, with a maximum dose less than one-third of the dose used in the present study. The strength of this study was targeting well-defined children with severe atopy and a more acute form of atopic dermatitis than that in adults. IgE involvement may be more relevant in children, and that patients with more positive baseline SPT results did better in this study may be evidence of this fact.

    Changes to the license of omalizumab meant that the 1200 mg/mo top dosage represents the highest dosage used in any study of atopic dermatitis, to our knowledge. Anti-IgE therapy is designed to bind to and neutralize free-circulating IgE. Participants were dosed up to the manufacturer’s recommended maximum dose for safety, to target a maximum total IgE level of 1500 IU/mL. However, the median baseline total IgE level in this study was much higher, at 120 times the top normal range of total IgE level and 5.6 times higher than the top dose of omalizumab is designed for. Participants with a lower baseline total IgE level responded more favorably, suggesting that anti-IgE medication may be more effective when the dose is high enough to neutralize free-circulating IgE.

    A number of questions remain, such as whether patients with less severe atopic dermatitis and a lower total IgE level should be targeted; whether higher doses of omalizumab may be more efficacious; and whether a higher-affinity, next-generation anti-IgE drug such as ligelizumab or MEDI4212, dosed appropriately, may be useful in these patients.

    Concomitant potent topical corticosteroids were permitted because participants had few treatment alternatives to manage disease activity. Despite similar baseline use, the median number of days of use across the treatment period was 48% higher and the median body surface area coverage was 102% greater in the placebo group. This effect on potent topical corticosteroid use persisted up to 24 weeks after omalizumab treatment ceased. Greater use of highly potent topical corticosteroid in the placebo group may have suppressed atopic dermatitis severity, reducing the objective SCORAD index in that group and thus the apparent relative treatment effect of omalizumab. Thus, the effect of omalizumab may have been even more marked in the absence of topical corticosteroid use. Because of corticosteroid sparing in the omalizumab group, excessive use of potent topical corticosteroid would not account for the improvement in this group, which is likely to be an effect of omalizumab treatment. Ultimately, corticosteroid sparing may lead families and clinicians, who are often cautious of the potential adverse effects of potent topical corticosteroids, to welcome options such as omalizumab.

    The systemic treatment burden was also higher in the placebo group than in the omalizumab group. The eczema severity of participants in the omalizumab group appeared to improve despite less potent topical corticosteroid use, and these participants had less recourse to other immunosuppressive systemic treatment compared with their placebo counterparts.

    Five participants withdrew from treatment, 4 of whom were in the placebo group. The 1 participant in the omalizumab group was withdrawn by the investigators because of a possible adverse reaction. This participant had a history of idiopathic anaphylaxis preceding the study and reported unexplained anaphylaxis 10 hours after the third dose of omalizumab at week 4. Delayed anaphylaxis to omalizumab has been reported in the literature,15 and treatment was discontinued for this participant. However, the same participant reported 2 more episodes of anaphylaxis 21 weeks later, when the length of time since the last injection made it unlikely that the anaphylaxis episodes were related to omalizumab. The origin of the index episode in this participant remains uncertain, but another study suggests that this patient may fall into a category of those at greater risk of reactions, in whom omalizumab should be used with caution.15

    This study had a high proportion of nonwhite participants, and other work has shown that nonwhite groups are prone to more severe atopic dermatitis (Table 1).16

    The treatment effect on eczema severity, including the objective SCORAD index and CDLQI/DLQI, widened between the omalizumab and placebo groups at week 24, when therapy was discontinued. This finding suggests the treatment effect increased over time and may have widened further if treatment was continued beyond week 24. The effect persisted, albeit to a lesser extent, to week 48. Tissue-bound IgE may be of more relevance in disease states like atopic dermatitis; although the half-life of serum IgE is just 2 to 3 days, tissue-bound IgE has a considerably longer half-life.17 This fact may explain why between-group differences became apparent at week 24 and then persisted to week 48 despite cessation of treatment. In line with data from other studies, this finding may suggest potential benefits from prolonged treatment, higher doses of anti-IgE drug, or higher-affinity anti-IgE therapy.

    This study showed an improvement in the PADQLQ score and SPT reactivity, suggesting omalizumab’s possible effects on associated atopic conditions. Fewer respiratory events were reported in the omalizumab group. Omalizumab has well-established roles in managing asthma and chronic spontaneous urticaria, is effective for rhinoconjunctivitis, and may have a role in treating food allergy.18-21 Anti-IgE medication may be a cost-effective option in the multisystem, difficult-to-manage allergic disease that burdens many children at the severe end of the atopic spectrum.

    Limitations

    Limitations of this study included the fact that participants were permitted to use topical corticosteroids ad libitum for symptom relief. Although we were able to demonstrate potent topical corticosteroid sparing in the omalizumab group compared with the placebo group, it may have been at the expense of minimizing the difference in the treatment effect observed between the 2 groups.

    Although this study is the largest of its kind, to our knowledge, with high adherence and follow-up rates, with a robust primary outcome through various sensitivity analyses, and was supported by the secondary outcomes, the sample size was limited. Thus, estimates for some of the uncommon secondary outcomes lacked precision.

    Conclusions

    To our knowledge, this is the largest randomized clinical trial of anti-IgE medication performed to date in children with severe atopic dermatitis. It found that omalizumab use improved disease severity and patient QOL. Future work with an even larger sample size, a longer duration, and higher-affinity versions of omalizumab would clarify the precise role of anti-IgE therapy and its ideal target population. Such a study would enable clarification of the optimal treatment duration, age at treatment, and baseline total IgE levels.

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    Article Information

    Accepted for Publication: July 11, 2019.

    Corresponding Author: Susan Chan, MH, MD, Children’s Allergy, Second Floor, Block B, South Wing, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH, United Kingdom (susan.chan@kcl.ac.uk).

    Published Online: November 25, 2019. doi:10.1001/jamapediatrics.2019.4476

    Author Contributions: Dr Chan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Chan, Cornelius, Harper, Lack.

    Acquisition, analysis, or interpretation of data: Chan, Cornelius, Cro, Lack.

    Drafting of the manuscript: Chan, Cornelius, Lack.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Cornelius, Cro.

    Obtained funding: Chan, Cornelius, Lack.

    Administrative, technical, or material support: Chan, Lack.

    Supervision: Chan, Cornelius, Harper.

    Conflict of Interest Disclosures: Dr Chan reported receiving grants from the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) Programme, grants from Guy's and St Thomas’ Charity, and active and placebo drugs from Novartis during the conduct of the study. Dr Cro reported receiving grants from the NIHR EME Programme and Guy's and St Thomas’ Charity during the conduct of the study. Dr Lack reported receiving grants from the NIHR EME Programme and Guy's and St Thomas' Charity during the conduct of the study; active and placebo drugs from Novartis, DBV Technologies, and Mighty Mission Me during the conduct of the study; and personal fees from Novartis outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was funded by the NIHR EME Programme and Guy’s and St Thomas’ Charity. It was cosponsored by Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. Novartis supplied the omalizumab and placebo used in the study.

    Role of the Funder/Sponsor: The staff of the NIHR EME Programme and Guy’s and St Thomas’ Charity conducted a peer review of the study design. The staff of the NIHR EME Programme also were invited to the trial steering committee meetings. The staff of Guy’s and St Thomas’ NHS Foundation Trust, King’s College London, and King’s Health Partners Clinical Trial Office were involved in study monitoring. These organizations had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: The following staff were involved in the ADAPT study: Aikaterini Anagnostou, MD, PhD, David Atherton, MB, BCHIR, FRCP, Emily Banks, Kathryn Brighouse, Helen Brough, MD, PhD, Natalia Cartledge, MBBS, MRCPCH, Richard Cleaver, Elizabeth Coombs, Mary De Sousa, Oliver Gallen (a volunteer), Erika Harnik, MSc, Katherine Knight, Marta Krawiec, MD, Melissa Llewellyn, Tom Marrs, MBBS, Elizabeth Mather, Devi Patkunam, Ann Marie Powell, MBBS, MD, MRCP, Gemma Scanlan, Kate Swan, MSc, Charlotte Walker, Louise Young, and Marta Zancolli. The clinical study team included the following: Muhsinah Adam, Freda Adjei, Susan Chan, MD, MRCP, MRCPCH, Louise Coverdale, Helen Fisher, Joanna Gambell, Claire Hearn, Jemma Jackson, Rahi Jahan, Christine Jameson, Patricia Kane, Colm Keenan, Gary McGreevy, Una O’Dwyer-Leeson, Victoria Offord, Suzana Radulovic, MD, Anjum Shah, Prabalini Thaventhiran, Victoria Timms, Fiona Watson, and Emma Wedgeworth, MA, MBBS, MRCP Derm, DCH. All were affiliated with Guy’s and St Thomas’ NHS Foundation Trust and King’s College London at the time of the study except as noted, and they received no additional compensation outside of their usual salary for their contributions.

    Data Sharing Statement: See Supplement 3.

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