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Figure 1.  CONSORT Diagram Through Week 108 of the IXORA-PEDS Trial
CONSORT Diagram Through Week 108 of the IXORA-PEDS Trial
Figure 2.  Proportion of Patients Achieving End Points and Observed and Imputed Response Rates
Proportion of Patients Achieving End Points and Observed and Imputed Response Rates

The numbers of responders at milestone intervals were as follows: Psoriasis Area and Severity Index (PASI) 90: 71 at week 12, 79 at week 48, 76 at week 60, and 74 at week 108; PASI 100: 44 at week 12, 51 at week 48, 50 at week 60, and 52 at week 108. NRI indicates nonresponder imputation; sPGA, static Physician’s Global Assessment.

Table 1.  Baseline Demographics and Disease Characteristics
Baseline Demographics and Disease Characteristics
Table 2.  Efficacy Outcomes at Week 60 and Week 108
Efficacy Outcomes at Week 60 and Week 108
Table 3.  Summary of Adverse Events From Ixekizumab Treatment at Week 108
Summary of Adverse Events From Ixekizumab Treatment at Week 108
1.
Paller  AS, Seyger  MMB, Alejandro Magariños  G,  et al; IXORA-PEDS study group.  Efficacy and safety of ixekizumab in a phase III, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS).   Br J Dermatol. 2020;183(2):231-241. doi:10.1111/bjd.19147 PubMedGoogle ScholarCrossref
2.
Napolitano  M, Megna  M, Balato  A,  et al.  Systemic treatment of pediatric psoriasis: a review.   Dermatol Ther (Heidelb). 2016;6(2):125-142. doi:10.1007/s13555-016-0117-6 PubMedGoogle ScholarCrossref
3.
Augustin  M, Glaeske  G, Radtke  MA, Christophers  E, Reich  K, Schäfer  I.  Epidemiology and comorbidity of psoriasis in children.   Br J Dermatol. 2010;162(3):633-636. doi:10.1111/j.1365-2133.2009.09593.x PubMedGoogle ScholarCrossref
4.
Libon  F, Lebas  E, De Schaetzen  V, Sabatiello  M, De Schepper  S, Nikkels  AF.  Biologicals for moderate-to-severe plaque type psoriasis in pediatric patients.   Expert Rev Clin Immunol. 2021;17(9):947-955. doi:10.1080/1744666X.2021.1958675 PubMedGoogle ScholarCrossref
5.
Gånemo  A, Wahlgren  CF, Svensson  Å.  Quality of life and clinical features in Swedish children with psoriasis.   Pediatr Dermatol. 2011;28(4):375-379. doi:10.1111/j.1525-1470.2010.01292.x PubMedGoogle ScholarCrossref
6.
Bronckers  IM, Paller  AS, van Geel  MJ, van de Kerkhof  PC, Seyger  MM.  Psoriasis in children and adolescents: diagnosis, management and comorbidities.   Paediatr Drugs. 2015;17(5):373-384. doi:10.1007/s40272-015-0137-1 PubMedGoogle ScholarCrossref
7.
Oostveen  AM, de Jager  ME, van de Kerkhof  PC, Donders  AR, de Jong  EM, Seyger  MM.  The influence of treatments in daily clinical practice on the Children’s Dermatology Life Quality Index in juvenile psoriasis: a longitudinal study from the Child-CAPTURE patient registry.   Br J Dermatol. 2012;167(1):145-149. doi:10.1111/j.1365-2133.2012.10996.x PubMedGoogle ScholarCrossref
8.
Sarma  N.  Evidence and suggested therapeutic approach in psoriasis of difficult-to-treat areas: palmoplantar psoriasis, nail psoriasis, scalp psoriasis, and intertriginous psoriasis.   Indian J Dermatol. 2017;62(2):113-122. doi:10.4103/ijd.IJD_539_16 PubMedGoogle ScholarCrossref
9.
Mahé  E.  Childhood psoriasis.   Eur J Dermatol. 2016;26(6):537-548. doi:10.1684/ejd.2016.2932 PubMedGoogle ScholarCrossref
10.
Nogueira  M, Paller  AS, Torres  T.  Targeted therapy for pediatric psoriasis.   Paediatr Drugs. 2021;23(3):203-212. doi:10.1007/s40272-021-00443-5 PubMedGoogle ScholarCrossref
11.
GlobeNewswire. Novartis Cosentyx receives FDA approval for treatment of children and adolescents with moderate to severe plaque psoriasis. June 1, 2021. Accessed October 6, 2021. https://www.globenewswire.com/news-release/2021/06/01/2239937/0/en/Novartis-Cosentyx-receives-FDA-approval-for-treatment-of-children-and-adolescents-with-moderate-to-severe-plaque-psoriasis.html
12.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
13.
Papp  KA, Blauvelt  A, Bukhalo  M,  et al.  Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis.   N Engl J Med. 2017;376(16):1551-1560. doi:10.1056/NEJMoa1607017PubMedGoogle ScholarCrossref
14.
Rich  P, Scher  RK.  Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis.   J Am Acad Dermatol. 2003;49(2):206-212. doi:10.1067/S0190-9622(03)00910-1PubMedGoogle ScholarCrossref
15.
van Geel  MJ, Maatkamp  M, Oostveen  AM,  et al.  Comparison of the Dermatology Life Quality Index and the Children’s Dermatology Life Quality Index in assessment of quality of life in patients with psoriasis aged 16-17 years.   Br J Dermatol. 2016;174(1):152-157. doi:10.1111/bjd.14163PubMedGoogle ScholarCrossref
16.
Perez-Chada  LM, Salame  NF, Ford  AR,  et al.  Investigator and patient global assessment measures for psoriasis clinical trials: a Systematic Review on Measurement Properties from the International Dermatology Outcome Measures (IDEOM) initiative.   Am J Clin Dermatol. 2020;21(3):323-338. doi:10.1007/s40257-019-00496-wPubMedGoogle ScholarCrossref
17.
Leonardi  C, Reich  K, Foley  P,  et al.  Efficacy and safety of ixekizumab through 5 years in moderate-to-severe psoriasis: long-term results from the UNCOVER-1 and UNCOVER-2 phase-3 randomized controlled trials.   Dermatol Ther (Heidelb). 2020;10(3):431-447. doi:10.1007/s13555-020-00367-x PubMedGoogle ScholarCrossref
18.
Blauvelt  A, Lebwohl  MG, Mabuchi  T,  et al.  Long-term efficacy and safety of ixekizumab: a 5-year analysis of the UNCOVER-3 randomized controlled trial.   J Am Acad Dermatol. 2021;85(2):360-368. doi:10.1016/j.jaad.2020.11.022 PubMedGoogle ScholarCrossref
19.
Paller  AS, Siegfried  EC, Eichenfield  LF,  et al.  Long-term etanercept in pediatric patients with plaque psoriasis.   J Am Acad Dermatol. 2010;63(5):762-768. doi:10.1016/j.jaad.2010.04.004 PubMedGoogle ScholarCrossref
20.
Thaçi  D, Papp  K, Marcoux  D,  et al.  Sustained long-term efficacy and safety of adalimumab in paediatric patients with severe chronic plaque psoriasis from a randomized, double-blind, phase III study.   Br J Dermatol. 2019;181(6):1177-1189. doi:10.1111/bjd.18029 PubMedGoogle ScholarCrossref
21.
Philipp  S, Menter  A, Nikkels  AF,  et al.  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.   Br J Dermatol. 2020;183(4):664-672. doi:10.1111/bjd.19018 PubMedGoogle ScholarCrossref
22.
Bodemer  C, Kaszuba  A, Kingo  K,  et al.  Secukinumab demonstrates high efficacy and a favourable safety profile in paediatric patients with severe chronic plaque psoriasis: 52-week results from a phase 3 double-blind randomized, controlled trial.   J Eur Acad Dermatol Venereol. 2021;35(4):938-947. doi:10.1111/jdv.17002 PubMedGoogle ScholarCrossref
23.
Ng  SC, Shi  HY, Hamidi  N,  et al.  Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.   Lancet. 2017;390(10114):2769-2778. doi:10.1016/S0140-6736(17)32448-0 PubMedGoogle ScholarCrossref
24.
Paller  AS, Schenfeld  J, Accortt  NA, Kricorian  G.  A retrospective cohort study to evaluate the development of comorbidities, including psychiatric comorbidities, among a pediatric psoriasis population.   Pediatr Dermatol. 2019;36(3):290-297. doi:10.1111/pde.13772 PubMedGoogle ScholarCrossref
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    Original Investigation
    April 13, 2022

    Long-term Efficacy and Safety of Up to 108 Weeks of Ixekizumab in Pediatric Patients With Moderate to Severe Plaque Psoriasis: The IXORA-PEDS Randomized Clinical Trial

    Author Affiliations
    • 1Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
    • 2Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
    • 3Department of Dermatology, Radboud University Medical Center, Nijmegen, the Netherlands
    • 4Psoriahue, Buenos Aires, Argentina
    • 5Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt, Frankfurt am Main, Germany
    • 6Mindful Dermatology and Modern Research Associates, Dallas, Texas
    • 7Eli Lilly and Company, Indianapolis, Indiana
    • 8K Papp Clinical Research and Probity Medical Research, Waterloo, Ontario, Canada
    JAMA Dermatol. 2022;158(5):533-541. doi:10.1001/jamadermatol.2022.0655
    Key Points

    Question  What is the long-term (up to 108 weeks) efficacy and safety of ixekizumab for pediatric patients with moderate to severe psoriasis?

    Findings  In this randomized clinical trial of 139 pediatric patients with plaque psoriasis, those who completed treatment with ixekizumab through week 108 achieved improvement in the Psoriasis Area and Severity Index as well as static Physician’s Global Assessment scores, and these results were sustained through week 108. There were no new safety findings, including no new cases of inflammatory bowel disease or candidal infection.

    Meaning  Findings of this trial show that the safety of ixekizumab in this pediatric population was consistent with previously reported data and the known safety profile of this treatment.

    Abstract

    Importance  About 1% of children and adolescents worldwide are affected by plaque psoriasis.

    Objective  To evaluate the long-term efficacy and safety of ixekizumab for pediatric patients with moderate to severe psoriasis.

    Design, Setting, and Participants  This multicenter randomized clinical trial (IXORA-PEDS) evaluated pediatric patients with plaque psoriasis. Participants were aged 6 years to younger than 18 years; had moderate to severe psoriasis, which was defined as Psoriasis Area and Severity Index (PASI) of 12 or higher, static Physician’s Global Assessment (sPGA) score of 3 or higher, and psoriasis-affected body surface area of 10% or greater at screening and baseline; were candidates for phototherapy or systemic therapy; or had psoriasis that was not adequately controlled by topical therapies. Data analysis, which followed the intention-to-treat principle, was conducted from May to October 2021.

    Interventions  Pediatric patients were randomized 2:1 to receive either a weight-based dose of ixekizumab every 4 weeks or placebo. After a 12-week placebo-controlled period, patients entered a 48-week, open-label ixekizumab maintenance period (weeks 12-60), followed by an extension period that lasted through 108 weeks. A substudy evaluated the randomized withdrawal of ixekizumab after week 60.

    Main Outcomes and Measures  Efficacy outcomes at week 108 included the percentage of patients achieving 75% (PASI 75), 90% (PASI 90), or 100% (PASI 100) improvement from baseline; an sPGA score of 0 or 1 or score of 0; and improvement of 4 points or higher from baseline in the Itch Numeric Rating Scale. Safety outcomes included assessments of adverse events (AEs), including treatment-emergent AEs, serious AEs, and AEs of special interest, as well as improvement from baseline in a range of challenging body areas. Missing data for categorical outcomes were imputed using modified nonresponder imputation.

    Results  A total of 171 patients (mean [SD] age, 13.5 [3.04] years; 99 female children [57.9%]) were randomized to either ixekizumab (n = 115) or placebo (n = 56). Of 166 patients who entered the maintenance period, 139 (83.7%) completed week 108 of the trial. Primary and gated secondary end points were sustained through week 108, with patients achieving PASI 75 (91.7% [n = 86]), PASI 90 (79.0% [n = 74]), PASI 100 (55.1% [n = 52]), sPGA 0 or 1 (78.3% [n = 74]), and sPGA 0 (52.4% [n = 49]). Fifty-five patients (78.5%) reported an Itch Numeric Rating Scale improvement of 4 points or higher. In patients who received ixekizumab, at week 108, clearance of nail psoriasis was reported in 68.1% (n = 28), clearance of palmoplantar psoriasis was reported in 90.0% (n = 10), clearance of scalp psoriasis was reported in 76.2% (n = 83), and clearance of genital psoriasis was reported in 87.5% (n = 24). There were no new safety findings during weeks 48 to 108 of the trial, including no new cases of inflammatory bowel disease or candida infection.

    Conclusions and Relevance  Results of this study showed improvements across patient-reported outcomes and objective measures of complete skin clearance of psoriasis among pediatric patients who received ixekizumab, and these response rates were sustained through week 108 of the trial. Safety of ixekizumab was consistent with previously reported findings in this population and the known safety profile of this treatment.

    Trial Registration  ClinicalTrials.gov Identifier: NCT03073200

    Introduction

    Pediatric plaque psoriasis affects approximately 1% of children and adolescents,1,2 with a median age at onset of 7 to 10 years.3 This condition impairs the quality of life4 of pediatric patients4 and their parents,5 interfering with self-esteem, family and social relationships, school, and work-life balance.6,7 Psoriasis in certain locations, such as the face, scalp, palms and soles, nails, and genital region, has a disproportionately greater effect on a patient’s quality of life because of its high visibility or challenge in treating given the involvement of more sensitive areas that may be more recalcitrant to topical agents.8 Similar to adults, pediatric patients with psoriasis can have comorbidities, including psoriatic arthritis, obesity, Crohn disease, hypertension, diabetes, and psychiatric disorders.9

    Phototherapy, methotrexate, and potent topical therapies have long been the mainstays of treatment for moderate to severe psoriasis and have been prescribed off-label for pediatric plaque psoriasis. However, 5 biologics (etanercept, adalimumab, ustekinumab, secukinumab, and ixekizumab) for pediatric psoriasis have recently been approved by the European Medicines Agency, 4 of which (etanercept, ustekinumab, secukinumab, and ixekizumab) have also been approved by the US Food and Drug Administration.10,11 These biologics are highly efficacious with excellent tolerance and safety profiles.4

    Ixekizumab, which is approved as a first-line option for treatment of moderate to severe psoriasis in children aged 6 years to younger than 18 years,1,4 was found to be superior to placebo after 12 weeks of treatment, and these responses were sustained through week 48 in the IXORA-PEDS (Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Efficacy of Ixekizumab in Patients From 6 to Less Than 18 Years of Age With Moderate-to-Severe Plaque Psoriasis) trial, a phase 3 randomized clinical trial.1 In this trial, we evaluated the long-term efficacy and safety of ixekizumab for pediatric patients with moderate to severe psoriasis up to 108 weeks.

    Methods
    Study Design

    The IXORA-PEDS trial was conducted from March 28, 2017, to March 23, 2021, in accordance with the ethical principles of the Declaration of Helsinki.12 Local investigators or appropriate representatives at each of the 68 participating sites provided documentation of its ethical review board approval of the protocol, and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use assent form was provided to Eli Lilly before the study began at the site. Parents or legal guardians provided written informed consent, and patients provided written assent before the study assessments, examinations, and/or procedures. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

    The full study methods of the IXORA-PEDS trial have been published.1 During a 12-week, double-blind treatment period, patients were randomized 2:1 to receive either a subcutaneous, weight-based dose of ixekizumab every 4 weeks or placebo (Figure 1). After this 12-week period, all patients entered a 48-week maintenance period in which they received open-label ixekizumab every 4 weeks (weeks 12-60). This period was followed by an extension period that lasted through week 108 (see the trial protocol in Supplement 1 and the primary study design in eAppendixes 1 and 2 and eFigure 1 in Supplement 2). Patients who changed weight category during the trial remained in their original categorization for the initial 12 weeks and then changed categories according to their updated weight.

    As part of a European Union protocol addendum, an etanercept reference group was included in the IXORA-PEDS trial to demonstrate the efficacy of ixekizumab in comparison to an approved therapy for pediatric psoriasis.1 In addition, participants with severe psoriasis (defined as Psoriasis Area and Severity Index [PASI] of ≥20 or static Physician’s Global Assessment [sPGA] score of ≥4) from European Union countries who met the response criterion (defined as sPGA score of 0 or 1) at week 60 were rerandomized 1:1 to either ixekizumab or placebo from weeks 60 to 108 during the double-blind, randomized withdrawal period (eAppendix 1 and eFigure 2 in Supplement 2). During this withdrawal period, the time to first clinical relapse was calculated as follows: (date of first sPGA score ≥2 during the 48-week double-blind, randomized withdrawal period) – (date of week 60 rerandomization +1). If a patient had not experienced relapse by completion or early discontinuation of the withdrawal period, the patient was censored at the date of their last visit during the withdrawal period.

    Patients

    Study participants were aged 6 years to younger than 18 years and had moderate to severe plaque psoriasis, which was defined as PASI of 12 or higher, sPGA score of 3 or higher, and psoriasis-affected body surface area of 10% or greater at screening and baseline. These patients were also candidates for phototherapy or systemic therapy, or they had psoriasis that was determined by a trial investigator (including A.S.P., M.M.B.S., G.A.M., A.P., J.C.C., and K.A.P.) to be not adequately controlled by topical therapies.

    Race data were self-reported by participants to the study investigators at each site. The categories represented were American Indian or Alaska Native, Asian, Black or African American, White, and multiple; 4 patients did not report the data.

    Efficacy and Safety Parameters

    The objective of the present trial was to evaluate the efficacy and safety of treatment throughout a long-term extension period. The efficacy end points at week 108 included percentage of patients who achieved at least 75% (PASI 75), 90% (PASI 90), or 100% (PASI 100) improvement from baseline in PASI; an sPGA score of 0 or 1 (sPGA 0 or 1, with 0 indicating clear or no signs of psoriasis [postinflammatory hyperpigmentation may be present], and 1 indicating almost clear or intermediate between mild and clear signs of psoriasis) or score of 0; and improvement of 4 points or higher from baseline in the Itch Numeric Rating Scale (NRS; with a score of 0 indicating no itch) in patients with a baseline score of 4 points or higher. For patients who had baseline scalp, nail, or palmoplantar involvement, efficacy was evaluated by the percentage of patients who achieved complete resolution based on the Psoriasis Scalp Severity Index (PSSI; score range: 0-72, with 0 indicating no psoriasis and higher scores indicating more severe disease13), Nail Psoriasis Severity Index (NAPSI; score range for each nail: 0-8; NAPSI score range: 0-8014), and the Palmoplantar Psoriasis Area and Severity Index (PPASI; score range, 0-72, with 0 indicating no psoriasis and higher scores indicating more severe disease13), respectively. The 11-point Itch NRS (score range, 0-10, with 0 indicating no itch and 10 indicating worst itch imaginable) evaluated quality of life in patients with baseline Itch NRS score higher than 0. Clearance of genital psoriasis (in patients with baseline genital psoriasis) was also evaluated.

    Safety outcomes included assessments of adverse events (AEs), including treatment-emergent AEs (TEAEs), serious AEs (SAEs), and AEs of special interest. Data on suspected inflammatory bowel disease (IBD) were adjudicated by an external clinical events committee (eAppendix 4 in Supplement 2). A list of all end points is provided in eAppendix 3 in Supplement 2.

    Statistical Analysis

    Analyses were provided for the week 108 final database lock. Efficacy for the combined treatment periods was summarized using descriptive statistics for all patients randomized to ixekizumab at week 0 who received ixekizumab throughout their trial participation through week 108. Efficacy was also analyzed according to baseline weight category (<25 kg, ≥25 kg to ≤50 kg, and >50 kg). In addition, efficacy was summarized using descriptive statistics for the randomized withdrawal period.

    Missing data in categorical outcomes for the combined treatment periods were imputed using modified nonresponder imputation unless otherwise specified. Specifically, only patients who discontinued treatment because of AEs or lack of efficacy were imputed as a nonresponder; otherwise, patients were imputed using multiple imputation. Missing data in categorical outcomes for the withdrawal period were imputed using nonresponder imputation. Continuous outcomes were analyzed using a mixed model for repeated measures analysis, including treatment, affected region, baseline sPGA score, baseline weight category, baseline value, visit, and treatment-by-visit and baseline-by-visit interactions as fixed factors. A 2-tailed t was used to test if least-squares mean (LSM) change from baseline value was significantly different than 0.

    Safety was summarized using descriptive statistics up to the week 108 final database lock for the all-ixekizumab safety population. This population comprised all patients who received at least 1 dose of ixekizumab, including patients who were initially randomized to receive placebo or etanercept.

    Statistical analyses were performed in SAS, version 9.4 (SAS Institute). A 2-sided P < .05 was considered statistically significant. Data analysis, which followed the intention-to-treat principle, was conducted from May to October 2021.

    Results

    A total of 171 patients were randomized to either ixekizumab every 4 weeks (n = 115) or placebo (n = 56). These patients had a mean (SD) age of 13.5 (3.04) years and consisted of 99 female (57.9%) and 72 male (42.1%) children; most patients (83.8% [n = 140 of 167]) were of White race; 4 patients did not report their race and thus this calculation was based on 167 patients. Of the 166 patients who entered the maintenance and extension periods, 139 (83.7%) completed week 108 and 27 (16.3%) discontinued their participation (Figure 1). Baseline demographics and disease characteristics were similar between treatment groups (Table 1).1 For results imputed by modified nonresponders imputation, response rates were obtained through the average response rate of imputation data and are presented as percentages with the number of patients in the analysis.

    Efficacy

    Primary and gated secondary end points that were achieved by week 12 were sustained through week 108, with patients achieving or maintaining PASI 75 (91.7% [n = 86]), PASI 90 (79.0% [n = 74]), PASI 100 (55.1% [n = 52]), sPGA 0 or 1 (78.3% [n = 74]), and sPGA 0 (52.4% [n = 49]) (Figure 2; Table 2). At week 60, 90.0% of patients (n = 94) attained PASI 75 and 80.3% of patients (n = 94) attained PASI 90 (Table 2). In addition, 78.5% of patients (n = 55) with a baseline Itch NRS score of 4 or higher reported an Itch NRS improvement of 4 points or higher at week 108. Children’s Dermatology Life Quality Index or Dermatology Life Quality Index (score range: 0-30, with higher scores indicating more impact on quality of life15) of 0 or 1 was achieved by 60.6% of patients (n = 57), and Patient’s Global Assessment of Disease Severity16 score of 0 or 1 was achieved by 83.5% of patients (n = 79), and these results were sustained through week 108 (Table 2).

    At baseline, 26.9% of patients (n = 46) had NAPSI higher than 0, 88.9% of patients (n = 152) had PSSI higher than 0, 15.2% patients (n = 26) had PPASI higher than 0, and 32.2% patients (n = 55) had genital psoriasis. Clearance of nail psoriasis (NAPSI = 0) increased from 22.8% (n = 28) at week 12 to 68.1% (n =  28) at week 108. Similarly, clearance of palmoplantar psoriasis (PPASI 100) increased from 46.2% (n = 13) at week 12 to 90.0% (n = 10) at week 108, and clearance of scalp psoriasis (PSSI = 0) increased from 70.7% (n = 83) at week 12 to 76.2% (n = 83) at week 108 (Table 2; eFigure 3 in Supplement 2). Clearance of genital psoriasis was reported in 83.3% of patients (n = 25) who received ixekizumab at week 12 and increased slightly to 87.5% (n = 24) at week 108 (Table 2; eFigure 3 in Supplement 2).

    Ixekizumab every 4 weeks resulted in a significantly greater LSM change from baseline at week 108 for Itch NRS score (LSM [SE], −3.21 [0.6]; P < .001), NAPSI (LSM [SE], −31.12 [2.2]; P < .001), PSSI (LSM [SE], −27.02 [1.3]; P < .001), and PPASI (LSM [SE], −10.47 [0.1]; P < .001) (Table 2).

    In analyses by baseline weight, the overall responses were maintained through week 108 for PASI 75, PASI 90, PASI 100, sPGA 0 or 1, and sPGA 0 in the subgroups of patients in the weight categories of 25 kg or greater to 50 kg or less and greater than 50 kg. All ixekizumab responses were numerically similar between these 2 subgroups (eFigure 4 in Supplement 2). Comparison of responses in patients with baseline weight less than 25 kg was limited because of the small number of patients in this category (n = 1).

    Double-blind Randomized Withdrawal Period
    Time to Relapse

    For those patients who were rerandomized to ixekizumab or placebo during the randomized withdrawal period, the median time to relapse in the placebo group was 149 (95% CI, 106-190) days. A total of 90.9% of patients (n = 30) who received placebo relapsed, compared with 17.6% of patients (n = 6) who were treated with ixekizumab (eFigure 5 in Supplement 2). Among patients who received ixekizumab, 100% achieved PASI 75, 92.9% achieved PASI 90, and 75% achieved PASI 100 at week 108, and 76.5% achieved an sPGA score of 0 or 1 (Figure 2C-F).

    Safety

    During the combined treatment period, in the all-ixekizumab safety population (n = 196) (defined as all patients who received at least 1 dose of ixekizumab, including patients initially randomized to placebo or etanercept), TEAEs were reported in 87.7% of patients (n = 172) who were treated with ixekizumab every 4 weeks. Of these patients, 41.3% (n = 81 of 196) experienced mild, 40.3% (n = 79) experienced moderate, and 6.1% (n = 12) experienced severe TEAEs (Table 3). Fifteen patients (7.7%) reported SAEs, including 2 with Crohn disease. In total, 5 patients (2.6%) discontinued study treatment because of an AE (including Crohn disease, astrocytoma, pityriasis rubra pilaris, and psoriasis) (Table 3). Treatment-emergent infections were reported in 74.0% of patients (n = 145), and no new cases of candidal infections were reported. A detailed list of infections is provided in eTable 1 in Supplement 2. No patient reported anaphylaxis, 10.2% (n = 20) reported allergic reactions or hypersensitivity, 1.5% (n = 3) reported cytopenia, 2.0% (n = 4) reported hepatic issues, 0.5% (n = 1) reported a malignant neoplasm, and 4.1% (n = 8) reported depression (Table 3). A breakdown of SAEs is included in eTable 2 in Supplement 2.

    Discussion

    In pediatric patients who received ixekizumab, significant improvements in skin condition and itch were reported at week 121 and were sustained through week 108. Among patients who were treated with ixekizumab every 4 weeks, 91.7% achieved PASI 75, 79.0% achieved PASI 90, and 55.1% achieved PASI at week 108, a sustained response from week 12.1 The complete clearance rates (PASI 100) demonstrated in pediatric patients were somewhat higher than the rates observed in trials for adult patients with psoriasis after 5 years (46.3% in the UNCOVER-1 and UNCOVER-2 trials17 and 46.2% in the UNCOVER-3 trial18).

    Although cross-trial comparison with other biologics approved for use in pediatric patients is not possible, ixekizumab demonstrated numerically greater long-term PASI 75 and PASI 90 responses at week 60 (90.0% and 80.3% of patients, respectively) and week 108 (91.7% and 79.0%, respectively) in the IXORA-PEDS trial, compared with etanercept (61% [PASI 75] and 30% [PASI 90] after 96 weeks),19 adalimumab (28%-47% [PASI 75] after 52 weeks),20 ustekinumab (88% [PASI 75] in patients aged 6-12 years and 71% [PASI 90] after 52 weeks),21 and secukinumab (80% [PASI 75] and 80% [PASI 90] after 52 weeks).22 To our knowledge, long-term PASI 100 responses have not been consistently reported. However, PASI 100 efficacy has been reported at 52 weeks for secukinumab, with 40.0% (low dose) and 46.5% (high dose) of patients achieving PASI 100 respectively.22 In this analysis, PASI 100 was achieved at week 108 by 55.1% of patients who received ixekizumab.

    Itch NRS improvement from baseline of 4 points or higher was reported in patients who were treated with ixekizumab every 4 weeks. Ixekizumab every 4 weeks provided meaningful improvements in itch for 78.5% of these patients at week 108. Patients who received ixekizumab every 4 weeks also reported significant improvements from baseline in challenging to treat body areas, including the scalp, nails, palms and soles, and genital region (Table 2; eFigure 3 in Supplement 2). For those patients with nail or palmoplantar involvement, extra time using the medication substantially increased the number of patients achieving clearance (NAPSI = 0 and PPASI 100), with numerically greater percentages observed at week 60 and week 108 (Table 2; eFigure 3 in Supplement 2). However, the small sample size for patients with palmoplantar involvement necessitated the use of observed data. This finding suggests that caution is needed when interpreting the PPASI 100 data. In addition, at week 108, responses with ixekizumab were generally consistent across weight subgroups, although analysis in patients with baseline weight less than 25 kg was limited by the small sample size (n = 1) (eFigure 4 in Supplement 2).

    Details on TEAEs, SAEs, and AEs during the double-blind treatment period are reported in Paller et al.1 There were no new safety events during the period between week 48 and week 108. Consistent with previously reported data, this study found that infections and injection site reactions were the most frequently reported TEAEs. There were no new cases of IBD in the extension period, and no candidal infections were observed throughout the 108-week IXORA-PEDS trial. During the trial, most TEAEs were mild to moderate in severity, SAEs occurred in 7.7% of patients, and 2.6% of patients discontinued participation because of AEs. No deaths occurred. The safety profile of ixekizumab was similar in adult and pediatric patients, with the exception of IBD, which has a substantially higher background rate in patients with pediatric onset of psoriasis.3,23,24

    Although this study showed that ixekizumab has a favorable efficacy and safety profile through 108 weeks, a number of open questions remain. Such questions include the effect of ixekizumab on additional patient-reported, health-related quality-of-life outcomes as well as the effectiveness and safety of ixekizumab for pediatric patients with psoriasis in the real world.

    Limitations

    This study has some limitations. First, the study lacked a comparator after week 12. Second, ixekizumab was administered on site, which may not be reflective of real-world administration for pediatric patients weighing more than 50 kg.

    Conclusions

    In pediatric patients with moderate to severe plaque psoriasis, ixekizumab provided rapid improvements across patient-reported outcomes and objective measures of complete skin clearance of psoriasis, including clearance of psoriasis, in challenging to treat body areas, and these results were sustained up to 108 weeks. Most patients achieved completely clear skin and nails. Safety findings were as previously observed in this population and consistent with the known safety profile of ixekizumab. No new cases of IBD were observed in the IXORA-PEDS trial, and there were no reported cases of candidal infection. Additional studies are warranted to address lingering questions, such as the effect of ixekizumab on additional patient-reported outcomes and the effectiveness and safety of ixekizumab for children with psoriasis in the real world.

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    Article Information

    Accepted for Publication: February 11, 2022.

    Published Online: April 13, 2022. doi:10.1001/jamadermatol.2022.0655

    Correction: This article was corrected on August 17, 2022, to fix the key for Figure 2A and B and footnote f for Table 3.

    Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Paller AS et al. JAMA Dermatology.

    Corresponding Author: Amy S. Paller, MD, Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, 676 N St Clair, Suite 1600, Chicago, IL 60611 (apaller@northwestern.edu).

    Author Contributions: Drs Paller and Zhu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Paller, Magariños, Pinter, Rodriguez-Capriles.

    Acquisition, analysis, or interpretation of data: Paller, Seyger, Pinter, Cather, Rodriguez-Capriles, Zhu, Somani, Garrelts, Papp.

    Drafting of the manuscript: Pinter, Rodriguez-Capriles.

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

    Statistical analysis: Rodriguez-Capriles, Zhu.

    Administrative, technical, or material support: Rodriguez-Capriles, Garrelts.

    Supervision: Paller, Magariños, Pinter, Cather, Rodriguez-Capriles.

    Conflict of Interest Disclosures: Dr Paller reported receiving personal fees for consulting from Eli Lilly, AbbVie, UCB, LEO Pharma, and Exicure outside the submitted work as well as receiving grants to institution as an investigator from Eli Lilly, AbbVie, Janssen, Novartis, and UCB outside the submitted work. Dr Seyger reported receiving grants from Eli Lilly and other funding from Amgen, Janssen, and Novartis outside the submitted work. Dr Magariños reported receiving personal fees from AbbVie, Biogen, Boehringer, Eli Lilly and Co, Janssen, Novartis, and Pfizer outside the submitted work. Dr Cather reported receiving personal fees for advisory board, speaking, and/or clinical trial from AbbVie, Amgen, Bristol Myers Squibb, Celgene, ChemoCentryx, Galderma, UCB, Janssen, Anaptys, and Eli Lilly outside the submitted work. Dr Somani reported receiving other as an employee and minor shareholder from Eli Lilly during the conduct of the study. Dr Garrelts reported receiving other as an employee and shareholder from Eli Lilly during the conduct of the study and outside the submitted work. Dr Papp reported receiving grants, personal fees, and other as a consultant from Eli Lilly during the conduct of the study as well as receiving grants and other as a consultant from AbbVie, UCB, and Novartis; other as a consultant from Sandoz; grants from Amgen, Arcutis, Avillion, Bausch Health, Dermavant, Incyte, LEO Pharma, Pfizer, and Sun Pharma; and personal fees from Bausch Health, Bristol Myers Squibb, Dermavant, and Novartis outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was funded by Eli Lilly and Company.

    Role of the Funder/Sponsor: The funder had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Group Information: The IXORA-PEDS Investigators are listed in Supplement 3.

    Additional Contributions: The authors worked on behalf of all IXORA-PEDS investigators. Geraldine Fahy, PhD, Eli Lilly, provided editorial assistance. She did not receive compensation beyond her usual salary for her contribution to this work.

    Meeting Presentation: The results of this study were presented as a poster at the American Academy of Dermatology meeting; March 27, 2022; Boston, Massachusetts.

    Data Sharing Statement: See Supplement 4.

    References
    1.
    Paller  AS, Seyger  MMB, Alejandro Magariños  G,  et al; IXORA-PEDS study group.  Efficacy and safety of ixekizumab in a phase III, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS).   Br J Dermatol. 2020;183(2):231-241. doi:10.1111/bjd.19147 PubMedGoogle ScholarCrossref
    2.
    Napolitano  M, Megna  M, Balato  A,  et al.  Systemic treatment of pediatric psoriasis: a review.   Dermatol Ther (Heidelb). 2016;6(2):125-142. doi:10.1007/s13555-016-0117-6 PubMedGoogle ScholarCrossref
    3.
    Augustin  M, Glaeske  G, Radtke  MA, Christophers  E, Reich  K, Schäfer  I.  Epidemiology and comorbidity of psoriasis in children.   Br J Dermatol. 2010;162(3):633-636. doi:10.1111/j.1365-2133.2009.09593.x PubMedGoogle ScholarCrossref
    4.
    Libon  F, Lebas  E, De Schaetzen  V, Sabatiello  M, De Schepper  S, Nikkels  AF.  Biologicals for moderate-to-severe plaque type psoriasis in pediatric patients.   Expert Rev Clin Immunol. 2021;17(9):947-955. doi:10.1080/1744666X.2021.1958675 PubMedGoogle ScholarCrossref
    5.
    Gånemo  A, Wahlgren  CF, Svensson  Å.  Quality of life and clinical features in Swedish children with psoriasis.   Pediatr Dermatol. 2011;28(4):375-379. doi:10.1111/j.1525-1470.2010.01292.x PubMedGoogle ScholarCrossref
    6.
    Bronckers  IM, Paller  AS, van Geel  MJ, van de Kerkhof  PC, Seyger  MM.  Psoriasis in children and adolescents: diagnosis, management and comorbidities.   Paediatr Drugs. 2015;17(5):373-384. doi:10.1007/s40272-015-0137-1 PubMedGoogle ScholarCrossref
    7.
    Oostveen  AM, de Jager  ME, van de Kerkhof  PC, Donders  AR, de Jong  EM, Seyger  MM.  The influence of treatments in daily clinical practice on the Children’s Dermatology Life Quality Index in juvenile psoriasis: a longitudinal study from the Child-CAPTURE patient registry.   Br J Dermatol. 2012;167(1):145-149. doi:10.1111/j.1365-2133.2012.10996.x PubMedGoogle ScholarCrossref
    8.
    Sarma  N.  Evidence and suggested therapeutic approach in psoriasis of difficult-to-treat areas: palmoplantar psoriasis, nail psoriasis, scalp psoriasis, and intertriginous psoriasis.   Indian J Dermatol. 2017;62(2):113-122. doi:10.4103/ijd.IJD_539_16 PubMedGoogle ScholarCrossref
    9.
    Mahé  E.  Childhood psoriasis.   Eur J Dermatol. 2016;26(6):537-548. doi:10.1684/ejd.2016.2932 PubMedGoogle ScholarCrossref
    10.
    Nogueira  M, Paller  AS, Torres  T.  Targeted therapy for pediatric psoriasis.   Paediatr Drugs. 2021;23(3):203-212. doi:10.1007/s40272-021-00443-5 PubMedGoogle ScholarCrossref
    11.
    GlobeNewswire. Novartis Cosentyx receives FDA approval for treatment of children and adolescents with moderate to severe plaque psoriasis. June 1, 2021. Accessed October 6, 2021. https://www.globenewswire.com/news-release/2021/06/01/2239937/0/en/Novartis-Cosentyx-receives-FDA-approval-for-treatment-of-children-and-adolescents-with-moderate-to-severe-plaque-psoriasis.html
    12.
    World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
    13.
    Papp  KA, Blauvelt  A, Bukhalo  M,  et al.  Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis.   N Engl J Med. 2017;376(16):1551-1560. doi:10.1056/NEJMoa1607017PubMedGoogle ScholarCrossref
    14.
    Rich  P, Scher  RK.  Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis.   J Am Acad Dermatol. 2003;49(2):206-212. doi:10.1067/S0190-9622(03)00910-1PubMedGoogle ScholarCrossref
    15.
    van Geel  MJ, Maatkamp  M, Oostveen  AM,  et al.  Comparison of the Dermatology Life Quality Index and the Children’s Dermatology Life Quality Index in assessment of quality of life in patients with psoriasis aged 16-17 years.   Br J Dermatol. 2016;174(1):152-157. doi:10.1111/bjd.14163PubMedGoogle ScholarCrossref
    16.
    Perez-Chada  LM, Salame  NF, Ford  AR,  et al.  Investigator and patient global assessment measures for psoriasis clinical trials: a Systematic Review on Measurement Properties from the International Dermatology Outcome Measures (IDEOM) initiative.   Am J Clin Dermatol. 2020;21(3):323-338. doi:10.1007/s40257-019-00496-wPubMedGoogle ScholarCrossref
    17.
    Leonardi  C, Reich  K, Foley  P,  et al.  Efficacy and safety of ixekizumab through 5 years in moderate-to-severe psoriasis: long-term results from the UNCOVER-1 and UNCOVER-2 phase-3 randomized controlled trials.   Dermatol Ther (Heidelb). 2020;10(3):431-447. doi:10.1007/s13555-020-00367-x PubMedGoogle ScholarCrossref
    18.
    Blauvelt  A, Lebwohl  MG, Mabuchi  T,  et al.  Long-term efficacy and safety of ixekizumab: a 5-year analysis of the UNCOVER-3 randomized controlled trial.   J Am Acad Dermatol. 2021;85(2):360-368. doi:10.1016/j.jaad.2020.11.022 PubMedGoogle ScholarCrossref
    19.
    Paller  AS, Siegfried  EC, Eichenfield  LF,  et al.  Long-term etanercept in pediatric patients with plaque psoriasis.   J Am Acad Dermatol. 2010;63(5):762-768. doi:10.1016/j.jaad.2010.04.004 PubMedGoogle ScholarCrossref
    20.
    Thaçi  D, Papp  K, Marcoux  D,  et al.  Sustained long-term efficacy and safety of adalimumab in paediatric patients with severe chronic plaque psoriasis from a randomized, double-blind, phase III study.   Br J Dermatol. 2019;181(6):1177-1189. doi:10.1111/bjd.18029 PubMedGoogle ScholarCrossref
    21.
    Philipp  S, Menter  A, Nikkels  AF,  et al.  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.   Br J Dermatol. 2020;183(4):664-672. doi:10.1111/bjd.19018 PubMedGoogle ScholarCrossref
    22.
    Bodemer  C, Kaszuba  A, Kingo  K,  et al.  Secukinumab demonstrates high efficacy and a favourable safety profile in paediatric patients with severe chronic plaque psoriasis: 52-week results from a phase 3 double-blind randomized, controlled trial.   J Eur Acad Dermatol Venereol. 2021;35(4):938-947. doi:10.1111/jdv.17002 PubMedGoogle ScholarCrossref
    23.
    Ng  SC, Shi  HY, Hamidi  N,  et al.  Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.   Lancet. 2017;390(10114):2769-2778. doi:10.1016/S0140-6736(17)32448-0 PubMedGoogle ScholarCrossref
    24.
    Paller  AS, Schenfeld  J, Accortt  NA, Kricorian  G.  A retrospective cohort study to evaluate the development of comorbidities, including psychiatric comorbidities, among a pediatric psoriasis population.   Pediatr Dermatol. 2019;36(3):290-297. doi:10.1111/pde.13772 PubMedGoogle ScholarCrossref
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