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)

A.S. Paller; M.M.B. Seyger; G. Alejandro Magariños; J. Bagel; A. Pinter; J. Cather; S. Keller; C. Rodriguez Capriles; R. Gontijo Lima; G. Gallo; C.A. Little; E. Edson-Heredia; L. Li; W. Xu; K. Papp

Disclosures

The British Journal of Dermatology. 2020;183(2):231-241. 

In This Article

Patients and Methods

Patients

Study participants were 6 to < 18 years of age and had moderate-to-severe plaque psoriasis, defined as Psoriasis Area and Severity Index (PASI) ≥ 12, static Physician's Global Assessment (sPGA) ≥ 3 and psoriasis-affected body surface area ≥ 10% at screening and baseline. They were also candidates for phototherapy or systemic therapy or their psoriasis was not adequately controlled by topical therapies as determined by the investigator. Patients with pustular, erythrodermic and/or guttate forms of plaque psoriasis or drug-induced psoriasis, or with clinical and/or laboratory evidence of untreated latent or active tuberculosis were excluded. Appendix S2 (see Supporting Information) provides complete eligibility criteria.

Study Design

IXORA-PEDS is a 108-week multicentre, double-blind, randomized, placebo-controlled, phase III study examining the efficacy and safety of IXE vs. placebo in paediatric patients with moderate-to-severe plaque psoriasis. During a 12-week double-blind treatment period, patients were randomized 2 : 1 to subcutaneous IXE every 4 weeks (Q4W) or placebo, administered according to baseline weight categories of > 50 kg, 25–50 kg and < 25 kg (Table S1; see Supporting Information). As part of a European Union protocol addendum, an etanercept reference arm was included in IXORA-PEDS to demonstrate the efficacy of IXE in the context of an approved therapy for paediatric psoriasis. At the time of trial commencement, etanercept was approved only for severe psoriasis in paediatric patients in the European Union. Therefore, patients with severe psoriasis (PASI ≥ 20 or sPGA ≥ 4) at baseline in countries where etanercept is approved only for severe paediatric psoriasis were eligible for inclusion in the protocol addendum. These patients were randomized 2 : 2 : 1 to IXE Q4W, open-label etanercept (0·8 mg kg−1 every 1 week, not exceeding 50 mg per dose) or placebo until approximately 75 patients were randomized. Efficacy assessments were conducted by blinded assessors to minimize potential bias in assessments of patients receiving open-label etanercept.

Patients completing the double-blind treatment period entered a 48-week open-label maintenance period (week 12 to week 60), during which patients initially randomized to IXE Q4W or placebo received IXE Q4W and patients initially randomized to etanercept received IXE Q4W after an 8-week washout period.

Enrolment for IXORA-PEDS occurred between 17 April 2017 and 13 November 2018. At the time of publication of this report, the study is currently ongoing. IXORA-PEDS (ClinicalTrials.gov: NCT03073200) was conducted in accordance with the ethical principles of the Declaration of Helsinki. The study was approved by the ethical review board at each participating site. A parent or legal guardian provided written informed consent and the patient provided written assent prior to conduct of study assessments, examinations or procedures. Appendix S3 (see Supporting Information) provides additional details on the study design.

Outcomes

The prespecified coprimary objectives of the study were to assess whether IXE Q4W was superior to placebo at week 12 as measured by the proportions of patients achieving ≥ 75% improvement from baseline in PASI (PASI 75) and an sPGA score of 0 or 1 [sPGA (0,1)]. The prespecified gated secondary objectives were to assess whether IXE Q4W was superior to placebo at week 12, as measured by the proportion of patients achieving PASI 90, an sPGA score of 0 [sPGA (0)], PASI 100 and ≥ 4-point improvement from baseline in the Itch Numerical Rating Scale (Itch NRS ≥ 4, in patients with baseline score ≥ 4); as well as PASI 75 and sPGA (0,1) at week 4. Other prespecified secondary outcomes included a 0 or 1 score on the Children's Dermatology Life Quality Index (CDLQI, patients aged 6–16 years) or Dermatology Life Quality Index (DLQI, patients aged ≥ 17 years), a score of 0 or 1 on the Patient's Global Assessment of Disease Severity [PatGA (0,1)], a Nail Psoriasis Severity Index score of 0 (NAPSI = 0, in patients with baseline NAPSI > 0), a Psoriasis Scalp Severity Index score of 0 (PSSI = 0, in patients with baseline PSSI > 0), 100% improvement from baseline in the Palmoplantar Psoriasis Area and Severity Index (PPASI 100, in patients with baseline PPASI > 0), clearance of genital psoriasis (in patients with baseline genital psoriasis), mean change from baseline in Itch NRS, and mean change from baseline in NAPSI, PSSI and PPASI for patients with baseline NAPSI > 0, PSSI > 0 and PPASI > 0, respectively. Appendixes S4 and S5 (see Supporting Information) provide further details on the objectives and outcomes.

Safety outcomes included assessments of adverse events (AEs) – including treatment-emergent AEs (TEAEs), serious AEs (SAEs) and AEs of special interest – laboratory tests and vital signs. Data on suspected inflammatory bowel disease (IBD) were adjudicated by an external clinical events committee. Appendixes S3 and S6 (see Supporting Information) provide details on antidrug antibody assays and safety outcomes.

Statistical Analyses

A gated multiple testing strategy was implemented for the primary and major secondary objectives to control the family-wise type I error rate at a two-sided α-level of 0·05. To assess whether IXE Q4W was superior to placebo, the primary and gated secondary endpoints were tested sequentially. If any test was not successful, all subsequent tests were not tested.

Analyses are provided for the week 12 and week 48 database locks. Efficacy analyses during the double-blind treatment period were performed on all randomized patients according to the initially assigned treatment. Efficacy was also summarized using descriptive statistics for all patients randomized to IXE at week 0 who received IXE throughout their study participation up to week 48. Additional efficacy analyses were performed according to the initially assigned treatment on all randomized patients with severe psoriasis in countries where etanercept was approved for severe psoriasis. Efficacy was also analysed according to baseline weight category (< 25 kg, ≥ 25 kg to ≤ 50 kg and > 50 kg).

Treatment group comparisons for categorical outcomes were performed using Fisher's exact test with nonresponder imputation for handling of missing data. Continuous outcomes were analysed using a mixed model for repeated-measures analysis, including treatment, region, baseline sPGA score, baseline weight category, baseline value, visit, treatment-by-visit and baseline-by-visit interactions as fixed factors. Type III tests for the least-squares means were used for statistical comparisons. Table S2 (see Supporting Information) lists the number of patients with nonmissing data at each postbaseline visit through week 48.

Safety was summarized using descriptive statistics. Safety analyses during the double-blind treatment period were performed on all randomized patients who took at least one dose of double-blind study treatment according to the initially assigned treatment. Safety was also summarized up to the week 48 interim database lock for the all-IXE safety population, defined as all patients who received at least one dose of IXE, including patients initially randomized to placebo or etanercept. Additional safety analyses were conducted in all randomized patients in etanercept-approved countries who took at least one dose of double-blind study treatment according to the initially assigned treatment.

Analyses of antidrug antibodies were conducted on all evaluable patients in the all-IXE safety population. Patients with treatment-emergent antidrug antibodies (TE-ADAs) were classified as having low, moderate or high titre if their last titre value within the baseline or postbaseline period was < 1 : 160, ≥ 1 : 160 to < 1 : 1280, or ≥ 1 : 1280, respectively. Appendix S7 (see Supporting Information) provides additional information on the statistical analyses.

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