This phase 3, multicenter, randomized, double-blind, placebo-controlled study was conducted between July 2019, and August 2022, at 41 centers in Japan. The study consisted of the screening period (from the day of consent until before initiating study intervention, ≤ 30 days), the 16-week, double-blind period, and the 52-week, open-label extension period (ClinicalTrials.gov identifier: NCT04061252; Online Resource 1, see the electronic supplementary material).

Eligible PPP patients were randomized at the case enrollment center in a 1:1 ratio to the brodalumab 210 mg group or the placebo group during the screening period by using a dynamic allocation scheme after considering the following factors: PPP Area and Severity Index (PPPASI) total score at enrollment (< 21, ≥ 21 and < 31, ≥ 31), presence or absence of pustulotic arthro-osteitis, smoking status (active smoker or nonsmoker) at enrollment, and the investigating site. In this double-blind trial, both physicians and patients were blinded to the treatment assignment. The respective interventions, either brodalumab 210 mg or the placebo, were subcutaneously (SC) administered at baseline, at weeks 1 and 2, and every 2 weeks (Q2W) thereafter during the double-blind period. At week 16, all patients entered a 52-week, open-label, extension phase and received brodalumab 210 mg SC Q2W until week 68.

Those included were patients aged ≥ 18 to ≤ 70 years, able to provide voluntary written informed consent, with a diagnosis of PPP (with or without osteoarticular lesions) for ≥ 24 weeks, and having a PPPASI total score ≥ 12 and a PPPASI severity score of pustules/vesicles on the palms or soles of ≥ 2 both at pre-examination and enrollment examination (details in Online Resource 2, see the electronic supplementary material). Briefly, patients had to meet all the following criteria for diagnosis of PPP: (1) pustules on the palms, soles, or both; (2) progression from vesicles to pustules; and (3) repeated occurrence of lesions at the same sites. Patients with a diagnosis of plaque psoriasis, pustular psoriasis, drug-induced PPP, or pompholyx were excluded. Moreover, patients with a known focal infection at the time of informed consent who had not received appropriate treatment or patients who had received treatment for focal infection (e.g., tonsillectomy and dental treatment) or treatment for metal allergy (e.g., change of dental materials) within 6 months before the start of the intervention were also excluded. Patients who used systemic antibiotics within 4 weeks before the start of the intervention were also excluded.

Concomitant use of topical medicines (except emollients) and systemic therapy with or without biologics for PPP, as well as phototherapy, were not permitted during the study period.

The primary efficacy endpoint was change from baseline in PPPASI total score at week 16. Secondary efficacy endpoints assessed at week 16 included the following: achievement of PPPASI-50/75/90 response (corresponding to 50%/75%/90% or greater improvement from baseline in the PPPASI total score), change from baseline in PPP Severity Index (PPP-SI) total score (Online Resource 2), PPP-SI-50/75/90 (corresponding to 50%/75%/90% or greater improvement from baseline in the PPP-SI total score), change from baseline in each PPP-SI component score, achievement of a Physician’s Global Assessment (PGA) score of 0 or 1, change in Dermatology Life Quality Index (DLQI) score from baseline, change from baseline in Numerical Rating Scale (NRS)-PPP pain score, change from baseline in NRS-PPP itch score, and change from baseline in pustule/vesicle severity score. Additionally, subgroup analyses comparing the improvement at 16 weeks from baseline PPPASI total score between brodalumab and placebo groups were performed by baseline characteristics. These included analyses by gender (male or female), age (< 65 or ≥ 65 years), body weight (< median or ≥ median), disease duration (< median or ≥ median), PPPASI total score at enrollment (< 21, ≥ 21 to < 31, or ≥ 31), change in PPPASI total score from screening to baseline (improved, unchanged, or deteriorated), presence of pustulotic arthro-osteitis (yes or no), smoking habit at enrollment (yes or no), body mass index (BMI) (< 25 or ≥ 25), PPP-SI total score at enrollment (≥ 4 to ≤ 9 or > 9), PGA at enrollment (< 4 or ≥ 4), pustule/vesicle severity score at enrollment < 3 or ≥ 3, nail findings at enrollment (yes or no), period at enrollment (January–March, April–June, July–September, or October–December), history of previous non-biological systemic treatment (yes or no), history of previous biological treatment (yes or no), previous systemic treatment (yes or no), topical treatment (yes or no), previous phototherapy (yes or no), previous therapy for focal infection (yes or no), history of granulocyte and monocyte absorption apheresis (yes or no), and treatment for metal allergy (yes or no).

For PPPASI scoring, the palms and soles were divided into four areas: right palm (RP), left palm (LP), right sole (RS), and left sole (LS), which account for 20%, 20%, 30%, and 30%, respectively, of the total surface area of the palms or soles. Each area is comprehensively evaluated for erythema (E), pustule/vesicle, including crusts, i.e., dried pustules (P), and desquamation/scales (D), each rated on a 5-point scale of none (0), mild (1), moderate (2), severe (3), and very severe (4). The total score, calculated as PPPASI = (E + P + D) area × 0.2 (RP) + (E + P + D) area × 0.2 (LP) + (E + P + D) area × 0.3 (RS) + (E + P + D) area × 0.3 (LS), ranges from 0 to 72, and a higher score indicates severe disease.

Key safety endpoints were evaluated after the administration of drugs as treatment-emergent adverse events (TEAEs) and drug-related TEAEs. Clinical laboratory test results, vital signs (systolic and diastolic blood pressures, pulse rate, respiratory rate, and body temperature), anti-brodalumab antibodies, Columbia-Suicide Severity Rating Scale (C-SSRS), and Patient Health Questionnaire (PHQ)-8 were reviewed to identify TEAEs.

The target sample size of 120 was set based on data from the previous phase 3, double-blind, placebo-controlled study of guselkumab in patients with PPP [18]. Assuming the mean value of change in the PPPASI total score of − 15.0 and − 8.0 in the brodalumab and placebo groups, respectively, with a standard deviation (SD) of 11.5 in both groups and an absolute mean difference between the two groups of 7.0, at week 16, the sample size was calculated to be 58 patients per group for the primary endpoint at a significance level of 0.05 (two-sided) and 90% or greater power.

The patients who dropped due to Good Clinical Practice (GCP) deviations were excluded from both safety and efficacy analyses if the patients had not provided consent as specified in the protocol. For descriptive analysis of efficacy data, quantitative variables were summarized as mean (SD), while qualitative variables were summarized as number (%). Changes from baseline in the PPPASI and PPP-SI total scores at week 16 were compared between the groups using a mixed model for repeated measures (MMRM), with fixed effects for the treatment group, time point, PPPASI total score at baseline, eligibility for pustulotic arthro-osteitis evaluation (yes/no), smoking habit (yes/no), and interaction of treatment groups with time points. The treatment effect for the brodalumab group compared to the placebo group at week 16 was estimated based on the least-squares (LS) mean differences; a t test was performed for these LS mean differences between the groups at week 16 at a significance level of 0.05 (two-sided). Additional exploratory analyses were conducted for evaluating the possible association between improvement from baseline DLQI, NRS-PPP itch, and NRS-PPP pain scores at week 16 and the achievement of PPPASI-50/75/90 responses.

For missing efficacy data at week 16 for PPPASI total score and PPP-SI total score, imputation was not performed, and only observed data were used as a part of the MMRM analysis. For the other missing continuous data, the baseline observation carried forward (BOCF) approach was used. For missing categorical (binary) data, nonresponder imputations (NRI) were performed.

All randomized patients who received an administration of the investigational drug were included in the modified intention-to-treat (mITT) population, with modification to exclude patients with ITT who had discontinued between informed consent and treatment initiation, and the efficacy was analyzed in the mITT population. The safety analysis population was set as the same as the mITT population. For the safety analysis, important identified risks and important potential risks of brodalumab were evaluated as adverse events (AEs) of special interest. Specifically, events related to neutrophil count decrease, serious infection, serious hypersensitivity, malignancy, inflammatory bowel disease, and suicide/self-injury-related events were evaluated. TEAEs were summarized by the treatment group using the Medical Dictionary for Regulatory Activities (MedDRA) (version 22.0) System Organ Class and Preferred Terms.

The study (NCT04061252) was conducted in compliance with the protocol, the Declaration of Helsinki (World Medical Association [WMA]) [36], the Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines [37], the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice Guidelines [38], and other applicable laws and regulations. It was approved by the concerned institutional review board. All participants gave written informed consent.