Difamilast, a selective phosphodiesterase 4 inhibitor, ointment in paediatric patients with atopic dermatitis: a phase III randomized double-blind, vehicle-controlled trial

Abstract

Background: In atopic dermatitis (AD), phosphodiesterase 4 (PDE4) inhibition reduces proinflammatory mediators and cytokines. Difamilast is a new selective PDE4 inhibitor.

Objectives: To demonstrate the superiority of topical difamilast to vehicle in Japanese paediatric patients with AD.

Methods: This was a phase III randomized, double-blind, vehicle-controlled trial. Patients aged 2-14 years with an Investigator Global Assessment (IGA) score of 2 or 3 received difamilast 0·3% (n = 83), difamilast 1% (n = 85) or vehicle (n = 83) ointment twice daily for 4 weeks.

Results: The primary endpoint was the percentage of patients with an IGA score of 0 or 1 with improvement by at least two grades at week 4. The success rates in IGA score at week 4 were 44·6%, 47·1% and 18·1% in the difamilast 0·3%, difamilast 1% and vehicle groups, respectively. Both difamilast groups demonstrated significantly higher success rates in IGA score compared with vehicle at week 4 [difamilast 0·3% (P < 0·001); difamilast 1% (P < 0·001)]. Regarding secondary endpoints, improvements in Eczema Area and Severity Index (EASI; improvement of ≥ 50%, ≥ 75% and ≥ 90% in overall score) at week 4 were significantly higher in patients in the difamilast 0·3% and 1% groups than those in the vehicle group. EASI score in the difamilast 0·3% and 1% groups was significantly reduced compared with that of patients in the vehicle group at week 1. The significant difference between both the difamilast groups and the vehicle groups was maintained from week 1 through to week 4. Most treatment-emergent adverse events were mild or moderate, and no serious events or deaths were reported.

Conclusions: Difamilast 0·3% and 1% ointments are superior to vehicle and well tolerated in Japanese paediatric patients with AD.

Trial registration: ClinicalTrials.gov NCT03911401.

Figure 1

Patient disposition throughout the phases of the trial.

Figure 2

Success rate in Investigator’s Global Assessment (IGA) score. The data represent the percentage of patients achieving an IGA score of 0 or 1 with an improvement of at least two grades at each timepoint. All timepoints: vehicle, n = 83; difamilast 0·3%, n = 83; difamilast 1%, n = 85. P‐values are for the comparison between each difamilast group and the vehicle group.

Figure 3

Success rate in Eczema Area and Severity Index (EASI) 50, EASI 75 and EASI 90 at week 4. The data represent the percentage of patients achieving ≥ 50% (EASI 50), ≥ 75% (EASI 75) and ≥ 90% (EASI 90) improvement in overall EASI score at week 4. Vehicle, n = 83; difamilast 0·3%, n = 83; difamilast 1%, n = 85. P‐values are for the comparison between each difamilast group and the vehicle group.

Figure 4

Least squares (LS) mean percentage change in overall Eczema Area and Severity Index (EASI) score from baseline at each timepoint. Week 1: vehicle, n = 81; difamilast 0·3%, n = 83; difamilast 1%, n = 85. Week 2: vehicle, n = 70; difamilast 0·3%, n = 82; difamilast 1%, n = 81. Week 4: vehicle, n = 59; difamilast 0·3%, n = 77; difamilast 1%, n = 77. P‐values are for the comparison between each difamilast group and the vehicle group. *P < 0·001.

Figure 5

Least squares (LS) mean change in Verbal Rating Scale (VRS) for pruritus score from baseline at each timepoint. Week 1: vehicle, n = 40; difamilast 0·3%, n = 42; difamilast 1%, n = 43. Week 2: vehicle, n = 37; difamilast 0·3%, n = 42; difamilast 1%, n = 42. Week 4: vehicle, n = 33; difamilast 0·3%, n = 38; difamilast 1%, n = 41. P‐values are for the comparison between each difamilast group and the vehicle group. *P < 0·05; **P < 0·01; ***P < 0·005.