Efficacy and Safety of PAC-14028 Cream – a Novel, Topical, Nonsteroidal, Selective TRPV1 Antagonist in Patients With Mild-to-moderate Atopic Dermatitis

A Phase IIb Randomized Trial

Y.W. Lee; C.-H. Won; K. Jung; H.-J. Nam; G. Choi; Y.-H. Park; M. Park; B. Kim


The British Journal of Dermatology. 2019;180(5):1030-1038. 

In This Article

Patients and Methods

Study Design and Oversight

A randomized, double-blind, vehicle-controlled phase IIb clinical trial was conducted at three centres in the Republic of Korea between October 2015 and July 2016 in adults with mild-to-moderate AD (NCT02757729). This trial was performed in compliance with the provisions of the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice guidelines, and applicable regulatory requirements. The institutional review board of Chung-Ang University Hospital, Asan Medical Center and Konkuk University Hospital approved all study protocols, informed consent forms, and relevant supporting data.

Patient Selection

Key inclusion criteria required male or female patients to be aged between 19 years and 70 years, have a clinical diagnosis of AD according to the Hanifin and Rajka diagnostic criteria,[12] 5% or more of affected body surface area (BSA), and an Investigator's Global Assessment (IGA) score of 2 (mild) or 3 (moderate) (scores range from 0 to 5). Patients who received the following therapies were excluded: corticosteroids, antibiotics or immunosuppressants as a systemic drug treatment or history of treatment based on photochemical therapy within 28 days; TCSs, TCIs or antibiotics within 14 days. Patients with the following conditions were also excluded: serious skin diseases other than AD or widespread scarring on the AD lesion site; skin disease resulting from other medical, psychotic and neuropathic causes; hepatic dysfunction; chronic medical disease; symptoms of systemic infection or eczema herpeticum on the skin; malignant tumour and/or active pruritus caused by chronic urticaria or allergen such as scabies, insect bites, etc.

Treatment Plan

Eligible patients were randomized (1 : 1 : 1 : 1) to three treatment groups (PAC-14028 cream 0·1%, 0·3% and 1·0%) or vehicle cream based on a computer-generated randomization scheme that was balanced using a permuted block method. This study was conducted under double-blind conditions for the PAC-14028 and vehicle groups. A detailed allocation of the identification codes was managed by the principal investigator using sealed individual double-blinded envelopes for each subject. The specific patient allocation and identification code information were not disclosed until the end of the clinical trial. There was no difference in the physical appearance, colour, texture and homogeneity of each of the strengths of the PAC-14028 cream or vehicle cream. During the 8-week treatment period, patients were required to apply the provided investigational product to AD-involved areas twice daily by evenly rubbing it to form a thin film. Patients were instructed to squeeze the cream out to the length of the last section of their index finger and apply it to an area twice the size of their palm. Patients were also allowed to use acceptable bland emollients to manage dry non-AD skin lesions. Assessments were conducted at baseline and weeks 1, 3, 6 and 8.

Efficacy and Safety Evaluations

The primary efficacy variable was the IGA success rate defined as the percentage of patients with an IGA score of 0 or 1 at week 8 as evaluated by a physician using a 6-point scale (0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe; 5, very severe).[13] The secondary efficacy variables included severity Scoring of Atopic Dermatitis (SCORAD)[14] and Eczema Area and Severity Index (EASI) score.[15] Pruritus visual analogue scale (VAS) and sleep disturbance score were also used as an assessment of subjective symptoms in the SCORAD index. Safety and tolerability were evaluated by AE reporting, clinical laboratory testing, electrocardiogram recordings, vital signs and physical examinations.

Statistical Analysis

Sample size determination. Study enrolment was planned for approximately 192 patients randomized 1 : 1 : 1 : 1 into treatment groups. As no prior data existed on IGA success rate, the sample size was calculated based on data from an assessment of the SCORAD index on day 28 of the phase IIa PAC-14028 cream trial for AD. We assumed the mean changes from baseline to day 28 in the SCORAD score would be −11·12 and −5·73 for PAC-14028 1·0% cream and vehicle, respectively. Using an alpha error of 0·05 and a power of 0·95, we calculated the desired sample size to be 36 participants per group. Therefore, we chose an optimal minimum sample size of 40 participants per group. We also explored the optimum dosage based on the primary efficacy end point for PAC-14028 cream and the treatment success rate based on IGA score in this clinical trial. Accounting for an anticipated dropout rate of 15%, we ultimately selected 48 participants per group and a total of 192 participants as targets.

Efficacy and safety analysis. All analyses were conducted as a two-sided test with the significance level set at 0·05. The full analysis set (FAS) population was used for all efficacy analyses. Patients who used topical or systemic calcineurin inhibitors or corticosteroids for the purpose of treating AD were excluded from the FAS analysis. During the FAS analysis, the last observation carried forward method was used for the missing data.

The primary end point was treatment success rate (%) according to IGA score, defined as the percentage of patients with an IGA score of 0 or 1 at week 8 from baseline. For primary analysis, differences between the treatment and vehicle groups were analysed using Pearson's χ 2-test. Analyses of SCORAD, EASI, pruritus VAS and sleep disturbance score were performed using a two-sample t-test or Wilcoxon rank sum test.

The safety population included all patients who were administered with the investigational product at least once. The occurrence of treatment-emergent AEs and adverse drug reactions (ADRs) was analysed using Pearson's χ 2-test or Fisher's exact test.