Treatment with delgocitinib cream improves itch, pain and other signs and symptoms of chronic hand eczema: Results from the Hand Eczema Symptom Diary in a phase IIb randomized clinical trial

Measuring patient‐reported outcomes is crucial to fully capture the burden of chronic hand eczema (CHE).

fissures. [1][2][3] Chronic hand eczema (CHE) is defined as HE that persists for more than 3 months or relapses at least twice yearly. 1,3 Itch and pain are the two most common and burdensome symptoms experienced by patients with CHE, and both can have a negative impact on health-related quality of life (HRQoL). 4,5 However, these symptoms are not captured by the commonly used clinical assessment tools such as Investigator's Global Assessment for chronic hand eczema (IGA-CHE) and the Hand Eczema Severity Index (HECSI). 6 Patient-reported outcomes (PROs) are complementary to clinicianreported outcomes (ClinROs) and can capture key symptoms and effects such as itch and pain. The value of PRO data has been recognized by global regulators, including the US Food and Drug Administration and the European Medicines Agency. 7,8 There are no topical treatments developed and approved specifically for CHE; however, topical corticosteroids are recommended as first-line treatment in all guidelines despite the adverse effects associated with their long-term use, such as skin atrophy. 1,9 Novel systemic and topical treatments are currently in development for CHE to address this unmet need, including the topical pan-Janus kinase (JAK) inhibitor delgocitinib. 10,11 In a phase IIb trial, twice-daily application of delgocitinib in a cream formulation for 16 weeks was efficacious and had no safety or tolerability issues in adults with mild to severe CHE. 11 The primary endpoint, IGA-CHE treatment success at Week 16, defined as a score of 0 (clear) or 1 (almost clear) with a ≥2-point improvement from baseline, was achieved by 36.5% of patients in the delgocitinib cream 8 mg/g group, 37.7% in the 20 mg/g group and 8.0% in the cream vehicle group. 11 Delgocitinib cream 8 and 20 mg/g showed a statistically significant treatment effect relative to cream vehicle at Week 16 (p < 0.001). 11 To gain further insight into the efficacy of delgocitinib cream, we evaluated PROs of CHE collected by the Hand Eczema Symptom Diary (HESD), an eDiary developed to capture daily patient data on signs and symptoms in trials for CHE. This phase IIb trial is the first trial to use the HESD assessment tool and here we report the effect of delgocitinib cream on itch and pain in patients with mild to severe CHE, along with nine other signs and symptoms of CHE, with the data from the trial being used for exploratory validation of the HESD. Confirmatory validation will be reported at a later date using data from a delgocitinib cream phase III trial in CHE.

| Study design
This was a double-blind, randomized, 5-arm, cream vehicle-controlled, parallel-group, multicentre, dose-ranging phase IIb trial. The trial was designed to establish a dose-response relationship and to investigate the efficacy and safety of delgocitinib cream in the treatment of adult patients with mild to severe CHE. The assessment of the effect of delgocitinib cream on HRQoL, as measured by PROs, was a secondary objective.
A total of 258 patients were randomized in a 1:1:1:1:1 ratio to delgocitinib cream 1, 3, 8 or 20 mg/g, or to cream vehicle ( Figure 1). The trial was conducted from November 2018 through April 2020 at 26 sites in three countries (USA, Denmark, Germany). The trial consisted of a ≤4-week screening period, a 16-week treatment period and a 2-week safety follow-up period. Full methods have been previously published. 11

| Ethical approval
The trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements, and was approved by independent ethics committees or institutional review boards at each study site. All patients provided written informed consent.

| Hand Eczema Symptom Diary
The HESD is a scale including 11 signs and symptoms of CHE, which patients assessed daily through an eDiary. The items present within the HESD were all identified as having a high impact on a patient's HRQoL in qualitative patient interviews conducted by Grant et al. 4 Three symptoms (itch, pain, burning feeling) and eight signs (cracking, redness, dryness, swelling, bleeding, thickening, flaking, oozing/weeping) were assessed. 4 Patients were asked, for example, to 'rate the severity of any itch on your hands, at its worst, over the past 24 h' using an 11-point numeric rating scale (NRS), with 0 indicating 'no itch' and 10 indicating 'severe itch'. Patients completed the HESD as an eDiary each evening, at the latest, from Week À1 until Week 16.
2.4 | Change in HESD symptom/sign score (weekly average) Daily HESD scores were derived into discrete weekly averages by taking the mean of the seven preceding days leading up to each calendar week relative to baseline, except for Week 16. A minimum of 4 daily HESD NRS scores in the 7-day period were required to calculate the weekly average for each individual symptom.
The change in HESD symptom/sign score (weekly average) from baseline to Week 16 was analysed using a mixed model for repeated measurements with an unstructured covariance matrix, Kenward-Roger approximation to estimate denominator degrees of freedom and the mean modelled as follows: Change from baseline in HESD symptom or sign score ¼ treatment Â visit þ baseline HESD symptom or sign score Â visit þ region þ baseline IGA À CHE:

| Change in HESD symptom/sign score (daily)
For the daily measurement analyses, only the first 14 days were modelled, and visit was exchanged with study day in the statistical model specified for the weekly average. All observed data collected prior to or on the visit of premature discontinuation of study treatment or initiation of rescue medication were included in the analysis.

| Reduction in itch or pain of ≥4 from baseline to Week 16
Patients with a baseline itch or pain (weekly average) score of ≥4, as   study treatment were used in the analysis. Non-responder imputation was completed for each scheduled assessment visit after initiation of rescue medication or premature discontinuation of study treatment, as well as for any other missing data. This phase IIb trial was only powered to assess the dose response, meaning that p-values aside from the dose response are nominal.

| Correlations between HESD itch/pain, IGA-CHE and HECSI
Spearman's correlation was used to analyse associations between HESD itch/pain and IGA-CHE and HECSI, respectively, as observed at Week 16 across treatment groups.

| Patients
All 258 randomized patients started study treatment and were included in both the full analysis and safety analysis sets. A full patient disposition flowchart was previously published. 11 Baseline demographics and characteristics were generally comparable, with minor differences observed between treatment groups with respect to age of CHE onset, CHE main diagnosis and previous systemic treatment (Tables S1 and S2). Baseline HESD values were comparable between treatment groups (Table 1).

| Signs
Overall   The Hand Eczema Core Outcome Set initiative identified a need for harmonization of outcome measurement instruments and generation of a core outcome set for HE to improve comparability of future HE trials. 14 Many of the signs assessed by patients in the HESD are present in physician-reported clinical tools such as HECSI for CHE, including erythema (redness), oedema (swelling) and dryness/scaling. 6 Their significance in CHE has also been recorded in qualitative patient interviews. 4 While the clinical assessment of these key signs is important in trials and routine practice, there may also be a role for patient assessment in CHE, similar to that provided in atopic dermatitis by the patient-oriented SCORAD (PO-SCORing Atopic Dermatitis). 15 Furthermore, a lack of diversity within the patient population is noted; thus, the conclusions presented should be treated with caution in patients with racial identities not represented or included in this trial. Some patients exhibited low baseline NRS scores, meaning they were ineligible for some responder analyses; this resulted in reduced patient numbers for the HESD analysis at Week 16 (ranging from 33 to 42 patients per group), down from approximately 50 per group at baseline. These reduced patient numbers may impact any conclusions that will be drawn.
The findings of this analysis, along with the correlation of the data with those using IGA-CHE and HECSI, indicate that the HESD has the potential to be used as an assessment tool to provide data on key signs and symptoms of CHE that can inform a patient-focused treatment decision. The pivotal phase III trials of delgocitinib cream for the treatment of CHE are ongoing (NCT04871711, NCT04872101); data from which will be used for confirmatory validation of the HESD. In this study, delgocitinib cream reduced itch and pain, as well as other signs and symptoms of CHE as recorded by patients using the HESD, further supporting the potential of delgocitinib cream as an effective topical treatment for patients with CHE.