Delgocitinib Cream Reduces Itch and Pain in Moderate to Severe Chronic Hand Eczema: Phase 3 DELTA 1 and 2 Pooled Analyses

Abstract

Introduction

Itch and pain are two of the most common and burdensome symptoms for moderate to severe Chronic Hand Eczema (CHE). Here, we assess changes in itch/pain in patients with moderate to severe CHE treated with delgocitinib cream 20 mg/g or cream vehicle for 16 weeks.

Methods

In a pooled DELTA 1 (NCT04871711)/DELTA 2 (NCT04872101) analysis (delgocitinib [n = 639]; cream vehicle [n = 321]; twice-daily), the Hand Eczema Symptom Diary captured patient-reported itch/pain severity on a numeric rating scale. Changes in itch/pain from baseline were assessed daily during week 1 and weekly from week 1 to 16.

Results

In delgocitinib-treated patients, a statistically significant least square mean reduction from baseline was observed for itch from day 1 ([delgocitinib cream/cream vehicle] 0.75/0.32; P < 0.001) and pain from day 3 (0.98/0.58; P = 0.001) after the first application. Among patients with ≥ 4-point baseline itch/pain score, a significantly greater percentage of delgocitinib-treated patients achieved ≥ 4-point reduction from week 2 (14.2%/17.3%) versus cream vehicle (6.3%/6.9%; P < 0.001). Reductions were maintained up to week 16 with delgocitinib cream treatment. Delgocitinib cream was well tolerated.

Conclusion

Early onset of itch/pain reduction was observed within week 1 for delgocitinib-treated patients, thereby providing further support of the use and efficacy of delgocitinib cream in adults with moderate to severe CHE.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-025-01611-y.

Key Summary Points

Why carry out this study?

Chronic Hand Eczema (CHE) is a common inflammatory disease affecting hands and wrists, with itch and pain being two of the most frequent symptoms.

The first-line recommended treatment is topical corticosteroids (TCS) and cumulative long-term use may cause adverse effects.

Data from the phase 3 DELTA 1 and DELTA 2 trials support using delgocitinib cream in patients with moderate to severe CHE as an efficacious and well-tolerated treatment.

What was learned from the study?

Our pooled analysis of DELTA 1 and DELTA 2 demonstrated a significant reduction of itch and pain in patients with moderate to severe CHE treated with delgocitinib cream for 16 weeks.

This was achieved from 1 day after the first application for itch and 3 days for pain, and maintained throughout the treatment period.

Our data provide further support for treating patients with moderate to severe CHE with delgocitinib cream.

Introduction

Chronic Hand Eczema (CHE) is one of the most frequent chronic inflammatory diseases affecting hands and wrists, with itch and pain being two of the most common and burdensome symptoms; therefore, it can strongly impair patients’ quality of life [1–10]. CHE denotes hand eczema that persists for more than 3 months or recurs at least twice yearly and occurs in more than 50% of patients with hand eczema [11, 12].

Clinical assessments of CHE, e.g. the Investigator’s Global Assessment for Chronic Hand Eczema (IGA-CHE) and the widely used Hand Eczema Severity Index (HECSI), are based on clinical signs and therefore do not assess symptoms, such as itch and pain [13, 14].

Patient-reported outcome measures (PROs), e.g. Hand Eczema Symptom Diary (HESD), have been recognised by global regulators (the US Food and Drug Administration and the European Medicines Agency) as they can enhance clinician-reported outcomes by evaluating key symptoms, e.g. itch and pain [15–18].

While topical corticosteroids (TCS) are recommended as first-line treatment in guidelines, cumulative long-term use of high doses may cause adverse effects, such as patient-reported skin atrophy [5, 7, 12]. In a cohort study involving 724 patients with CHE, 84.8% of the patients reported adverse events (AEs) caused by TCS and more than three-quarters (76.4%) confirmed they would prefer a nonsteroidal topical treatment instead of TCS [7]. Delgocitinib, a topical non-steroidal pan-Janus kinase (JAK) inhibitor impacting JAK enzymatic activity and targeting key mediators of CHE with broad anti-inflammatory effects, has been approved in multiple countries for treatment of moderate to severe CHE in adults for whom TCS are inadequate or inappropriate [19–22]. The data from the pivotal phase 3 DELTA 1 and DELTA 2 trials support the use of delgocitinib cream 20 mg/g in adult patients with moderate to severe CHE as an efficacious and well-tolerated treatment [23].

Here, we assess changes in itch and pain over 16 weeks, as reported using HESD, in patients with moderate to severe CHE treated with twice-daily delgocitinib cream 20 mg/g or cream vehicle in the DELTA 1 and DELTA 2 trials.

A Plain Language Summary can be found in the Supplementary Information.

Methods

DELTA 1 and DELTA 2 Design

Data were pooled from the two randomised, double-blind, cream vehicle-controlled, parallel-group, multi-site, phase 3 DELTA 1 (NCT04871711) and DELTA 2 (NCT04872101) trials. In both trials, adult patients with moderate to severe CHE were treated with delgocitinib cream 20 mg/g or cream vehicle twice daily for 16 weeks. Full methods have been previously published [23]. In the 10 countries where DELTA 1 and DELTA 2 were conducted, prior to screening of patients, the institutional review board or independent ethics committee at all centres approved the protocol, investigator’s brochure, and any information provided to patients (Table S1). The trials were conducted according to the ethical principles of the Declaration of Helsinki. All patients provided written informed consent.

Participants

For DELTA 1 and DELTA 2, enrolled patients were adults (aged ≥ 18) with a diagnosis of moderate to severe CHE and had a history of inadequate response to treatment with TCS within 1 year before screening or who could not use TCS for medical reasons, e.g. important side effects or safety risks. Patients were randomised 2:1 to delgocitinib cream 20 mg/g or cream vehicle, which was applied twice daily to the areas affected by CHE over a 16-week treatment period. CHE was graded according to the IGA-CHE 5-point scale (0, ‘clear’; 1, ‘almost clear’; 2, ‘mild’; 3, ‘moderate’; and 4, ‘severe’). A full list of inclusion and exclusion criteria has been previously reported [23].

Assessments

Itch and pain were assessed using HESD, a validated 6-item PRO instrument designed to assess the severity of CHE signs and symptoms (itch, pain, cracking, redness, dryness, and flaking). Patients had to complete the HESD in the eDiary every evening until week 16. It captured patient-reported worst severity of itch and pain over the past 24 h on an 11-point numeric rating scale (0 = ‘no itch/pain’ to 10 = ‘severe itch/pain’). Changes in HESD itch and pain scores were assessed daily from baseline to day 6 (i.e. 7 days after the first application of the treatment) and weekly from week 1 to 16. Additionally, an analysis was performed for patients with a baseline itch or pain (weekly average) HESD score of ≥ 4, to determine the proportion of these patients who achieved a reduction in itch or pain (weekly average) of ≥ 4 points from baseline to week 16, as well as subgroup analyses of ≥ 4-point reduction from baseline in itch and pain according to baseline IGA-CHE scores (moderate/severe), environmental trigger factors (e.g. irritants or allergens), and baseline HECSI score (≤ 37; 38–116; ≥ 117) [24].

AEs were assessed by the investigator and summarised in terms of number and percentages of patients, number of events and the event rate per 100 patient years of observation time.

Statistical Analyses

For binary endpoints, the Cochran–Mantel–Haenszel test stratified by trial identification (DELTA 1 or DELTA 2 trials), region and baseline IGA-CHE score was used to analyse the difference in pooled response rates between delgocitinib cream and cream vehicle groups. For continuous endpoints, the pooled difference in mean change (or percentage change) from baseline between delgocitinib cream and cream vehicle groups was analysed using an analysis of covariance (ANCOVA) model with effects of treatment group trial identification, region, baseline IGA-CHE score, and baseline value. Least squares (LS) means, representing estimated averages adjusted for the covariates in the ANCOVA model, were reported for the change from baseline in daily and weekly HESD itch and pain scores for each treatment group. For both binary and continuous endpoints, the primary estimand composite strategy evaluated the treatment effect in patients with moderate to severe CHE, without initiation of rescue treatment or permanent discontinuation of treatment. Missing data were considered as non-response.

Efficacy was assessed on the basis of the full analysis set, which comprised all randomized patients who were exposed to trial treatment. Safety was assessed on the basis of the safety analysis set, which comprised all trial participants who received at least one dose of trial treatment.

Multiplicity control has been applied to the confirmatory endpoints in the testing hierarchy in DELTA 1 and DELTA 2 trials, including a ≥ 4-point reduction in HESD itch (weeks 2, 4, 8, and 16) and HESD pain (weeks 4, 8, and 16), and change in HESD itch and pain from baseline to week 16 [23]. The remaining efficacy analyses in this publication have not been adjusted for multiplicity testing.

Results

Baseline Characteristics

This DELTA 1 and DELTA 2 pooled analysis included 960 patients (DELTA 1, n = 487 [50.7%]; DELTA 2, n = 473 [49.3%]), recruited from 10 countries (Belgium, Canada, Denmark, France, Germany, Italy, Poland, Spain, the Netherlands and the UK). In total, 639 (66.6%) patients received delgocitinib cream 20 mg/g and 321 (33.4%) cream vehicle; 959 (99.9%) patients were included in the full analysis set and safety analysis set. Overall, 879 (91.6%) patients completed the trial, with a larger percentage of discontinuations occurring in the cream vehicle group (18.4%) compared with the delgocitinib cream 20 mg/g group (7.2%). Baseline demographics and patient characteristics were similar between patients treated with delgocitinib cream and those treated with cream vehicle (Table 1). More than 99% of patients had a recent history of inadequate response to TCS treatment.

Table 1.

Patient demographics, baseline characteristics and HESD sign/symptom scores in a pooled analysis of DELTA 1 and DELTA 2

	Total (N = 960)	Delgocitinib cream 20 mg/g (N = 639)	Cream vehicle (N = 321)
Age, median years, (Q1;Q3)	44.0 (32.0;55.0)	45.0 (33.0;56.0)	42.0 (31.0;54.0)
Sex, n (%)
Male	342 (35.6)	233 (36.5)	109 (34.0)
Female	618 (64.4)	406 (63.5)	212 (66.0)
Race, n (%)
White	868 (90.4)	578 (90.5)	290 (90.3)
Black or African American	7 (0.7)	5 (0.8)	2 (0.6)
Asian	34 (3.5)	22 (3.4)	12 (3.7)
Other/not reported	51 (5.3)	34 (5.3)	17 (5.3)
Region, n (%)
Europe	766 (79.8)	510 (79.8)	256 (79.8)
North America	194 (20.2)	129 (20.2)	65 (20.2)
Age at onset of CHE, median, years (Q1;Q3)	33.0 (21.0;48.0)	34.0 (22.0;48.0)	32.0 (21.0;46.0)
Duration of CHE, median, years (Q1;Q3)	5.0 (2.0;13.0)	5.0 (2.0;13.0)	5.0 (2.0;14.0)
IGA-CHE, n (%)
Moderate	687 (71.6)	457 (71.5)	230 (71.7)
Severe	273 (28.4)	182 (28.5)	91 (28.3)
HESD ≥ 4-point baseline score (weekly average)
Itch, n (%)	949 (99.4)	632 (99.4)	317 (99.4)
Pain, n (%)	875 (91.6)	585 (92.0)	290 (90.9)
HESD and CHE symptom NRS scores (weekly average)
n	955	636	319
HESD (weekly average)
Median (Q1;Q3)	7.1 (6.0;8.3)	7.1 (6.1;8.2)	7.1 (6.0;8.3)
CHE symptoms
HESD itch score (weekly average)
Median (Q1;Q3)	7.2 (5.9;8.2)	7.1 (5.9;8.2)	7.2 (5.9;8.3)
HESD pain score (weekly average)
Median (Q1;Q3)	6.9 (5.4;8.1)	6.9 (5.4;8.1)	6.9 (5.4;8.1)

Discrepancies in patient numbers for some assessments are due to some patients missing assessments at baseline. HESD scores are on a scale ranging from 0 to 10

CHE Chronic Hand Eczema, HESD Hand Eczema Symptoms Diary, IGA-CHE Investigator’s Global Assessment for CHE, N number of patients in analysis set, n number of patients with data available at baseline, NRS numeric rating scale

Efficacy

Statistically significant LS mean reduction in daily HESD itch score was seen 1 day after the first application of delgocitinib cream 20 mg/g (0.75 vs 0.32 cream vehicle; difference 0.43 [95% confidence interval (95% CI) 0.23, 0.63]; P < 0.001) (Fig. 1a), and was maintained up to week 16, reaching a weekly average of 3.5 in the delgocitinib cream 20 mg/g treatment group vs 1.7 in the cream vehicle group (difference 1.8 [95% CI 1.5, 2.2]; P < 0.001) (Fig. 2a). For pain, significant LS mean reduction in daily HESD score was detected 3 days after the first delgocitinib cream application (0.98 vs 0.58 cream vehicle; difference 0.40 [95% CI 0.16, 0.65]; P = 0.001) (Fig. 1b) and maintained throughout (week 16, weekly average of 3.3 vs 1.5, respectively; difference 1.8 [95% CI 1.4, 2.2]; P < 0.001) (Fig. 2b).

Fig. 1.

Change in daily HESD score from baseline to day 6 (over 7 days) for a itch and b pain in a pooled analysis of DELTA 1 and DELTA 2 (full analysis set, WOCF). ***P < 0.001. Baseline was defined as day − 1, and the time of the first treatment application as day 0. For the composite estimand strategy, data were considered non-response by using WOCF (including the baseline value) after the initiation of the rescue treatment or after permanent discontinuation of treatment. Missing data were imputed using WOCF (including the baseline value). CI confidence interval, HESD Hand Eczema Symptoms Diary, LS least squares, n number of patients with data available at baseline, WOCF worst observation carried forward

Fig. 2.

Change in HESD score (weekly average) from baseline to week 16 for a itch and b pain in a pooled analysis of the DELTA 1 and DELTA 2 (full analysis set, WOCF). ***P < 0.001. For the composite estimand strategy, data were considered non-response by using WOCF (including the baseline value) after the initiation of the rescue treatment or after permanent discontinuation of treatment. Missing data were imputed using WOCF (including the baseline value). CI confidence interval, HESD Hand Eczema Symptoms Diary, LS least squares, n number of patients with data available at baseline, WOCF worst observation carried forward

Among patients with ≥ 4-point baseline HESD itch score (n = 949), a statistically significantly greater percentage of those in the delgocitinib cream 20 mg/g group achieved a ≥ 4-point reduction from week 2 ([week 2] 14.2%) versus those in the cream vehicle group ([week 2] 6.3%; difference 7.9 [95% CI 4.1, 11.8]; P < 0.001). This reduction was maintained through to week 16, with the proportion of patients reaching 47.2% in the delgocitinib cream 20 mg/g group vs 21.5% in the cream vehicle group (difference 25.7 [95% CI 19.7, 31.7]; P < 0.001) (Fig. 3a). Among patients with ≥ 4-point baseline HESD pain score (n = 875), the percentage of delgocitinib-treated patients achieving a ≥ 4-point reduction from week 2 was 17.3% compared with 6.9% of those treated with cream vehicle (difference 10.5 [95% CI 6.3, 14.7]; P < 0.001). This reduction was maintained up to week 16 (48.9% in the delgocitinib cream 20 mg/g group vs 25.2% in the cream vehicle group; difference 23.8 [95% CI 17.3, 30.3]; P < 0.001) (Fig. 3b). A subgroup analysis of ≥ 4-point reduction according to disease severity at baseline (based on IGA-CHE) showed no pronounced difference in efficacy between the subgroups (Fig. S1).

Fig. 3.

HESD ≥ 4-point reduction (weekly average) from baseline to week 16 among patients with ≥ 4-point baseline itch/pain score to 16 weeks for a itch and b pain in a pooled analysis of the DELTA 1 and DELTA 2 (full analysis set, NRI). ***P < 0.001. For the composite estimand strategy, data were considered non-response after the initiation of the rescue treatment or after permanent discontinuation of treatment. Missing data were considered non-response. CI confidence interval, HESD Hand Eczema Symptoms Diary, n number of patients with data available at baseline, NRI non-responder imputation

Delgocitinib-treated patients demonstrated a higher ≥ 4-point reduction in HESD itch versus those treated with cream vehicle from week 2 (with environmental trigger factors at baseline; 18.6% [delgocitinib] and 6.4% [cream vehicle]; difference 12.4 [95% CI 6.7, 18.2]; nominal P < 0.001) or week 3 (without environmental trigger factors at baseline; 19.1% [delgocitinib] and 10.5% [cream vehicle]; difference 8.7 [95% CI 1.5, 15.8]; nominal P = 0.032) (Fig. S2). Similar results were seen for HESD pain (Fig. S2). In a subgroup analysis according to baseline HECSI score, the proportion of patients who achieved a ≥ 4-point reduction in HESD itch and HESD pain was higher in those with higher baseline HECSI scores vs those with lower baseline HECSI scores (Fig. S3).

Safety

Treatment with delgocitinib cream 20 mg/g for 16 weeks was well tolerated (Table 2). AEs were reported in a similar percentage of patients treated with delgocitinib cream and the cream vehicle (delgocitinib cream, 45.6%; cream vehicle, 47.7%). The majority of AEs were mild to moderate and not considered related to the trial treatment, with the most frequently reported being COVID-19, nasopharyngitis, and headache. AEs leading to discontinuation of trial treatment were reported in a lower proportion of patients in the delgocitinib cream group (0.5%) compared with the cream vehicle group (3.4%). Few serious AEs were reported in the delgocitinib cream group (1.7%) and vehicle cream group (1.9%), with all being assessed as not related to the trial treatment by both the trial investigator and sponsor. There was no apparent pattern, and no AE led to any safety concerns. No specific treatment-emergent safety concerns were identified nor were there any AEs of special interest (eczema herpeticum, deep vein thrombosis, or pulmonary embolism) reported. None of the changes or differences between treatment groups in haematology, biochemistry, vital signs, physical examination, or ECG were assessed to be of clinical relevance.

Table 2.

Summary of AEs in a pooled analysis of DELTA 1 and DELTA 2

	Delgocitinib cream 20 mg/g (N = 638; PYO = 196.7)			Cream vehicle (N = 321; PYO = 93.9)
	n (%)	E	R	n (%)	E	R
All events	291 (45.6)	579	294.3	153 (47.7)	307	326.9
Serious AEs	11 (1.7)	12	6.1	6 (1.9)	8	8.5
Severity of AEs
Mild	223 (35.0)	391	198.8	120 (37.4)	199	211.9
Moderate	118 (18.5)	167	84.9	60 (18.7)	92	98.0
Severe	15 (2.4)	21	10.7	9 (2.8)	16	17.0
AEs probably or possibly related to trial drug	34 (5.3)	47	23.9	24 (7.5)	32	34.1
AEs leading to discontinuation of trial drug	3 (0.5)	3	1.5	11 (3.4)	12	12.8
Frequent AEs (≥ 2% in any treatment group)
COVID-19	71 (11.1)	71	36.1	34 (10.6)	34	36.2
Nasopharyngitis	44 (6.9)	49	24.9	24 (7.5)	26	27.7
Headache	28 (4.4)	38	19.3	13 (4.0)	17	18.1
Hand dermatitisa	4 (0.6)	4	2.0	13 (4.0)	16	17.0

AE adverse event, CHE Chronic Hand Eczema, COVID-19 coronavirus disease 2019, E number of events, N number of patients in analysis set, n number of patients with data available at baseline, PYO patient-years of observation, R rate calculated as (E/PYO) × 100, SAE serious adverse event

^aAEs for hand dermatitis represented a worsening of CHE that exceeded normal disease fluctuation or the appearance of lesions in an area not typically affected by CHE

Discussion

This pooled analysis of the DELTA 1 and DELTA 2 trials confirmed the superiority of delgocitinib cream compared with cream vehicle in adults with moderate to severe CHE [23]. Itch and pain, two of the most common and burdensome symptoms experienced by patients with CHE, negatively affect their quality of life and cause difficulty at work [1–3, 9, 25, 26]. Itch may worsen other CHE symptoms and is frequently connected to bleeding, redness, and flaking, while pain, which often derives from cracking, affects patients’ ability to carry out daily activities [1, 27]. In patients treated with delgocitinib cream, a statistically significant greater reduction of itch and pain (P < 0.001) was achieved early (1 and 3 days after the first application of delgocitinib cream, respectively), with the response being maintained up to week 16.

In this pooled analysis, a significantly higher proportion of delgocitinib-treated patients with HESD itch and pain scores of ≥ 4 points at baseline achieved a ≥ 4-point reduction of HESD itch and pain scores from week 2 when compared to those treated with the cream vehicle (P < 0.001). Itch/pain numeric rating scales (NRS) are instruments utilized in clinical context to measure itch and pain intensity in diverse settings, e.g. atopic dermatitis [28–30]. Patients rate their itch/pain on a scale from 0 to 10, with 10 representing the “worst pain (or) worst itch imaginable at the worst moment” [15]. Conversely, HESD is the first PRO diary measure developed specifically for CHE that has been validated in line with regulatory guidance as a reliable tool to assess itch and pain, as well as other signs and symptoms of CHE (at its worst, over the past 24 h using a 0–10 NRS) [15]. The differences in defining a score of 10 between HESD and NRS itch/pain instruments may not allow for direct comparisons and should be interpreted with caution [15, 31, 32]. Itch and pain correlated positively with CHE severity (IGA-CHE and HECSI scores) and reduced quality of life (Dermatology Life Quality Index) [3].

Environmental trigger factors, such as wet work, have been shown to significantly increase the risk of developing CHE, particularly in women [12, 33]. Regardless of known environmental trigger factors at baseline, the ≥ 4-point reduction in HESD itch and HESD pain was significantly higher in patients treated with delgocitinib cream compared with those treated with cream vehicle from week 3 (P < 0.05). The data also confirmed that delgocitinib cream 20 mg/g was well tolerated during the 16-week treatment period, as most AEs were mild with no safety concerns.

There are limitations to this analysis. HESD is a relatively new tool for the clinical management of CHE which has its limitations, mostly needing to be validated on a broader population across countries including a larger proportion of non-white/Caucasian patients [15]. Although the protocol required avoidance of known and relevant irritants and allergens for inclusion, there remains some uncertainty around the potential influence of environmental trigger factors that had not been previously identified or exposures that could have been altered during the course of the trials. The trials involved were of a short duration of 16 weeks; however, in the open-label, 36-week, multi-site extension DELTA 3 trial (NCT04949841), delgocitinib cream 20 mg/g treatment remained well tolerated in patients who had completed the parent trials (DELTA 1 or DELTA 2 trials) [34]. Furthermore, the phase 3 DELTA FORCE trial in patients with severe CHE evaluated the efficacy and safety of delgocitinib cream 20 mg/g versus orally administered alitretinoin (once daily) (NCT05259722). Compared with orally administered alitretinoin, delgocitinib cream 20 mg/g demonstrated superior efficacy and a more favourable safety profile over 24 weeks of treatment [35]. For DELTA 3 and DELTA FORCE, future post hoc analyses will investigate HESD itch and pain maintenance up to 52 weeks (DELTA 3) and compare delgocitinib cream with alitretinoin treatment (DELTA FORCE) in patients with CHE.

Conclusions

The findings from this DELTA 1 and DELTA 2 pooled analysis provide further support for the use and efficacy of delgocitinib cream to rapidly address the symptomatic burden in adults with moderate to severe CHE.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Andrea Bauer, Marie-Louise Schuttelaar, Keith Baranowski, Ursula Plohberger, Laura Sørensen, and Margitta Worm interpreted the data, provided critical input to manuscript drafts and approved the submission of the manuscript for publication. All authors take responsibility for the accuracy and completeness of the data and analyses and vouch for the fidelity of the trial to the protocol. All investigators had confidentiality agreements with the sponsor.

Funding

This DELTA 1 and DELTA 2 pooled analysis was sponsored by LEO Pharma A/S, Ballerup, Denmark. The journal’s Rapid Service Fee was funded by LEO Pharma A/S, Ballerup, Denmark.

Data Availability

Data sets are available on request. Further information can be obtained at: https://www.leopharmatrials.com/en/for-researchers.

Declarations

Conflict of Interest

Andrea Bauer has been a speaker, advisor, or investigator, and/or received research funding from AbbVie, Almirall, Amgen, AstraZeneca, Biofrontera, Blueberry Therapeutics, Celldex, Centogene, Escient, Galderma, Genentech, Gilead, Incyte, Jasper, LEO Pharma A/S, Lilly, L’Oréal, Novartis, Pfizer, Sanofi, Regeneron, and Takeda. Marie-Louise Schuttelaar has been a consultant, advisory board member, investigator, and/or speaker for AbbVie, Amgen, Eli Lilly, Galderma, LEO Pharma A/S, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., and Sanofi Genzyme. Keith Baranowski, Ursula Plohberger, and Laura Sørensen, are shareholders and employees of LEO Pharma A/S. Margitta Worm reports grants and personal fees from AbbVie Deutschland, Allergopharma, Aimmune, ALK-Abello, Almirall S. A., Amgen GmbH, Biotest, Bristol-Myers Squibb GmbH & Co., DBV Technologies, KGaA, LEO Pharma A/S, Lilly Deutschland, Mylan Germany, Novartis, Pfizer Deutschland GmbH, Regeneron Pharmaceuticals, and Sanofi Aventis, outside the submitted work and is past WAO co-chair of the anaphylaxis committee.

Ethical Approval

In the 10 countries where DELTA 1 and DELTA 2 were conducted, prior to screening of patients, the institutional review board or independent ethics committee at all centres approved the protocol, investigator’s brochure, and any information provided to patients (Table S1). The trials were conducted according to the ethical principles of the Declaration of Helsinki. All patients provided written informed consent.