Antihistamine-resistant chronic spontaneous urticaria remains undertreated: 2-year data from the AWARE study

Background: Real-world evidence describing the benefits of recommended therapies and their impact on the quality of life (QoL) of chronic urticaria (CU) patients is limited. Objective: To investigate disease burden, current treatment schedule, and the use of clinical resources by patients with H 1 -antihistamine-refractory CU in Europe. Methods: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is a global, prospective, non-interventional study in the real-world setting, sponsored by the manufacturer of omalizumab. Disease characteristics, pharmacological treatments, and health-related QoL of patients (N = 2727) ≥18 years of age diagnosed with H 1 -antihistamine-refractory chronic spontaneous urticaria (without inducible urticaria) for > 2 months are reported here. Results: Of the 2727 patients included, 1232 (45.2%) and 1278 (46.9%) were successfully followed up for any assessment and for the key outcome, the urticaria control test (UCT) score, respectively, and patients with complete remission (14.1%) were excluded from analyses.The proportion of patients with uncontrolled CSU (UCT score < 12) dropped from 78% (n/N = 1641/2104) at baseline to 28.7% (n/N = 269/936) after two years of participation in the AWARE study. In addition, the proportion of patients with no impact of CSU on their QoL (assessed by the Dermatological Life Quality Index) increased to 57% (n/N = 664/1164


| INTRODUC TI ON
Chronic urticaria (CU) is characterized by itching, burning or sometimes painful hives (wheals), and/or angioedema (swelling in the deeper layers of the skin) for at least 6 weeks. 1 The estimated prevalence of CU varies from 0.1% in North America to 1.4% in the Asian population. 2 In patients with CU, symptoms may occur spontaneously without a definite trigger, known as chronic spontaneous urticaria (CSU), or in response to a specific trigger, known as chronic inducible urticaria (CIndU). 3,4About 20% of CU patients may experience CSU and CIndU concurrently. 57][8] The international guideline for urticaria (EAACI/GA 2 LEN/EDF/WAO) recommends a stepwise treatment approach to improve symptom control and reduce disease burden among patients with CU. 1 Second-generation non-sedating H 1 -antihistamines (nsAH) at approved doses are the first-line therapy; however, up to 60% of patients do not respond adequately within 2-4 weeks of starting the treatment and require increased doses (upto 4-fold of the licensed dose), which is the second-line recommendation. 1,9At the time the AWARE study was initiated, the EAACI/GA 2 LEN/EDF/WAO urticaria guideline recommended third-line add-on therapy with ciclosporin, leukotriene receptor agonists such as montelukast, or omalizumab, if no adequate response was achieved with higher than standard doses of H 1 -antihistamines; however, this recommendation was changed in the 2017 update and revision of this guideline. 1,10e 2017 guideline provides a strong recommendation for the use of omalizumab as third-line add-on therapy to H 1 -antihistamines, if no adequate response is observed after 2-4 weeks (or earlier if symptoms are intolerable) of treatment with an up-dosed nsAH.Patients who remain inadequately controlled with omalizumab after 6 months (or earlier if symptoms are intolerable) are recommended to receive add-on therapy with ciclosporin A as a fourth-line agent (off-label). 1 Real-world evidence on the benefits of the recommended therapeutic medications and their impact on the QoL of CU patients in Europe is limited.Previous reports suggest that physicians show poor adherence to guidelines in the diagnosis and therapeutic management of CSU leading to an unmet need in the CU patient population. 11Baseline findings of the AWARE study in Europe revealed that CU is largely uncontrolled, undertreated, and associated with a high healthcare resource use burden, and that it has a large effect on QoL, work, and activity. 12Furthermore, the majority of data on CU that is inadequately controlled with H 1 -antihistamines are limited to patient populations derived from specialized urticaria centres such as Urticaria Centers of Reference and Excellence (UCAREs), 13 which may not represent the general CU population. 11,14AWARE is a prospective, non-interventional study that examines real-world treatment patterns, burden of disease, and rates of healthcare resource utilization of patients with CU that is inadequately controlled with H 1 -antihistamines.Here, we report any changes in the treatment regimen, symptoms, and health-related QoL (HR-QoL) throughout the 2-year period of the study with patients with CSU inadequately controlled by H 1antihistamines in 12 European countries.

| Patients and study design
AWARE was a multicentre, prospective, non-interventional study that followed patients with CU for 2 years, who were inadequately controlled with at least one approved dose of H 1 -antihistamine. 15is report focuses on patients enrolled in urticaria centres and office-based dermatological and allergological practices across 12 European countries (Germany, Spain, the United Kingdom, Italy, Greece, Russia, France, Denmark, Belgium, Portugal, Norway, and Sweden) at 418 sites between March 2014 and October 2015.
Patients were included if they had physician-confirmed CU for at least 2 months with inadequate response to standard-doses of H 1antihistamine treatment.Patients were also required to be ≥18 years of age and be able to provide informed consent.Enrolled patients were followed up for at least 2 years.Patients were excluded from the study if urticaria was present for less than 2 months or due to unanticipated difficulties in the follow-up of the patient in the 2-year study period, or if they were simultaneously participating in any other clinical CU study.All patients met the following criteria: fulfilment of all inclusion criteria, no violation of any exclusion criteria, written informed consent prior to study enrolment, and all core baseline characteristics (gender, age, and diagnosis) available.
Although patients with CIndU were also included in the AWARE study, this manuscript focuses on patients diagnosed with CSU (with or without angioedema).The study protocol was approved by the institutional review board of each participating centre.The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) and in compliance with all federal, local, and regional requirements.AWARE was sponsored by the manufacturer of omalizumab.

| Patient-reported outcome measures
Patient-reported outcome (PRO) measures were used to assess disease activity, to measure the impact on the QoL as recommended by international guidelines and control CU. 10 PROs included the angioedema, chronic spontaneous urticaria, quality of life, urticaria 7-day Urticaria Activity Score (UAS7; weekly diary for disease activity), [16][17][18] Dermatology Life Quality Index (DLQI; questionnaire for psychosocial effects of chronic skin disease), 19 Chronic Urticaria QoL Questionnaire (CU-Q 2 oL), 20 Angioedema QoL Questionnaire (AE-QoL), 21,22 Urticaria Control Test (UCT; to assess urticaria control: UCT ≥12, poorly controlled disease: UCT <12), 23,24 Work Productivity and Activity Impairment Questionnaire (WPAI), 25 and monthly Angioedema Activity Score (AAS). 26Each patient was observed for a period of 2 years.After the baseline visit (Visit 1), patients had eight follow-up visits in quarterly intervals.The various treatment groups examined are presented in Figure S1.

| Statistical analysis
All statistical analyses were performed on the analysis population and assessed using descriptive statistics.Means, medians, standard deviation (SD), maximum, and minimum are stated for quantitative, absolute, and relative frequencies for categorical measurements.

| Demographics and clinical characteristics
Patient disposition and diagnostic groups are shown in Table 1.Of the 3683 patients included in the analysis, 74.0% (n = 2727) had only CSU, 5.3% (196) had only CIndU, and 20.6% (n = 760) had concomitant CSU and CIndU.The mean ± SD age of CSU patients was 46.7 ± 15.7 years, and 70.9% (n = 1933) of patients were female (Table 2).The mean ± SD for total duration of disease was 4.7 ± 7.2 years.In all, 1589 (43.5%) patients discontinued the study.
Lost to follow-up (62.9%) of patients was the main reasons for discontinuation, followed by withdrawal of informed consent (20.3%) and spontaneous remission of CU (14.1%).The total patients available for assessment at each visit are described in Table S1.

| Treatment pattern over 2 years in AWARE study
With regard to medication groups, 17.3% (n/N = 473/2727) of CSU patients were treated with approved doses of nsAH (Figure 3 Other treatments, such as ciclosporin and sedating antihistamines (sAH), were rarely used, and none of them were prescribed in more than 5% of patients (Figure 3).Interestingly, the non-recommended use of "on-demand" nsAH increased from 3.1% (n/N = 85/2727) before enrolment to 12.8% (n/N = 163/1278) at Month 24.The number of patients on "no treatment" was small throughout the study and decreased from 37.0% (n/N = 1008/2727) prior enrolment to F I G U R E 2 QoL measures: (A) DLQI, (B) CU-Q 2 oL, and (C) AE-QoL a .n, number of patients where a particular evaluation form was available at each visit; N, total number of patients at each visit.a The number of patients with evaluation at each visit varied because of the registry nature of AWARE.AAS, angioedema activity score; AE-QoL, angioedema quality of life questionnaire; CU-Q 2 oL, chronic urticaria quality of life questionnaire; DLQI, dermatology life quality index [Colour figure can be viewed at wileyonlinelibrary.com]  in Portugal) (Figure 5).Non-recommended therapies, such as combination of nsAH and sAH, were rarely used and rates of patients reported as receiving "no treatment" were low to none.
In Germany, the United Kingdom, Spain, and Sweden, patients were frequently up-dosed to nsAH, but a substantial amount of patients were either not up-dosed at all (Germany with 19.4%

| D ISCUSS I ON
The present study aims to prospectively collect real-world data to evaluate disease burden and treatment in CU patients inadequately treated with H1-antihistamine.The 2-year results from AWARE in Europe confirm that CSU remains undertreated.8][29] Concomitant angioedema was reported in almost half of enrolled CU patients within the last six months.At baseline, 89.4% and 45% of patients reported hives and angioedema, respectively.Although there was improvement in the F I G U R E 3 Numbers (and percentages) of patients receiving different treatments at each visit.N, total number of patients at each visit.CSU, chronic spontaneous urticaria.Other third-line treatment options (as defined in 2014 guidelines) were rarely used.Prior to AWARE enrolment, ciclosporin was prescribed in 2.6% (n = 71) of patients, which reduced to 0.3% (n = 4) at the end of the observational period.Similarly, montelukast was prescribed for 3.6% (n = 97) of patients with chronic urticaria before enrolment and prescriptions reduced to 1.9% (n = 24) at Month 24 (Figure 4).The non-recommended sedative antihistamines were similarly rarely prescribed, with 4.1% before enrolment reduced to 3.0% (n = 38) after the 2 years of observational period [Colour figure can be viewed at wileyonlinelibrary.com]  disease condition over time, a substantial proportion of patients continued to have hives and/or angioedema after 2 years.Angioedema plays a significant role in the burden of CSU, with a negative impact on HR-QoL and is known to drive direct costs. 6The frequency of CSU with comorbid CIndU has not been well-documented to date; however, in this broad observational study, the rate of comorbid CIndU in these patients with CSU inadequately controlled with H 1antihistamines was 20.6%. 1,5 baseline, patients with CSU were undertreated and had high medical resource utilization.Also, 4 of 5 patients had poorly controlled CSU (UCT <12).Nearly 55% of CU patients had at least a moderate, large, or extremely large impact on their QoL.The CU-Q 2 oL score at baseline confirmed a moderate to high impact of urticaria on patients' QoL.
The most frequent medications reported prior enrolment were The burden of CSU on HR-QoL was evident from PROs with high DLQI and CU-Q 2 oL scores.Despite treatment and expert care, about one in five patients had moderate to extremely large effects on their HR-Q oL after 2 years.[32][33][34] Unsurprisingly, for a 2-year observation period, CSU patients showed high medical resource utilization, with multiple dermatologists and general practitioners being involved with patient care.
Our results show that many patients after two years of expert care, either receive treatment that does not help them control their urticaria or receive no treatment at all.In this study, 23.2% of patients with CSU who remained uncontrolled (UCT < 12) with nsAH should ideally have at least received up-dosed nsAH in an attempt to improve symptoms.Similarly, 41.9% of patients whose symptoms were uncontrolled with up-dosed nsAH should have received further escalation to a third-line treatment option.6][37] A web-based survey of patients diagnosed with CU in Germany revealed that only 40% of symptomatic patients were under physician care, with the majority of them choosing to stop their consultations, as they felt doctors were unable to help them or that they knew how to treat the CU symptoms themselves. 38Similar results on survey of patients were reported in Italy. 35The guidelines recommend omalizumab as an add-on treatment (to H 1 -antihistamines) and upon de-escalation patients should stop omalizumab and continue H 1 -antihistamines; however, there appears to be a persistence of omalizumab use in patients with withdrawal of other treatments.Omalizumab is shown to be safe and effective across randomized placebo-controlled trials 28,29,39 and several real-world studies, [40][41][42][43][44] with a total patient exposure of 1,328,183 patient years (Novartis data on file, Dec 2019).
The strength of this study as a reflection of real-world practice is also its main limitation.There were no pre-defined or ran- European countries included in this study have unique healthcare systems and currently not all guideline-recommended therapies are available; for instance, omalizumab was not available in the UK during the study period or affordable for all patients with CSU.
For example, certain countries experience specific reimbursement constraints that make it mandatory to stop third-line treatment (omalizumab) after a certain period of time.The countries may also have local guidelines that can differ from EAACI/GA 2 LEN/EDF/ WAO guidelines.In addition, it is also likely that health economic factors in different countries might affect prescription practices.
When interpreting subgroup analyses by country, it has to be considered that patient numbers per country varied significantly: from 28 patients in Sweden up to 2226 patients in Germany.The data obtained within this study were assessed using descriptive statistics and were not used for comparative analysis.

1TA B L E 2 9 )
Abbreviations: CIndU, chronic inducible urticaria; CSU, chronic spontaneous urticaria.a Patients excluded from the analysis due to missing core variables or a violation of the inclusion/exclusion criteria.b Percentage based on patients included in the analysis (N = 3683).
n = 76 n = 78 n = 82 n = 50 n = 2226 n = 252 n = 28 n = 273 n = 92 n = 247 n = 134 CU guideline-recommended nsAHs.According to the 2014 urticaria guidelines established at the time of the AWARE study, 10 patients not responding to first-line (approved dose of nsAH) and second-line treatment (up-dosed nsAH) were to be prescribed third-line add-on therapy with omalizumab, montelukast, or ciclosporin.Since individual CSU patients differ in their responses to the recommended treatment algorithm, the focus of the present study was to evaluate the proportion of patients in different treatment groups and their corresponding UCT scores where available.Patients improved substantially over the 2-year observational period as evident by all investigated objectives, with more than 70% of patients with CSU achieving symptom control.A substantial proportion of patients had poorly controlled CSU after the two-year period, and after being seen by a specialist.As with a previous observational study by Curto-Barredo et al 5 where 32.4% and 17.3% of patients with CSU required medical care after 3 and 5 years, respectively, this AWARE study shows the necessity of long-term medical case in CSU.
domized group assessments of patients, instead data describing the treatment strategy of a patient were assessed on an ongoing basis and could also vary during the study.The only inclusion criteria applied, next to the patient providing informed consent and age ≥18 years, were a medically confirmed diagnosis of CU with symptoms of more than 2 months and inadequate control with H 1antihistamines.No explicit exclusion criteria apart from anticipated difficulties in the follow-up of the patient and simultaneous participation in any other clinical urticaria trial were applied.Number of patients available for assessment decreased over 2 years primarily due to loss of follow-up.The calculation of percentages was based on the valid data per parameter, excluding patients with missing values.Patients with complete remission of urticaria (14.1%) were also excluded from the analysis.Additional factors yielding a selection bias of patients cannot be completely ruled out.The observed frequent lack of treatment escalation might be related to variability in prescription practices across European countries, cost and/or availability of treatment, or tolerability issues-the present study did not systematically collect safety and tolerability data; therefore, these factors cannot be excluded.The Numbers (and percentages) of poorly controlled (UCT <12) well-controlled patients (UCT ≥12) receiving different treatments at each visit.N, total number of patients at each visit.CSU, chronic spontaneous urticaria [Colour figure can be viewed at wileyonlinelibrary.com] F I G U R E 5Treatment groups (current medication) by country based on escalation to third-line therapies (2014 EAACI/GA 2 LEN/EDF/ WAO guidelines).Results reported for the entire CU population (N = 3683).CU, chronic urticaria.BEL, Belgium; DNK, Denmark; ESP, Spain; FRA, France; GER, Germany; GRC, Greece; ITA, Italy; NOR, Norway; PRT, Portugal; RUS, Russia; SWE, Sweden; UK, United Kingdom [Colour figure can be viewed at wileyonlinelibrary.com]