Impact of omalizumab on patient-reported outcomes in chronic idiopathic urticaria: Results from a randomized study (XTEND-CIU)

Clinical Implications•Omalizumab treatment resulted in rapid and sustained improvements in patient-reported outcome measures over 48 weeks in patients with moderate-to-severe chronic idiopathic urticaria in the phase IV Xolair Treatment Efficacy of Longer Duration in Chronic Idiopathic Urticaria (XTEND-CIU) study. •Omalizumab treatment resulted in rapid and sustained improvements in patient-reported outcome measures over 48 weeks in patients with moderate-to-severe chronic idiopathic urticaria in the phase IV Xolair Treatment Efficacy of Longer Duration in Chronic Idiopathic Urticaria (XTEND-CIU) study. Chronic idiopathic (CIU)/spontaneous urticaria (CSU) is a debilitating skin disease that can profoundly impact health-related quality of life (HRQOL) and performance of daily activities.1Engin B. Uguz F. Yilmaz E. Ozdemir M. Mevlitoglu I. The levels of depression, anxiety and quality of life in patients with chronic idiopathic urticaria.J Eur Acad Dermatol Venereol. 2008; 22: 36-40PubMed Google Scholar, 2Maurer M. Abuzakouk M. Bérard F. Canonica W. Oude Elberink H. Giménez-Arnau A. et al.The burden of chronic spontaneous urticaria is substantial: real-world evidence from ASSURE-CSU.Allergy. 2017; 72: 2005-2016Crossref PubMed Scopus (157) Google Scholar Anxiety, depression, sleep deprivation, and work-related and social impairment are particularly common. The negative impact of CIU on HRQOL has been likened to that experienced by patients with severe coronary artery disease,2Maurer M. Abuzakouk M. Bérard F. Canonica W. Oude Elberink H. Giménez-Arnau A. et al.The burden of chronic spontaneous urticaria is substantial: real-world evidence from ASSURE-CSU.Allergy. 2017; 72: 2005-2016Crossref PubMed Scopus (157) Google Scholar, 3O'Donnell B.F. Lawlor F. Simpson J. Morgan M. Greaves M.W. The impact of chronic urticaria on the quality of life.Br J Dermatol. 1997; 136: 197-201Crossref PubMed Scopus (532) Google Scholar and correlates with disease severity.2Maurer M. Abuzakouk M. Bérard F. Canonica W. Oude Elberink H. Giménez-Arnau A. et al.The burden of chronic spontaneous urticaria is substantial: real-world evidence from ASSURE-CSU.Allergy. 2017; 72: 2005-2016Crossref PubMed Scopus (157) Google Scholar Patient-reported outcome (PRO) measures may therefore be a useful indicator of disease status and treatment efficacy. Current guidelines recommend licensed doses of second-generation H1-antihistamines for first-line management of CIU, with updosing recommended as second-line therapy.4Zuberbier T. Aberer W. Asero R. Abdul Latiff A.H. Baker D. Ballmer-Weber B. et al.The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria: the 2017 revision and update.Allergy. 2018; 15: 13397Google Scholar However, many patients remain symptomatic despite antihistamine dose escalation at 4 times or less the approved dose.5Maurer M. Weller K. Bindslev-Jensen C. Giménez-Arnau A. Bousquet P.J. Bousquet J. et al.Unmet clinical needs in chronic spontaneous urticaria: a GA2LEN task force report.Allergy. 2011; 66: 317-330Crossref PubMed Scopus (554) Google Scholar Omalizumab, an anti-IgE mAb, has been approved since 2014 as an add-on therapy for the treatment of CIU in adults and adolescents (aged ≥12 years) who remain symptomatic despite optimized H1-antihistamine treatment.6Xolair [prescribing information]. Genentech, Inc, South San Francisco, CA2018https://www.gene.com/download/pdf/xolair_prescribing.pdfDate accessed: November 9, 2018Google Scholar The phase IV, US-based, multicenter Xolair Treatment Efficacy of Longer Duration in Chronic Idiopathic Urticaria (XTEND-CIU) study enrolled patients aged 12 to 75 years with symptomatic CIU despite H1-antihistamine treatment at 4 times or less the approved dose. The study was conducted in 4 phases: 14-day screening period, 24-week open-label period where patients received omalizumab 300 mg every 4 weeks, 24-week double-blind phase in which responders (7-day Urticaria Activity Score [UAS7] ≤ 6 in weeks 23 and 24) in the open-label period were subsequently randomized to continue omalizumab or switch to placebo, and follow-up period (weeks 48-60).7Casale T.B. Win P.H. Bernstein J.A. Rosen K. Holden M. Iqbal A. et al.Omalizumab response in patients with chronic idiopathic urticaria: insights from the XTEND-CIU study.J Am Acad Dermatol. 2018; 78: 793-795Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar During the double-blind period, randomized patients with investigator-assessed clinical worsening of disease (UAS7 ≥ 12 for ≥2 consecutive weeks) were eligible to transition to open-label omalizumab through to week 48. Preliminary findings from XTEND-CIU study's open-label period showed that PRO measures improved in all areas evaluated, with even protocol-defined nonresponders (UAS7 > 6 in weeks 23 and 24) experiencing clinically significant improvements in Dermatology Life Quality Index (DLQI), Insomnia Severity Index (ISI), and Work Productivity and Activity Impairment (WPAI) scores.7Casale T.B. Win P.H. Bernstein J.A. Rosen K. Holden M. Iqbal A. et al.Omalizumab response in patients with chronic idiopathic urticaria: insights from the XTEND-CIU study.J Am Acad Dermatol. 2018; 78: 793-795Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar The present analysis explored long-term effects of CIU on HRQOL and the potential of omalizumab to durably improve HRQOL measures using PRO data from both the open-label and double-blind phases of the XTEND-CIU study. Patients recorded symptoms (itch severity score, number of hives, size of largest hive) twice daily using the Urticaria Patient Daily Diary. Average daily scores for itch severity and number of hives were totaled each week to derive the UAS7, which assessed treatment response. HRQOL PROs were assessed at baseline and weeks 12 and 24 in the open-label period, and at weeks 36 and 48 in the double-blind phase (see Table E1 in this article's Online Repository at www.jaci-inpractice.org). Pearson correlation coefficients were calculated to assess strength of associations between PRO measures and disease activity. Safety analyses for the XTEND-CIU study have been published previously.8Maurer M. Kaplan A. Rosén K. Holden M. Iqbal A. Trzaskoma B.L. et al.The XTEND-CIU study: long-term use of omalizumab in chronic idiopathic urticaria.J Allergy Clin Immunol. 2018; 141: 1138-1139.e7Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Of 205 patients enrolled in the XTEND-CIU study who received treatment in the open-label phase, 134 met randomization criteria for the double-blind phase and received omalizumab (n = 81) or placebo (n = 53; see Figure E1 in this article's Online Repository at www.jaci-inpractice.org). Demographic and clinical characteristics were generally similar between groups (Table I). Predictably, weekly itch score, weekly hive score, and number of days with angioedema in the past week were lower at the start of the double-blind phase (week 24) versus the start of the open-label period (baseline; Table I). At baseline (open-label period), patients reported severe interference of disease symptoms with sleep, anxiety, work productivity, and activity, with few differences between the group subsequently randomized in the double-blind phase and the nonrandomized group (Figure 1). By week 12 of open-label omalizumab treatment, substantial improvements in PRO measures were observed across all domains, which were sustained to the end of the open-label period (Figure 1). These improvements were observed irrespective of clinical response, but were greatest in clinical responders (ie, subsequently randomized patients; Figure 1).Table IDemographic characteristics of patients in the open-label period (baseline [week 0]; N = 205) and double-blind phase (randomization [week 24]; N = 134) of the XTEND-CIU studyCharacteristicOpen-label period (N = 205)Double-blind phase (N = 134)Omalizumab (n = 81)Placebo (n = 53)Age (y), mean ± SD∗At baseline (start of the open-label period).44.6 ± 14.543.1 ± 14.748.5 ± 13.2Sex: female, n (%)153 (74.6)60 (74.1)40 (75.5)Race, n (%) White168 (82.0)68 (84.0)42 (79.2) Black23 (11.2)6 (7.4)7 (13.2) Asian5 (2.4)2 (2.5)3 (5.7) American Indian/Alaskan Native2 (1.0)2 (2.5)0 Other7 (3.4)3 (3.7)1 (1.9)BMI (kg/m2), mean ± SD∗At baseline (start of the open-label period).30.3 ± 6.829.8 ± 6.330.8 ± 7.7Smoker (current or former), n (%)†At screening (days –14 to 1 of the open-label period).51 (24.9)16 (19.8)12 (22.6)Duration of CIU symptoms (mo), mean ± SD†At screening (days –14 to 1 of the open-label period).79.1 ± 109.677.0 ± 118.873.6 ± 67.3Systemic corticosteroids, n (%)‡For symptomatic control in the previous 12 mo.99 (48.3)37 (45.7)23 (43.4)Weekly hives score, mean ± SD16.8 ± 4.5∗At baseline (start of the open-label period).0.3 ± 0.7§At randomization (start of the double-blind phase [week 24]).0.3 ± 0.8§At randomization (start of the double-blind phase [week 24]).Weekly itch score, mean ± SD15.5 ± 3.6∗At baseline (start of the open-label period).0.4 ± 0.8§At randomization (start of the double-blind phase [week 24]).0.5 ± 1.1§At randomization (start of the double-blind phase [week 24]).No. of days with angioedema in past week, mean ± SD2.1 ± 2.7∗At baseline (start of the open-label period).0.0 ± 0.1§At randomization (start of the double-blind phase [week 24]).0.0 ± 0.2§At randomization (start of the double-blind phase [week 24]).BMI, Body mass index.∗ At baseline (start of the open-label period).† At screening (days –14 to 1 of the open-label period).‡ For symptomatic control in the previous 12 mo.§ At randomization (start of the double-blind phase [week 24]). Open table in a new tab BMI, Body mass index. Substantial improvements in HRQOL scores generally occurred within 24 weeks of treatment initiation (Figure 1), with previously reported moderate clinical insomnia (mean ISI, 15.8 ± 6.9) and mild anxiety (mean Generalized Anxiety Disorder 7-item Scale [GAD-7] score, 7.6 ± 6.3) at baseline resolved by week 24 (mean ISI, 4.5 ± 5.8; GAD-7 score, 2.9 ± 3.8). Perception of impact of skin disease (Urticaria Activity and Impact Measure [U-AIM]) and urticaria control (Urticaria Control Test [UCT]) also improved from baseline (mean DLQI score, 14.8 ± 6.9; U-AIM score, 35.8 ± 6.7; UCT score, 2.5 ± 2.5) to week 24 (mean DLQI score, 2.2 ± 4.4; U-AIM score, 8.2 ± 11.3; UCT score, 13.6 ± 3.8) in omalizumab-treated patients (DLQI minimally important difference = 3). Moderate Pearson correlation coefficients (r) were seen between UAS7 and DLQI (r = 0.552; n = 175), ISI (r = 0.502; n = 175), and WPAI overall work (r = 0.470; n = 130) and activity impairment (r = 0.537; n = 173) scores, but not between UAS7 and GAD-7 (r = 0.288; n = 174) and WPAI work time missed (r = 0.116; n = 132) scores. Percentage of patients with worsening DLQI scores (increase ≥3 points) at the end of the double-blind phase (week 48) was significantly higher in patients randomized to placebo versus omalizumab (DLQI score, 66.0% [95% CI, 51.7%-78.5%] vs 19.8% [95% CI, 11.7%-30.1%], respectively; P < .0001).8Maurer M. Kaplan A. Rosén K. Holden M. Iqbal A. Trzaskoma B.L. et al.The XTEND-CIU study: long-term use of omalizumab in chronic idiopathic urticaria.J Allergy Clin Immunol. 2018; 141: 1138-1139.e7Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar This greater worsening of DLQI scores among placebo- versus omalizumab-treated patients was paralleled by the pattern of clinical worsening measured by UAS7 greater than or equal to 12 for 2 consecutive weeks (60.4% [95% CI, 46.0%-73.5%] vs 21.0% [95% CI, 12.7%-31.5%], respectively; P < .0001) and corresponded with worsening of HRQOL scores in the placebo group (Figure 1).8Maurer M. Kaplan A. Rosén K. Holden M. Iqbal A. Trzaskoma B.L. et al.The XTEND-CIU study: long-term use of omalizumab in chronic idiopathic urticaria.J Allergy Clin Immunol. 2018; 141: 1138-1139.e7Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar In contrast, patients who continued omalizumab beyond 24 weeks maintained HRQOL improvements over the course of 48 weeks (Figure 1). However, mean change in GAD-7 and WPAI work time missed scores was not significantly different between treatment groups (P = .5360 and P = .5640, respectively). A limitation of the study included the small number of patients (n = 25) in the placebo group who completed the double-blind phase. Studies have previously shown that patients with CIU experience considerable HRQOL burden, with negative effects increasing with increasing disease severity.2Maurer M. Abuzakouk M. Bérard F. Canonica W. Oude Elberink H. Giménez-Arnau A. et al.The burden of chronic spontaneous urticaria is substantial: real-world evidence from ASSURE-CSU.Allergy. 2017; 72: 2005-2016Crossref PubMed Scopus (157) Google Scholar, 9Finlay A.Y. Kaplan A.P. Beck L.A. Antonova E.N. Balp M.M. Zazzali J. et al.Omalizumab substantially improves dermatology-related quality of life in patients with chronic spontaneous urticaria.J Eur Acad Dermatol Venereol. 2017; 31: 1715-1721Crossref PubMed Scopus (29) Google Scholar The XTEND-CIU study demonstrated that omalizumab treatment substantially and sustainably improved CIU symptoms and consequent impairment of HRQOL, including sleep, anxiety, work productivity, and activity, as measured by PROs. Improvements occurred as early as week 12 (first reported measurement) and were sustained for the entire duration of the 48-week treatment period in patients receiving omalizumab. The results highlight the significant disease burden of CIU and the important role of omalizumab in improving HRQOL outcomes in addition to urticaria lesions and pruritus. Benjamin L. Trzaskoma, MS, and Ming Yang, PhD, of Genentech, Inc., provided statistical support. Jamie A. Le, PhD, formerly of Genentech, Inc. (current employee of Aimmune Therapeutics), provided writing assistance for poster development. Third-party writing assistance was provided by Jordana Campbell, BSc, of Envision Pharma Group, and funded by Genentech, Inc., a member of the Roche Group, and Novartis Pharmaceuticals Corporation. Table E1Description of PRO measures used in the XTEND-CIU studyPRO measureItems and purposeScoringDLQIA 10-item questionnaire evaluating patient's perception of the impact of dermatological symptoms on 6 dimensions (symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment)Range, 0-30; higher scores indicate higher negative impact of skin diseaseISIA 7-item questionnaire measuring self-perception of insomnia symptoms and impact on patient health and daily lifeRange, 0-28; higher scores indicate more severe insomniaGAD-7A 7-item questionnaire used to assess anxiety symptomsTotal score range, 0-21, with cutoff points of 5, 10, and 15 representing mild, moderate, and severe levels of anxiety, respectivelyWPAIA 6-item questionnaire measuring absenteeism, presenteeism, work productivity loss, and activity impairmentScores are generated as percentages for each domain, with higher scores indicating greater productivity issuesUCTA 4-item instrument used to assess urticarial control and to screen patients with urticaria with poorly controlled diseaseRange, 0-16; lower scores indicate more poorly controlled diseaseU-AIMA 9-item instrument designed to assess the activity and impact of patient's urticaria symptoms during the past 7 d, including severity and bothersome nature of itch, hives and angioedema, interference with daily activities and sleep, and self-perceived controlRange, 0-34; higher scores indicate greater impactP-GICA single-item scale designed to evaluate a patient's perception about the efficacy of treatmentRange, 0-7, with cutoff points of 3, 4, and 7 representing disease improvement, stable disease, or disease deterioration, respectivelyP-GIC, Patient Global Impression of Change. Open table in a new tab P-GIC, Patient Global Impression of Change.