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OBJECTIVE: To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab-induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell-dependent antigen), pneumococcal polysaccharide (T cell-independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed-type hypersensitivity (DTH). METHODS: In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab-treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a >/=4-fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2-3 days following placement. RESULTS: Responses to tetanus toxoid vaccine (>/=4-fold rise) were similar in both groups (39.1% of rituximab-treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab-treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab-treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2-fold rise in titer in response to >/=1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti-KLH IgG, compared with 93% of patients treated with MTX alone). CONCLUSION: Recall responses to the T cell-dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab-treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell-independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses. [ABSTRACT FROM AUTHOR]

The presence of angioedema, or deep skin swelling, in addition to hives (wheals) in patients with chronic spontaneous urticaria (CSU) can complicate disease management. There is evidence that omalizumab is effective for patients with CSU with angioedema, but the time to a clinically meaningful response has not been assessed. This post hoc analysis examined data from the phase 3, randomized, double-blind ASTERIA I and ASTERIA II studies: patients with CSU with hives were grouped by presence (n = 216) or absence of angioedema (n = 265) at baseline. The time to minimally important difference (MID, change from baseline of ≥11 points) in weekly Urticaria Activity Score (UAS7) was analyzed using Kaplan-Meier analyses. Median time to MID for omalizumab 300 mg was similar in patients with and without angioedema. Median time to MID for omalizumab 150 mg was similar to 300 mg for patients without angioedema, and was longer for patients with angioedema. Therefore, the response to omalizumab for patients with CSU with angioedema was dose dependent. We recommend that the best approach for clinicians, in line with guidelines, would be initial administration of omalizumab 300 mg every 4 weeks for all patients., Clinical Trials Registration: Clinicaltrials.gov NCT01287117 (registered 27 January 2011) and NCT01292473 (registered 7 February 2011)., Competing Interests: Thomas Casale is a consultant and speaker bureau member for Genentech, Inc.; consultant for Novartis Pharmaceuticals Corporation. Benjamin Trzaskoma and Michael Holden are employees of Genentech, Inc.; stockholders in Roche. Jonathan Bernstein is a consultant and PI for Genentech, Inc., Novartis, Amgen, GSK, Sanofi-Regeneron, AstraZeneca, Celldex, Allakos, Escient, Teva, Takeda/Shire, CSL Behring, Biocryst, Kalvista, Ionis, Biomarin, Pharming, Jasper. Marcus Maurer is a speaker and/or advisor for and/or has received research funding from Allakos, Alexion, Almirall, Alvotech, Amgen, Aquestive, Arcensus, argenX, AstraZeneca, Astria, BioCryst, Blueprint, Celldex, Celltrion, Clinuvel, Cogent, CSL Behring, Escient, Evommune, Excellergy, Genentech, GSK, Incyte, Jasper, Kashiv, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Mitsubishi Tanabe Pharma, Moxie, Noucor, Novartis, Orion Biotechnology, Pharvaris, Resonance Medicine, Sanofi/Regeneron, Santa Ana Bio, Septerna, Servier, Takeda, Teva, Third HarmonicBio, Valenza Bio, Vitalli Bio, Yuhan Corporation, Zurabio., (© 2024 The Authors.)

Background: Across the HAVEN clinical trial program, the efficacy of emicizumab has been demonstrated in children, adolescents, and adults with hemophilia A, with or without factor VIII inhibitors. After the 4-week loading dose period, emicizumab concentrations are expected to remain at levels that provide bleed protection throughout the entire dosing interval, regardless of the chosen maintenance dosing regimen, ie, weekly, every 2 weeks, or every 4 weeks., Objectives: The objective of this study was to examine the timing of treated bleeds within the dosing intervals for emicizumab administered during the HAVEN 1 to 4 studies., Methods: In this post hoc analysis, we pooled data from all the participants of the HAVEN 1 to 4 studies and analyzed the timing of treated bleeds in relation to the emicizumab dose., Results: A total of 392 participants were included in this analysis, with a median (range) age of 28.0 years (1.1-77.0 years). Target joints were identified in 237 of 392 (60.5%) participants before the study entry. Overall, 211 of 392 (53.8%) participants experienced 907 treated bleeding events. The total mean (SD) annualized bleeding rate across the 4 studies was 1.6 (5.9). There was no evidence that bleeding events clustered on any 1 particular day in any dosing schedule from HAVEN 1 to 4 ( P > .05 for all 3 treatment regimens)., Conclusion: Data from the HAVEN 1 to 4 trials show consistent bleed prevention within the dosing interval, regardless of the dosing regimen chosen. These findings provide further evidence of the sustained efficacy of emicizumab across all approved dosing regimens to reduce bleeding in people with hemophilia A., (© 2023 The Authors.)

Introduction: Identification of clinical characteristics associated with prognosis for idiopathic pulmonary fibrosis (IPF) may help to guide management decisions. This analysis utilized data from the Pulmonary Fibrosis Foundation Patient Registry to examine the relationships between clinical outcomes and both body mass index (BMI) at study enrollment (hereafter referred to as baseline BMI) and annualized percent change in body weight in patients with IPF in a real-world setting., Methods: The following outcomes over 24 months were stratified by baseline BMI and annualized percent change in body weight: all-cause mortality; annualized change in percent predicted forced vital capacity (%FVC), percent predicted diffusing capacity for carbon monoxide, and 6-min walk distance; all-cause and respiratory-related hospitalizations; and acute exacerbations., Results: Overall, 600 patients with IPF were included (baseline BMI: < 25 kg/m 2 , n = 120; 25 to < 30 kg/m 2 , n = 242; ≥ 30 kg/m 2 , n = 238; annualized percent change in body weight: no loss, n = 95; > 0% to < 5% loss, n = 425; ≥ 5% loss, n = 80). Enrollment demographics and characteristics were generally similar across subgroups. There was no association between mortality and BMI. All-cause mortality was lower among patients who experienced no annualized weight loss versus those with ≥ 5% (OR [95% CI] 3.28 [1.15, 10.95]) or > 0 to < 5% weight loss (OR [95% CI] 2.83 [1.14, 8.62]) over 24 months. Patients with baseline BMI < 25 kg/m 2 had a significantly greater estimated annualized decline in %FVC versus patients with baseline BMI ≥ 30 kg/m 2 (difference [95% CI] 1.47 [0.01, 2.93]). No relationship was observed between %FVC and weight loss. Other clinical outcomes were generally similar across subgroups., Conclusions: Some clinical outcomes may be worse in patients with IPF who have a low BMI (< 25 kg/m 2 ) or who experience weight loss over 24 months, but the causation for these relationships is unknown. These results may help to inform management decisions for patients with IPF., Gov Identifier: NCT02758808., (© 2022. The Author(s).)

Many people with hemophilia A (PwHA) undergo surgery in their lifetime, often because of complications of their disease. Emicizumab is the first bispecific monoclonal antibody prophylactic therapy for PwHA, and its efficacy and safety have been previously demonstrated; however, there is a need to build an evidence base on the management of PwHA on emicizumab undergoing surgery. Data from the HAVEN 1-4 phase 3 clinical trials were pooled to provide a summary of all minor and major surgeries in PwHA with or without factor VIII (FVIII) inhibitors who were receiving emicizumab prophylaxis. Overall, 233 surgeries were carried out during the HAVEN 1-4 trials: 215 minor surgeries (including minor dental and joint procedures, central venous access device placement or removal, and endoscopies) in 115 PwHA (64 with FVIII inhibitors) and 18 major surgeries (including arthroplasty and synovectomy) in 18 PwHA (10 with FVIII inhibitors). Perioperative hemostatic support was at the discretion of the treating physician. Overall, the median (interquartile range [IQR]) age was 33.5 (13.0-49.0) years and the median (IQR) emicizumab exposure time before surgery was 278.0 (177.0-431.0) days. Among the 215 minor surgeries, 141 (65.6%) were managed without additional prophylactic factor concentrate, and of those, 121 (85.8%) were not associated with a postoperative bleed. The majority (15 of 18 [83.3%]) of major surgeries were managed with additional prophylactic factor concentrate. Twelve (80.0%) of these 15 surgeries were associated with no intraoperative or postoperative bleeds. The data demonstrate that minor and major surgeries can be performed safely in PwHA receiving emicizumab prophylaxis. These trials are registered at www.clinicaltrials.gov as #NCT02622321, #NCT02795767, #NCT02847637, and #NCT03020160., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The 32-item Motor Function Measure (MFM32) is an assessment of motor function used to evaluate fine and gross motor ability in patients with neuromuscular disorders, including spinal muscular atrophy (SMA). Reliability and validity of the MFM32 have been documented in individuals with SMA. Through semi-structured qualitative interviews ( N = 40) and an online survey in eight countries ( N = 217) with individuals with Types 2 and 3 SMA aged 2-59 years old and caregivers, the meaning of changes on a patient-friendly version of the MFM32 was explored. In an independent analysis of clinical trial data, anchor- and distribution-based analyses were conducted in a sample of individuals with Type 2 and non-ambulant Type 3 SMA to estimate patient-centered quantitative MFM32 meaningful change thresholds. The results from this study demonstrate that, based on patient and caregiver insights, maintaining functional ability as assessed by a patient-friendly version of the MFM32 is an important outcome. Quantitative analyses using multiple anchors (median age range of 5-8 years old across anchor groups) indicated that an ~3-point improvement in MFM32 total score represents meaningful change at the individual patient level. Overall, the qualitative and quantitative findings from this study support the importance of examining a range of meaningful change thresholds on the MFM32 including ≥0 points change reflecting stabilization or improvement and ≥3 points change reflecting a higher threshold of improvement. Future research is needed to explore quantitative differences in meaningful change on the MFM32 based on age and functional subgroups., Competing Interests: HS, JB, and TW are employees and shareholders of Roche Products Ltd. KG is an employee and shareholder of F. Hoffmann-La Roche Ltd. BT is an employee and shareholder of Genentech. TD serves on advisory boards and receives consultancy fees for Roche, Genentech, Biogen, Novartis and Cure SMA. CV is a PI for Roche clinical trials and has received consultancy fees from Roche, Biogen, and Avexis. TD, CV, and AB received consultancy fees from Roche for this project. NG is a volunteer of SMA Europe and SMA Schweiz, mother of a child living with SMA advisor and lecturer for Novartis Gene Therapies (AveXis) Biogen, Novartis, and Roche. RC was an employee with Cure SMA at the time of the study. LG is an employee of Analystat Corporation working in US Medical Affairs at Genentech and Roche as a statistical consultant and has received payment from Genentech Inc. SR is an employee of Adelphi Values, a health outcomes research agency, commissioned and paid by Roche to conduct the qualitative interview part of the study. LY is an employee of Charles River Associates, commissioned and paid by Roche to conduct the online survey part of the study. The authors declare that this study received funding from Roche Products Ltd/F. Hoffmann-La Roche. The funder (F. Hoffmann-La Roche) had the following involvement: qualitative interviews and survey parts of the study, design of the study and interpretation of the data. The funder (F. Hoffmann-La Roche) had the following involvement in the SUNFISH part 2 post-hoc analyses: design, analysis and interpretation of the data. Medical writing and editorial support were funded by F Hoffmann-La Roche., (Copyright © 2022 Duong, Staunton, Braid, Barriere, Trzaskoma, Gao, Willgoss, Cruz, Gusset, Gorni, Randhawa, Yang and Vuillerot.)

Objective: Constitutional delay of growth and puberty (CDGP) is a tempo variant with a good prognosis. Healthy late-maturing adolescents grow slower than postulated by age-related references, and therefore, CDGP is frequently confused with growth hormone deficiency (GHD). For differential diagnosis, height velocity references for CDGP are needed., Design and Patients: Here, we provide height velocity data for late-maturing boys based on mixed longitudinal and cross-sectional observations in a group of 38 German adolescents with proven CDGP and compare them with cross-sectional observations in a group of 164 adolescents with organic GHD from the National Cooperative Growth Study registry., Results: In the critical age interval from 13.4 to 14.9 years, the growth of prepubertal adolescents with CDGP was faster (mean/median height velocity, 5.2/5.4 cm/years; quartiles, 4.4-6.2 cm/years) than that of prepubertal adolescents with organic GHD (3.5/3.2 cm/years; quartiles, 2.0-4.4 cm/years) in the cross-sectional analysis (p < .0001). Based on our mixed longitudinal and cross-sectional analysis, the height velocity of adolescent boys with CDGP exceeded previous model calculations on average by 1.0 cm., Conclusions: In conclusion, prepubertal adolescents with CDGP grow faster than patients with organic GHD. Previous model estimates underestimated height velocity of boys with CDGP., (© 2020 John Wiley & Sons Ltd.)

Background: Declines in percent predicted FVC (% predicted FVC), declines in 6-min walk distance (6MWD), and respiratory hospitalizations are events associated with disease progression and mortality in idiopathic pulmonary fibrosis. The incidence of multiple events in the same patient over 12 months of pirfenidone treatment is unknown., Methods: Patients who received pirfenidone 2,403 mg/d (n = 623) or placebo (n = 624) in the ASCEND (study 016; NCT01366209) and CAPACITY (studies 004 and 006; NCT00287716 and NCT00287729) phase III trials were included in this post hoc analysis. Disease progression events were defined as relative decline in % predicted FVC ≥ 10%, absolute decline in 6MWD ≥ 50 m, respiratory hospitalization, or death from any cause. The incidence of disease progression events over 12 months was assessed., Results: The most frequent disease progression events were declines in % predicted FVC (pirfenidone vs placebo; 202 vs 304 events) and declines in 6MWD (pirfenidone vs placebo; 265 vs 348 events). Fewer patients who received pirfenidone had more than one progression event compared with placebo (17.0% vs 30.1%; P < .0001). Death following one or more progression event occurred less frequently in the pirfenidone group than in the placebo group (2.1% vs 6.3%; P = .0002)., Conclusions: Pirfenidone significantly reduced the incidence of multiple progression events and death after a progression event over 12 months of treatment compared with placebo. These findings suggest that continued treatment with pirfenidone confers a benefit despite the occurrence of any single disease progression event., Trial Registry: ClinicalTrials.gov; Nos. NCT01366209, NCT00287716, and NCT00287729; URL: www.clinicaltrials.gov., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Omalizumab has demonstrated efficacy in clinical trials of patients with asthma, but real-world data are needed., Objective: To assess outcomes after omalizumab initiation in patients with asthma in a real-world setting., Methods: Patients aged 12 years and older with allergic asthma who were candidates for omalizumab on the basis of physician-assessed need were enrolled in a US-based, prospective, single-arm, 48-week multicenter study, the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab. Monthly assessments included exacerbations, health care utilization, asthma control test (ACT), and adverse events. At baseline, 6 months, and end of study, biomarkers (blood eosinophils and fractional exhaled nitric oxide) were collected and spirometry performed., Results: Of 806 enrollees, 801 (99.4%) received omalizumab and 622 (77.2%) completed the study. The exacerbation rate significantly improved from a mean of 3.00 ± 3.28 in the 12 months before baseline to 0.78 ± 1.37 through month 12 (P < .001) and was similar in adults and adolescents; there was a reduction of 81.9% in the percentage of patients with 1 or more hospitalizations. Lung function remained generally unchanged. A mean improvement of 4.4 ± 4.9 in ACT scores was observed. Eighty-seven percent of patients were responders on the basis of clinical improvement in exacerbations, lung function, or ACT scores. Baseline biomarker status was associated with ACT scores and lung function improvement, but the magnitude of this improvement was not clinically relevant. No new safety signals emerged., Conclusions: Omalizumab initiation in patients with asthma resulted in improved exacerbation rates, reduced hospitalizations, and improved ACT scores compared with pretreatment values, regardless of biomarker status., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Few data are available to assist clinicians with decisions regarding long-term use of asthma therapies, including omalizumab., Objective: We sought to evaluate the benefit and persistence of response in subjects continuing or withdrawing from long-term omalizumab treatment., Methods: Evaluating the Xolair Persistency Of Response After Long-Term Therapy (XPORT) was a randomized, double-blind, placebo-controlled withdrawal study that included subjects with moderate-to-severe persistent asthma receiving long-term omalizumab. Subjects were randomized by using a hierarchical dynamic randomization scheme to continue their same dose of omalizumab or withdraw to placebo and were then followed every 4 weeks for 1 year. The primary outcome was any protocol-defined severe asthma exacerbation. The secondary outcome was time to first protocol-defined severe asthma exacerbation. Exploratory outcomes included changes in Asthma Control Questionnaire and Asthma Control Test scores., Results: Significantly more subjects in the omalizumab group (67%) had no protocol-defined exacerbation than in the placebo group (47.7%); an absolute difference of 19.3% (95% CI, 5.0%, 33.6%) represents a 40.1% relative difference. Time to first protocol-defined exacerbation analysis revealed a significantly different between-group exacerbation pattern that was consistent with the primary analysis. Subjects continuing omalizumab had significantly better asthma control (mean [SD] change from baseline to week 52: Asthma Control Test score, -1.16 [4.14] vs placebo, -2.88 [5.38], P = .0188; Asthma Control Questionnaire score, 0.22 [0.66] vs placebo, 0.63 [1.13], P = .0039). Discontinuation of omalizumab was associated with an increase in free IgE levels and an increase in basophil expression of the high-affinity IgE receptor. No safety concerns were noted., Conclusion: Continuation of omalizumab after long-term treatment results in continued benefit, as evidenced by improved symptom control and reduced exacerbation risk., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Asthma is one of the most common chronic diseases of childhood. Allergen sensitization and high frequencies of comorbid allergic diseases are characteristic of severe asthma in children. Omalizumab, an anti-IgE mAb, is the first targeted biologic therapeutic approved for the treatment of moderate-to-severe persistent allergic asthma (AA) that remains uncontrolled despite high-dose inhaled corticosteroids plus other controller medications. Since its initial licensing for use in adults and adolescents 12 years of age and older, the clinical efficacy, safety, and tolerability of omalizumab have been demonstrated in several published clinical trials in children aged 6 to less than 12 years with moderate-to-severe AA. These studies supported the approval of the pediatric indication (use in children aged ≥6 years) by the European Medicines Agency in 2009 and the US Food and Drug Administration in 2016. After this most recent change in licensing, we review the outcomes from clinical trials in children with persistent AA receiving omalizumab therapy and observational studies from the past 7 years of clinical experience in Europe. Data sources were identified by using PubMed in 2016. Guidelines and management recommendations and materials from the recent US Food and Drug Administration's Pediatric Advisory Committee meeting are also reviewed., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Angioedema, present in some patients with chronic idiopathic/spontaneous urticaria (CIU/CSU), may have a negative effect on patient quality of life., Objective: To describe patient-reported angioedema and its management in the pivotal omalizumab studies (ASTERIA I, ASTERIA II, GLACIAL)., Methods: Enrolled patients with CIU/CSU remained symptomatic despite treatment with histamine 1 (H 1 )-antihistamines at licensed doses (ASTERIA I, ASTERIA II) or H 1 -antihistamines at up to 4 times the approved dose plus H 2 -antihistamines and/or a leukotriene receptor antagonist (GLACIAL). All studies administered omalizumab (75, 150, or 300 mg in ASTERIA I and ASTERIA II; 300 mg in GLACIAL) or placebo subcutaneously every 4 weeks for at least 12 weeks. Urticaria Patient Daily Diary entries were completed by patients and summarized., Results: At baseline, angioedema prevalence was higher in GLACIAL (53.1%) than in ASTERIA I (47.5%) or ASTERIA II (40.7%). The mean proportion of angioedema-free days during weeks 4 to 12 was greater for patients treated with 300 mg of omalizumab than placebo in ASTERIA I (96.1% vs 88.2%, P < .001), ASTERIA II (95.5% vs 89.2%, P < .001), and GLACIAL (91.0% vs 88.7%, P = .006). Most patient-reported angioedema was managed by low-intensity interventions (doing nothing or taking medication)., Conclusion: Treatment with 300 mg of omalizumab was efficacious in reducing patient-reported angioedema. Low-intensity interventions were generally used to manage angioedema episodes., Trial Registration: clinicaltrials.gov Identifiers: NCT01287117 (ASTERIA I), NCT01292473 (ASTERIA II), and NCT01264939 (GLACIAL)., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with chronic idiopathic/spontaneous urticaria (CIU/CSU) report difficulty with sleep., Methods: We examined the effect of omalizumab on sleep-related outcomes during 3-6 months omalizumab or placebo treatment and a 16-week follow-up period within three Phase III double-blind randomized placebo-controlled pivotal trials in CIU/CSU: ASTERIA I, ASTERIA II, and GLACIAL. Sleep quality was assessed in all three studies using sleep-related questions included in an electronic diary, the Chronic Urticaria Quality of Life Questionnaire, and the Medical Outcomes Study Sleep Scale. Score changes from baseline in the treatment arms were compared with that in the placebo arm and adjusted for baseline score and weight. We also examined correlations of sleep scores at baseline, week 12, and week 24 and the slopes of change between sleep and itch and hive., Results: Patients treated with omalizumab reported a larger reduction in sleep problems than those in the placebo arm; omalizumab 300 mg demonstrated the greatest improvement on all sleep components among all treatment arms. The largest reduction in sleep problems was reported within the first 4 weeks of therapy. After treatment discontinuation, sleep quality worsened. Sleep scores demonstrated moderate-to-strong correlation between them, and the change in sleep scores was associated with changes in itch and hives., Conclusions: Improvement in sleep was reported after the first dose of omalizumab. Sleep continued to improve throughout the active treatment period. Patients receiving omalizumab 300 mg achieved greater improvement in sleep than those in other treatment arms. Trial registration ClinicalTrials.gov, NCT01287117 (ASTERIA I), NCT01292473 (ASTERIA II), and NCT01264939 (GLACIAL).

Background: Few data are available that describe response patterns in patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) treated with omalizumab., Objective: We sought to describe response patterns by using data from the 3 pivotal omalizumab CIU/CSU trials., Methods: Every 4 weeks, randomized patients received dosing with placebo or 75, 150, or 300 mg of omalizumab (ASTERIA I: n = 318, 24 weeks; ASTERIA II: n = 322, 12 weeks) or placebo or 300 mg of omalizumab (GLACIAL: n = 335, 24 weeks). Response was defined as well-controlled urticaria (weekly Urticaria Activity Score [UAS7] ≤ 6) or complete response (UAS7 = 0)., Results: Response rates were dose dependent and highest with 300 mg of omalizumab. Some patients responded early (before week 4). At week 12, a higher proportion of patients treated with 300 mg of omalizumab reported a UAS7 ≤ 6 (26.0% [75 mg of omalizumab], 40.0% [150 mg of omalizumab], 51.9% [300 mg of omalizumab], and 11.3% [placebo] for ASTERIA I; 26.8% [75 mg of omalizumab], 42.7% [150 mg of omalizumab], 65.8% [300 mg of omalizumab], and 19.0% [placebo] for ASTERIA II; and 52.4% [300 mg of omalizumab] and 12.0% [placebo] for GLACIAL) or a UAS7 = 0 (11.7% [75 mg of omalizumab], 15.0% [150 mg of omalizumab], 35.8% [300 mg of omalizumab], and 8.8% [placebo] for ASTERIA I; 15.9% [75 mg of omalizumab], 22.0% [150 mg of omalizumab], 44.3% [300 mg of omalizumab], and 5.1% [placebo] for ASTERIA II; and 33.7% [300 mg of omalizumab] and 4.8% [placebo] for GLACIAL). In patients receiving 300 mg of omalizumab with 24 weeks of treatment, median time to achieve a UAS7 ≤ 6 was 6 weeks (ASTERIA I and GLACIAL) and median time to achieve a UAS7 = 0 was 12 or 13 weeks (ASTERIA I and GLACIAL, respectively). Some patients who achieved well-controlled urticaria or complete response sustained response throughout the treatment period., Conclusion: Benefits of omalizumab treatment were evident early (before week 4) in some patients and persisted to week 24. Use of 300 mg of omalizumab demonstrated best results in controlling CIU/CSU symptoms., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Dornase alfa administered via jet nebulizer is indicated as a chronic respiratory medication for cystic fibrosis (CF) patients. Efficacy and safety of dornase alfa via an electronic nebulizer with vibrating membrane technology have not been formally assessed in randomized clinical trials., Methods: 87 CF patients (≥6 years) were randomized in a crossover study to receive dornase alfa 2.5 mg/d in 2-week periods with the Pari eRapid and Pari LC Plus jet nebulizers. The primary end point was comparison of forced expiratory volume in the first second. Safety, quality of life, and treatment satisfaction/preference were also compared between devices., Results: Lung function was equivalent between nebulizers. Most domain scores from the Cystic Fibrosis Questionnaire-Revised and Treatment Satisfaction Questionnaire for Medication instruments were similar but patients strongly preferred the eRapid. Mean patient-reported administration times were shorter with the eRapid vs the LC Plus (2.7 vs 10.2 min). Adverse events were similar between devices., Conclusions: Administration of dornase alfa via the eRapid nebulizer resulted in comparable efficacy and safety, shorter nebulization times, and higher patient preference., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Data from the 3 omalizumab pivotal trials in patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) represent the largest database of patients reported to date with refractory disease (omalizumab, n = 733; placebo, n = 242)., Objective: The objective of this study was to compare results from ASTERIA I and II, which included only approved doses of H1-antihistamine as background therapy based on regulatory authority requirements, to those from GLACIAL, which permitted higher doses of H1-antihistamines as well as other types of background therapy, in a post hoc analysis., Methods: Efficacy data from the placebo, omalizumab 150-mg, and omalizumab 300-mg treatment arms of ASTERIA I and II were pooled and analyzed (n = 162 and n = 160, respectively). The 300-mg treatment arm analyses were compared with the analysis of data from GLACIAL (n = 252) using analysis of covariance models. The key efficacy endpoint was change from baseline to week 12 in mean weekly itch severity score (ISS); other endpoints were also evaluated. Safety data were pooled from all 3 studies., Results: Mean ISS was significantly reduced from baseline at week 12 in the pooled ASTERIA I and II omalizumab 150- and 300-mg treatment arms and in the GLACIAL omalizumab 300-mg arm. The weekly ISS reduction magnitude at week 12 was similar between the omalizumab 300-mg groups in the ASTERIA I and II pooled and GLACIAL studies. Similar treatment effect sizes were observed across multiple endpoints. Omalizumab was well tolerated and the adverse-event profile was similar regardless of background therapy for CIU/CSU. The overall safety profile was generally consistent with omalizumab therapy in allergic asthma., Conclusion: Omalizumab 300 mg was safe and effective in reducing CIU/CSU symptoms regardless of background therapy., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Asthma poses a significant disease burden worldwide. Current guidelines emphasize achieving and maintaining asthma control., Objective: To describe longitudinal changes of asthma control and asthma-related work, school, and activity impairment for patients with moderate-to-severe asthma treated with omalizumab and those who did not receive omalizumab in a real-world setting., Methods: This study used 5 years of data from patients ages ≥12 years old with moderate-to-severe persistent allergic asthma who were enrolled in the Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma observational study. Asthma control was assessed with the Asthma Control Test for 5 years, and asthma-related work, school, and activity impairment was measured with the Work Productivity/Activity Impairment-Asthma questionnaire for the first 2 years., Results: The percentage of patients treated with omalizumab (n = 4930) and with well-controlled asthma (Asthma Control Test score, >20) increased from 45% at baseline to 61% at month 60, and it was 49% (baseline) and 67% (month 60) for the non-omalizumab-treated cohort (n = 2779). For new starters to omalizumab (n = 576), the percentage with well-controlled asthma increased from 25% at baseline to 51% at month 6, and to 60% at month 60. Patients in the omalizumab-treated cohort and those in the non-omalizumab-treated cohort experienced a reduction in asthma-related work, school, and activity impairment. The amount of improvement in asthma control achieved and the reduction in asthma-related work, school, and activity impairment were similar, regardless of asthma severity., Conclusion: On average, patients in the Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma observational study who initiated omalizumab experienced clinically significant improvement in asthma control, which was observed within 6 months and persisted for 5 years.

Background: Adherence to omalizumab is not well characterized and its association with asthma control has not been well established., Objective: To evaluate adherence in patients initiating omalizumab in the Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate to Severe Asthma (EXCELS) observational study., Methods: Adherence was assessed over 5 years using the proportion of patients who missed any dose, rates of doses missed, and proportions of patients with good (<10% doses missed) or poor (≥30% doses missed) adherence. Multivariable analyses identified independent predictors of good adherence. Associations between adherence and asthma control were assessed using the minimum important difference for the Asthma Control Test at various time points., Results: A total of 289 patients newly initiated on omalizumab completed 5 years of EXCELS. Of these, 83.0% on the 2-week dosing regimen (n = 152) and 65.0% on the 4-week dosing regimen (n = 137) missed at least 1 dose. More frequent dosing was associated with a larger number of missed doses. Older age (odds ratio per year 1.02, 95% confidence interval 1.01-1.03) and lower prebronchodilator percentage of predicted forced expiratory volume in 1 second (<76; odds ratio 1.88, 95% confidence interval 1.09-3.24) were independent predictors of good adherence., Conclusion: Adherence to omalizumab is characterized by distinct factors. Patients receiving the 4-week dosing regimen achieved better adherence than those treated every 2 weeks. Improved adherence could be associated with better asthma control. Age and lung function could interact with dosing frequency to affect patient adherence, thus warranting prospective planning at the time of prescribing to support long-term adherence., (Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Omalizumab is a recombinant humanized monoclonal anti-IgE antibody approved in adults and adolescents with moderate-to-severe persistent allergic asthma inadequately controlled with inhaled corticosteroids (ICS). EXCELS is an ongoing prospective observational cohort study of approximately 5000 omalizumab-treated and >2800 non-omalizumab-treated patients aged ≥12 years., Objective: We evaluated concomitant medication use changes (total ICS dose [including monotherapy and combination therapy, fluticasone equivalent], short-acting beta-agonists [SABA], and leukotriene modifier [LTM]) over 2 years among subsets of patients enrolled in EXCELS., Methods: Patient subsets included "new starts" (omalizumab initiated at baseline [n = 549], "established users" (omalizumab initiated >7 days before baseline [n = 4421]), and "non-omalizumab" patients (not treated with omalizumab [n = 2867])., Results: At baseline, mean ± SD total daily ICS doses were 680 ± 414 μg/d in new starts, 642 ± 431 μg/d in established users, and 548 ± 382 μg/d in non-omalizumab patients. From baseline through year 2, total ICS dose decreased in 65% of new starts (mean ± SD change, -393 ± 504 μg/d), 57% of established users (-287 ± 492 μg/d), and 54% of non-omalizumab patients (-232 ± 431 μg/d). At baseline, SABA use for new starts, established users, and non-omalizumab patients was 1.9, 1.3, and 1.4 puffs/d, respectively. At year 2, SABA use decreased in 65% of new starts, 55% of established users, and 54% of non-omalizumab patients. At year 2, LTM dose decreased in 52% of new starts, 44% of established users, and 40% of non-omalizumab patients., Conclusion: Omalizumab therapy initiation was associated with decreased doses of ICS, SABA, and LTM over 2 years of follow-up for the majority of patients in a "real-world" cohort study of moderate-to-severe allergic asthma patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The goal of this study was to determine the association of multiple antibiotic-resistant Pseudomonas aeruginosa (MARPA) acquisition with lung function decline in patients with cystic fibrosis (CF)., Methods: Using data from Epidemiologic Study of Cystic Fibrosis (ESCF), we identified patients with spirometry data and MARPA, defined as PA (1) resistant to gentamicin and either tobramycin or amikacin, and (2) resistant to ≥1 antipseudomonal beta lactam. MARPA had to be detected in a respiratory culture after ≥2 years of PA-positive but MARPA-negative respiratory cultures. Multivariable piecewise linear regression was performed to model the annual rate of decline in forced expiratory volume in 1 second (FEV(1)) % predicted 2 calendar years before and after the index year of MARPA detection, adjusting for patient characteristics and CF therapies., Results: In total, 4349 patients with chronic PA and adequate PFT data were identified; 1111 subsequently developed MARPA, while 3238 patients were PA positive but MARPA negative. Compared with patients who did not acquire MARPA, MARPA-positive patients had lower FEV(1) and received more oral (p<0.013) and inhaled (p<0.001) antibiotic therapy. Mean FEV(1) decline did not change significantly after MARPA detection (-2.22% predicted/year before detection and -2.43 after, p=0.45). There was no relationship between persistent infection or FEV(1) quartile and FEV(1) decline., Conclusions: Newly detected MARPA was not associated with a significant change in the rate of FEV(1) decline. These results suggest that MARPA is more likely to be a marker of more severe disease and more intensive therapy, and less likely to be contributing independently to more rapid lung function decline., (Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The severity of asthma (SOA) score is based on a validated disease-specific questionnaire that addresses frequency of asthma symptoms, use of systemic corticosteroids, use of other asthma medications, and history of hospitalization/intubation for asthma. SOA does not require measurements of pulmonary function. This study compared the ability of SOA to predict clinical outcomes in the EXCELS (Epidemiological Study of Xolair [omalizumab]: Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate to Severe Asthma) patient population vs three other asthma assessment tools. EXCELS is a large, ongoing, observational study of patients with moderate to severe persistent asthma and reactivity to perennial aeroallergens., Methods: Baseline scores for SOA, asthma control test (ACT), work productivity and impairment index-asthma (WPAI-A), and FEV(1) % predicted were compared for their ability to predict five prespecified adverse clinical outcomes in asthma: serious adverse events (SAEs) reported as exacerbations, SAEs leading to hospitalizations, the incidence of unscheduled office visits, ED visits, and po or IV corticosteroid bursts related to asthma. Logistic regression analysis, area under receiver operating characteristic curves (AUCROCs), and classification and regression tree (CART) analysis were used to evaluate the ability of the four tools to predict adverse clinical outcomes using baseline and 1-year data from 2,878 patients enrolled in the non-omalizumab cohort of EXCELS., Results: SOA was the only assessment tool contributing significantly in all five statistical models of adverse clinical outcomes by logistic regression analysis (full model AUCROC range, 0.689-0.783). SOA appeared to be a stand-alone predictor for four of five outcomes (reduced model AUCROC range, 0.689-0.773). CART analysis showed that SOA had the greatest variable importance for all five outcomes., Conclusions: SOA score was a powerful predictor of adverse clinical outcomes in moderate to severe asthma, as evaluated by either logistic regression analysis or CART analysis., Trial Registry: ClinicalTrials.gov; No.: NCT00252135; URL: www.clinicaltrials.gov.

We consider a class of futility rules based on a Bayesian approach for computing the predictive probability of success for large clinical trials, given a certain amount of observed data. This paper focuses on outcomes trials in particular, thus we are concerned with binary response variables. The proposed method determines the likelihood of observing a statistically significant treatment effect at the end of a study, conditional on the data observed at an interim time point and assuming that event rates governing future observations follow beta distributions. In particular, the prior distributions for the event rates of interest are updated based on the observed data at an interim time point, such that means and variances are intuitive functions of the data. Computational aspects will be discussed for the case in which event counts are functions of sample size and event rates only, and for situations in which they are functions of sample size, event rates, and exposure duration. We will discuss appropriate thresholds for declaring futility based on this approach, and the potential impact of overdispersion, a common phenomenon particularly in global outcomes trials.