BACKGROUND:The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) assessed the long-term safety of omalizumab in a clinical practice setting as part of a phase IV US Food and Drug Administration postmarketing commitment. OBJECTIVE:We sought to evaluate long-term safety in omalizumab-treated and nonomalizumab-treated patients. Primary outcome measures focused on assessment of malignancies. METHODS:EXCELS was a prospective observational cohort study in patients (≥12 years of age) with moderate-to-severe allergic asthma. There were 2 cohorts: omalizumab (taking omalizumab at baseline) and nonomalizumab (no history of omalizumab treatment). Primary outcomes included all confirmed, incident, study-emergent primary malignancies (malignancies), including and excluding nonmelanoma skin cancer (NMSC); all malignancies were externally adjudicated. RESULTS:The omalizumab cohort had a higher proportion of patients with severe asthma compared with the nonomalizumab cohort (50.0% vs 23.0%). Median follow-up was approximately 5 years for both cohorts. Crude malignancy rates were similar in the omalizumab and nonomalizumab cohorts, with a rate ratio of 0.84 (95% CI, 0.62-1.13) for all malignancies and 0.98 (95% CI, 0.71-1.36) for all malignancies excluding NMSC. Kaplan-Meier plots of time to first confirmed study-emergent primary malignancy were similar for the 2 treatment cohorts. Cox proportional hazards modeling, adjusting for confounders and risk factors, resulted in a hazard ratio (omalizumab vs nonomalizumab) of 1.09 (95% CI, 0.87-1.38) for all malignancies and 1.15 (95% CI, 0.83-1.59) for all malignancies excluding NMSC. CONCLUSION:Results from EXCELS suggest that omalizumab therapy is not associated with an increased risk of malignancy.

Background:Adjustment for differing risks among patients is usually incorporated into newer payment approaches, and current risk models rely on age, sex, and diagnosis codes. It is unknown the extent to which controlling additionally for disease severity improves cost prediction. Failure to adjust for within-disease variation may create incentives to avoid sicker patients. We address this issue among patients with chronic obstructive pulmonary disease (COPD). Methods:Cost and clinical data were collected prospectively from 1202 COPD patients at Kaiser Permanente. Baseline analysis included age, sex, and diagnosis codes (using the Diagnostic Cost Group Relative Risk Score) in a general linear model predicting total medical costs in the following year. We determined whether adding COPD severity measures—forced expiratory volume in 1 second, 6-Minute Walk Test, dyspnea score, body mass index, and BODE Index (composite of the other 4 measures)—improved predictions. Separately, we examined household income as a cost predictor. Results:Mean costs were $12,334/y. Controlling for Relative Risk Score, each ½ SD worsening in COPD severity factor was associated with $629 to $1135 in increased annual costs (all P<0.01). The lowest stratum of forced expiratory volume in 1 second (<30% normal) predicted $4098 (95% confidence interval, $576–$8773) additional costs. Household income predicted excess costs when added to the baseline model (P=0.038), but this became nonsignificant when also incorporating the BODE Index. Conclusions:Disease severity measures explain significant cost variations beyond current risk models, and adding them to such models appears important to fairly compensate organizations that accept responsibility for sicker COPD patients. Appropriately controlling for disease severity also accounts for costs otherwise associated with lower socioeconomic status.

Background: Since initial registration, the omalizumab clinical trial database has expanded considerably, with a doubling of patients exposed in the clinical trial environment. Previous pooled data (2003) from phase I to III studies of omalizumab showed a numeric imbalance in malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%). The previous analysis was based on limited available data, warranting further investigation.Objective: We sought to examine the incidence of malignancy using comprehensive pooled data from clinical trials of omalizumab-treated patients.Methods: This pooled analysis included data from 67 phase I to IV clinical trials. The prespecified primary analysis assessed the incidence of primary malignancy in 32 randomized, doubleblind, placebo-controlled (RDBPC) trials.Results: There were 11,459 unique patients in all clinical trials (7,789 received omalizumab). The primary analysis identified malignancies in 25 patients (RDBPC trials): 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients. Incidence rates per 1,000 patient-years of observation time for omalizumab-and placebo-treated patients were 4.14 (95% CI, 2.26-6.94) and 4.45 (95% CI, 2.22-7.94), respectively; the corresponding rate ratio was 0.93 (95% CI, 0.39-2.27). Primary malignancies were of varying histologic type and occurred in a number of different organ systems; no cluster of histologies was identified.Conclusions: In this pooled analysis no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials; the rate ratio was below unity. The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely. (J Allergy Clin Immunol 2012;129:983-9.)

BACKGROUND:Obesity contributes to respiratory symptoms and exercise limitation, but the relationships between obesity, airflow obstruction (AO), respiratory symptoms and functional limitation are complex. AIMS:To determine the relationship of obesity with airflow obstruction (AO) and respiratory symptoms in adults without a previous diagnosis of chronic obstructive pulmonary disease (COPD). METHODS:We analysed data for potential referents recruited to be healthy controls for an ongoing study of COPD. The potential referents had no prior diagnosis of COPD or healthcare utilisation attributed to COPD in the 12 months prior to recruitment. Subjects completed a structured interview and a clinical assessment including body mass index, spirometry, six-minute walk test (SMWT), and the Short Performance Physical Battery (SPPB). Multiple regression analyses were used to test the associations of obesity (body mass index >30 kg/m2) and smoking with AO (forced expiratory volume in 1s/forced vital capacity ratio <0.7). We also tested the association of obesity with respiratory symptoms and impaired functional capacity (SPPB, SMWT), adjusting for AO. RESULTS:Of 371 subjects (aged 40-65 years), 69 (19%) had AO. In multivariate analysis, smoking was positively associated with AO (per 10 pack-years, OR 1.24; 95% CI 1.04 to 1.49) while obesity was negatively associated with AO (OR 0.54; 95% CI 0.30 to 0.98). Obesity was associated with increased odds of reporting dyspnoea on exertion (OR 3.6; 95% CI 2.0 to 6.4), productive cough (OR 2.5; 95% CI 1.1 to 6.0), and with decrements in SMWT distance (67 ± 9 m; 95% CI 50 to 84 m) and SPPB score (OR 1.9; 95% CI 1.1 to 3.5). None of these outcomes was associated with AO. CONCLUSIONS:Although AO and obesity are both common among adults without an established COPD diagnosis, obesity (but not AO) is linked to a higher risk of reporting dyspnoea on exertion, productive cough, and poorer functional capacity.

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 mono-therapy 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 mu g/d in new starts, 642 +/- 431 mu g/d in established users, and 548 +/- 382 mu g/d in non-omalizumab patients. From baseline through year 2, total ICS dose decreased in 65% of new starts (mean +/- SD change, -393 +/- 504 mu g/d), 57% of established users (-287 +/- 492 mu g/d), and 54% of non-omalizumab patients (-232 +/- 431 mu g/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. (c) 2012 Elsevier Ltd. All rights reserved.

Background: Omalizumab is a biologic for the treatment of moderate-to-severe persistent allergic asthma that is inadequately controlled with inhaled corticosteroids. At the time of FDA approval, the incidence of malignant neoplasms was higher among patients who had received omalizumab (0.5%) compared to placebo (0.2%) in clinical trials. Objective: The EXCELS study is an FDA postmarketing commitment to evaluate the long-term safety of omalizumab. Methods: EXCELS is an ongoing prospective observational study of approximately 5000 omalizumab-treated and 2500 non-omalizumab-treated moderate-to-severe persistent allergic asthma patients aged ≥12 years from 448 US centers who are followed for up to 5 years. All reported potential malignancies are reviewed by an independent oncology panel. The primary analysis includes confirmed, incident study-emergent primary malignancies. Results: This analysis of malignancy rates was based on interim study report 6 (data through 11/30/2010) which comprises 18,860 person-years in the omalizumab cohort and 10,947 person-years in the non-omalizumab cohort. Both cohorts had an average follow-up of 3.8 person-years. The incidence of study-emergent primary malignancy was 12.78 and 14.48 per 1000 person-years in the omalizumab and the non-omalizumab cohorts, respectively, corresponding to a rate difference of -1.70 per 1000 person-years (95% CI: -6.43 to 2.21). Conclusions: In this analysis, the incidence of malignancy was similar in the omalizumab and non-omalizumab cohorts. These interim results are preliminary and the study is still ongoing. Because the study is observational, selection and other biases cannot be excluded. Funding Source: Genentech, Inc and Novartis Pharmaceuticals Corp.

OBJECTIVES Cotinine is the most widely used biomarker to distinguish active versus passive smoking. However, there is an overlap in cotinine levels when comparing light or occasional smokers versus heavily exposed passive smokers. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a tobacco-specific nitrosamine measurable in urine with a much longer half-life than cotinine. The aim of the study was to determine optimal cutoff points to discriminate active versus passive smokers and to compare sensitivity and specificity for the use of cotinine, NNAL, and the ratio of the NNAL/cotinine in urine. METHODS Cotinine and NNAL were measured in urine of 373 active smokers and 228 passive smokers. RESULTS Geometric mean cotinine levels were 2.03 ng/ml (interquartile interval: 0.43-8.60) and 1,043 ng/ml (658-2,251) and NNAL levels were 5.80 pg/ml (2.28-15.4) and 165 pg/ml (90.8-360) pg/ml in passive and active smokers, respectively. NNAL/cotinine ratio in urine was significantly higher for passive smokers when compared with active smokers (2.85 vs. 0.16, p < .01). The receiver operating characteristics analysis determined optimal cutoff points to discriminate passive versus active smokers: 31.5 ng/ml for cotinine (sensitivity: 97.1% and specificity: 93.9%), 47.3 pg/ml for NNAL (87.4% and 96.5%), and 0.74 x 10⁻³ for NNAL/cotinine ratio (97.3% and 87.3%). CONCLUSIONS Both urine cotinine and NNAL are sensitive and specific biomarkers for discriminating the source of tobacco smoke exposure. Cotinine is the best overall discriminator when biomarkers are measured while a person has ongoing exposure to tobacco smoke. NNAL because of its long half-life would be particularly useful when there is a delay between exposure and biomarker measurement. The NNAL/cotinine ratio provides similar sensitivity but poorer specificity at discriminating passive versus active smokers when compared with NNAL alone.

Previous pooled data from the omalizumab clinical trial programme (Phase I–III clinical studies) showed a numerical imbalance in cancers arising in omalizumab recipients. The incidence of malignancies in the omalizumab group was similar to that expected in the general population but higher compared with control, raising a question over omalizumab9s long-term safety. To fully address this potential safety concern, a further analysis was conducted using additional pooled data to examine malignancy in omalizumab-treated patients. We used data from 32 randomized, double-blind, placebo-controlled trials (RDBPCTs) to assess incidence of primary malignancy. 7432 patients (4254 omalizumab, 3178 placebo) were included. Total observation times censored at first malignancy were 3382 and 2473 patient-years for omalizumab- and placebo-treated patients, respectively, including treatment exposure durations of 2143.9 and 1689.1 patient-years, respectively. Malignancy rates and corresponding changes in rate ratios over time are shown in the Table. No specific cluster of neoplasm was identified. Results of this pooled analysis show a progressive reduction of the rate ratio to below unity in cancers arising in the omalizumab group compared with control in RDBPCTs, and suggest that a causal relationship between omalizumab therapy and cancer is unlikely.

Background Although chronic obstructive pulmonary disease (COPD) is a common cause of death and disability, little is known about the effects of socioeconomic status (SES) and race-ethnicity on health outcomes.Methods The aim of this study is to determine the independent impacts of SES and race-ethnicity on COPD severity status, functional limitations and acute exacerbations of COPD among patients with access to healthcare. Data were used from the Function, Living, Outcomes and Work cohort study of 1202 Kaiser Permanente Northern California Medical Care Plan members with COPD.Results Lower educational attainment and household income were consistently related to greater disease severity, poorer lung function and greater physical functional limitations in cross-sectional analysis. Black race was associated with greater COPD severity, but these differences were no longer apparent after controlling for SES variables and other covariates (comorbidities, smoking, body mass index and occupational exposures). Lower education and lower income were independently related to a greater prospective risk of acute COPD exacerbation (HR 1.5; 95% CI 1.01 to 2.1; and HR 2.1; 95% CI 1.4 to 3.4, respectively).Conclusion Low SES is a risk factor for a broad array of adverse COPD health outcomes. Clinicians and disease management programs should consider SES as a key patient-level marker of risk for poor outcomes.

Background: Matrix metalloproteinase-9 (MMP-9) may be important in the progression of emphysema, but there have been few longitudinal clinical studies of MMP-9 including pulmonary status and COPD exacerbation outcomes. Methods: We utilized data from the placebo arm (n = 126) of a clinical trial of patients with alpha1-antitrypsin deficiency (AATD) and emphysema to examine the links between plasma MMP-9 levels, pulmonary status, and COPD exacerbations over a one year observation period. Pulmonary function, computed tomography lung density, incremental shuttle walk test (ISWT), and COPD exacerbations were assessed at regular intervals over 12 months. Prospective analyses used generalized estimating equations to incorporate repeated longitudinal measurements of MMP-9 and all endpoints, controlling for age, gender, race-ethnicity, leukocyte count, and tobacco history. A secondary analysis also incorporated highly-sensitive C-reactive protein levels in predictive models. Results: At baseline, higher plasma MMP-9 levels were cross-sectionally associated with lower FEV1 (p = 0.03), FVC (p < 0.001), carbon monoxide transfer factor (p = 0.03), resting oxygen saturation (p = 0.02), and ISWT distance walked (p = 0.02) but were not associated with radiographic lung density or total lung capacity (TLC). In longitudinal analyses, MMP-9 predicted a further decline in transfer factor (p = 0.04) and oxygen saturation (p < 0.001). MMP-9 also predicted worsening lung density (p = 0.003), increasing TLC (p = 0.02), and more frequent COPD exacerbations over follow-up (p = 0.003). Controlling additionally for hs-CRP levels did not substantively change the longitudinal associations between MMP-9 and these outcomes. Conclusions: Increased plasma MMP-9 levels generally predicted pulmonary status declines, including worsening transfer factor and lung density as well as greater COPD exacerbations in AATD-associated emphysema.

PURPOSE: Omalizumab is a recombinant humanized monoclonal anti-IgE antibody approved for the treatment of 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 2500 non-omalizumab-treated patients aged ≥12 years. This analysis evaluated the impact of omalizumab treatment on concomitant medication use (total ICS dose [including monotherapy and combination-therapy, fluticasone equivalent], short-acting beta agonists [SABA], and leukotriene receptor antagonists [LTRA]) over 2 years among subsets of patients enrolled in EXCELS.