James L. Zazzali

Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy

BACKGROUND Patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) often continue to experience symptoms despite receiving standard-of-care therapy with H1-antihistamines along with 1 or more add-on therapies. OBJECTIVES We sought to evaluate the safety and efficacy of 24 weeks of treatment with omalizumab in patients with persistent CIU/CSU despite treatment with H₁-antihistamines at up to 4 times the approved dose plus H₂-antihistamines, leukotriene receptor antagonists, or both. METHODS In this phase III study patients were randomized to receive 6 subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo, followed by a 16-week observation period. The primary objective of the study was to evaluate the overall safety of omalizumab compared with placebo. Efficacy (itch severity, hive, and urticaria activity scores) was evaluated at weeks 12 and 24. RESULTS The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients; the safety profile was consistent with omalizumab in patients with allergic asthma. At week 12, the mean change from baseline in weekly itch severity score was -8.6 (95% CI, -9.3 to -7.8) in the omalizumab group compared with -4.0 (95% CI, -5.3 to -2.7) in the placebo group (P < .001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24. CONCLUSION Omalizumab was well tolerated and reduced the signs and symptoms of CIU/CSU in patients who remained symptomatic despite the use of H₁-antihistamines (up to 4 times the approved dose) plus H₂-antihistamines, leukotriene receptor antagonists, or both.

Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab

Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial. All patients underwent MRI and neurocognitive testing at baseline and every 6 weeks thereafter. Memory, visuomotor scanning speed, and executive function were evaluated using the Hopkins Verbal Learning Test-Revised, the Trail Making Test, and the Controlled Oral Word Association test, respectively. NCF relative to baseline for patients with an OR, PFS >6 months, or disease progression was evaluated at time of OR, 24 weeks, and time of progression, respectively. For patients with an OR or PFS >6 months, median standardized test scores were examined from baseline to week 24. Most patients with an OR or PFS >6 months had poorer NCF performance compared to the general population at baseline and had improved or stable NCF at the time of response or at the 24-week assessment, respectively; most patients with progressive disease had neurocognitive decline at the time of progression. For patients with an OR or PFS >6 months, median standardized test scores were largely stable across the first 24 weeks on study. Neurocognitive testing was an objective, valid, and feasible method of monitoring NCF in patients with recurrent glioblastoma.

Evaluating the minimally important difference of the urticaria activity score and other measures of disease activity in patients with chronic idiopathic urticaria

BACKGROUND The Urticaria Activity Score (UAS) is a widely used patient-reported outcome measure for patients with chronic idiopathic urticaria (CIU) that includes 2 items: intensity of pruritus and number of hives. Items are scored individually, and the UAS7 is calculated as the sum of pruritus and number of hives over 1 week. Recently, its instructions were enhanced. OBJECTIVE To assess the measurement properties of the enhanced UAS. METHODS Seventy-three subjects with CIU completed the UAS with enhanced instructions, other measures of disease activity including the size of the largest hive, and collateral measures during a multicenter, randomized, double-blind, placebo-controlled study of omalizumab for the treatment of CIU. The minimal important difference (MID) was estimated through distribution- and anchor-based approaches. Test-retest reliability was assessed with the intraclass correlation coefficient (ICC); internal consistency reliability was evaluated with Cronbachs alpha; 3 responsiveness coefficients were calculated; known groups validity was assessed based on physician in-clinic UAS scores; and construct validity was assessed through Spearman correlation coefficients with collateral measures. RESULTS The MID ranged from 9.5 to 10.5 for the UAS7, 5.0 to 5.5 for number of hives (weekly average), and 4.5 to 5.0 for pruritus and size of largest hive (weekly average). Internal consistency was supported by alpha coefficients greater than 0.80. The ICC values for test-retest reliability ranged from 0.602 to 0.884. For subjects on active treatment, responsiveness coefficients were greater than 0.80. Known-groups validity was supported for most UAS scores; and construct validity was demonstrated by relationships with collateral measures. CONCLUSIONS The enhanced UAS has adequate measurement properties to support its use in clinical research.

Cost, utilization, and patterns of medication use associated with chronic idiopathic urticaria

BACKGROUND The literature on chronic idiopathic urticaria (CIU) lacks large-scale population-based studies. OBJECTIVE To characterize an insured population with CIU, including their demographic characteristics and comorbidities. METHODS We conducted a cross-sectional analysis using insurance claims. We included patients with 1 outpatient claim with an International Classification of Diseases, 9(th)Edition, Clinical Modification (ICD-9-CM) code for idiopathic, other specified, or unspecified urticaria (ICD-9-CM 708.1, 708.8, or 708.9) and either (1) another of these claims 6 or more weeks later; (2) a claim for angioedema (ICD-9-CM 995.1) 6 or more weeks from the urticaria diagnosis; or (3) overlapping claims for 2 prescription medications commonly used for CIU. RESULTS We identified 6,019 patients who had claims consistent with CIU. The mean age was 36 years. Fifty-six percent of patients had primary care physicians as their usual source of care, 14% had allergists, and 5% had dermatologists. Allergic rhinitis was diagnosed in 48%, asthma in 21%, other allergy in 19%, and atopic dermatitis in 8%. Sixty-seven percent of patients used prescription antihistamines, 54% used oral corticosteroids (OCSs), 24% used montelukast, and 9% used oral doxepin. Antihistamine users received a mean of 152 days of prescription antihistamines, OCS users 30 days of OCSs, montelukast users 190 days of montelukast, and oral doxepin users 94 days of doxepin. CONCLUSIONS Primary care physicians managed most patients with CIU. Antihistamines were the most common treatment for CIU, although OCSs were frequently prescribed. Thirty days of OCS supply among users may represent multiple steroid bursts each year. Given the known risks of OCSs, identifying other CIU treatments with more favorable safety profiles may be beneficial.

Longitudinal Changes in Asthma Control with Omalizumab: 2-Year Interim Data from the EXCELS Study

Background. Asthma guidelines emphasize the importance of achieving and maintaining asthma control; however, many patients with moderate to severe asthma fail to achieve adequate control. Objective. This 2-year interim analysis evaluated the longitudinal effects of omalizumab on asthma control in patients treated in real-world clinical practice settings. Methods. EXCELS is an ongoing observational cohort study of approximately 5000 omalizumab-treated and 2500 non-omalizumab-treated patients aged ≥12 years with moderate to severe asthma. Asthma control was measured using the Asthma Control Test (ACT) every 6 months. Results. Subgroups of the omalizumab cohort included those who initiated omalizumab at baseline (new starts, n = 549) and those treated with omalizumab >7 days before baseline (established users, n = 4421). For reference, data are also presented for patients who were not receiving omalizumab prior to or at the time of enrolment (non-omalizumab, n = 2867). Over half of the new starts (54%) achieved improvement in ACT consistent with the minimally important difference (MID, defined as ≥3-point improvement) by Month 6 and this proportion increased throughout the follow-up period, reaching 62% at Month 24. Similar results were observed in patients stratified by moderate and severe asthma. Established users of omalizumab maintained asthma control throughout the observation period. Conclusion. Over a 2-year period, patients initiating omalizumab therapy experienced clinically relevant improvements in asthma control, which were maintained during 2 years of longitudinal follow-up. Established users of omalizumab maintained asthma control over the 2-year period with a small improvement similar to that seen in non-omalizumab users.

Risk of corticosteroid-related adverse events in asthma patients with high oral corticosteroid use.

BACKGROUND Oral corticosteroids (OCS) are a mainstay of asthma treatment. Their use increases the risk of various corticosteroid-related adverse events, but the extent of risk is poorly characterized. OBJECTIVE To determine the incremental risk of possible corticosteroid-related adverse events (AE) in asthma among patients with high OCS use compared with patients who do not use OCS. METHODS Patients with asthma in a commercial health care claims data base who were high-OCS users (≥30 days of OCS use annually) were matched to no-OCS users by age, sex, and geographic region, and the presence or absence of chronic obstructive pulmonary disease (COPD) as a comorbidity. We examined bone-related conditions, pneumonia, opportunistic infections, diabetes mellitus, and other disorders as potential AEs by using χ(2) tests to compare potential AE prevalence between the cohorts, with and without stratification by a COPD diagnosis. We controlled for the number of inhaled steroids (ICS) canisters filled. RESULTS A total of 3604 patients with asthma and high OCS use were matched to 3604 patients who did not use OCS (mean age, 54.4; 68.1% female; 44.9% with COPD). Patients with high OCS use had statistically significantly higher rates of any potential AE compared with patients who did not use OCS (83.5% versus 78.1%), (p < 0.001). Rates of individual potential AEs were also higher in patients who used higher doses of OCS. Patterns of AEs were similar in patients with and those without COPD, with statistically significantly higher overall AE risk and individual risks in high-OCS users. The number of ICS canisters filled was not a significant predictor of AE. CONCLUSION Patients with asthma who were treated with OCS for ≥30 days per year have a greater overall risk of possible corticosteroid-related AEs compared with those patients with no OCS use, whether or not they had COPD.

Adaptation and validation of the Urticaria Patient Daily Diary for adolescents.

The Urticaria Patient Daily Diary, including the Urticaria Activity Score, has recently been validated in adults with chronic idiopathic urticaria (CIU), but its validity in adolescents is unknown. This study was designed to (1) assess the content validity of the Adolescent Urticaria Patient Daily Diary and, (2) collect exploratory data on symptom experiences, sleep interference, and health-related quality of life (HRQOL) of adolescents with CIU. The Urticaria Patient Daily Diary was modified to increase its relevance with an adolescent population. A qualitative, cross-sectional, multicenter study was then conducted in the United States so that adolescent subjects could provide information on the impact of urticaria on their lives and comment on the diary. Data were collected via in-person semistructured interviews with subjects 12-17 years of age with moderate-to-severe CIU. The most bothersome symptom was itching (44%). The impact of CIU on HRQOL varied. The majority of subjects (78%) reported waking up at least once a night. Overall, subjects found the diary to be clear, easy to comprehend, and easy to complete. Revisions were made to the diary based on feedback from subjects. After nine interviews, no new information was received. The symptoms of CIU are bothersome to adolescents, particularly itch, and urticaria has a negative impact on the sleep of adolescent patients. The final Adolescent Urticaria Patient Daily Diary has evidence of content validity in patients with CIU ranging from 12 to 17 years of age.

Changes in asthma control, work productivity, and impairment with omalizumab: 5-year EXCELS study results.

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.

Omalizumab substantially improves dermatology-related quality of life in patients with chronic spontaneous urticaria

Chronic spontaneous/idiopathic urticaria (CSU/CIU) has substantial detrimental effects on health‐related quality of life (HRQoL) with an effect comparable to or worse than many other skin diseases.

Omalizumab adherence in an observational study of patients with moderate to severe allergic asthma.

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.