Linda Nelsen

Adherence to Prescribed Treatment for Asthma: Evidence from Pharmacy Benefits Data

Background. Failure to use asthma controller medications as prescribed is associated with more asthma-related adverse events. Medication utilization may vary with ease of drug administration, efficacy, and tolerability as well as other factors. We hypothesized that in usual-care clinical practice settings, there would be greater adherence to oral controller than to inhaled controller asthma medications. Methods. We compared adherence to newly initiated asthma controller therapy among patients initiating monotherapy with leukotriene receptor antagonists (LTRAs), inhaled corticosteroids (ICS), or inhaled long-acting β-agonists (ILBA) from 03 1998 to 07 1999. We measured adherence as the sum of drug supply days between first and last fill dates divided by length of drug therapy. Analyses were stratified by the number of short-acting β-agonists (SBA) prescriptions per year to control for disease severity. Results. Pharmacy claims data from 48,751 subjects (6 to 55 years) were analyzed (mean age 30.4 years; 56% female). Mean adherence to new start monotherapy on LTRA was 67.7%, to ICS was 33.8%, and to ILBA was 40.0%. Adherence to all three controller agents increased with increasing SBA use. The percent of patients persistent to asthma controller monotherapy at both 6 and 9 months was significantly greater among those on LTRA monotherapy than on either ICS or ILBA. Conclusions. In clinical practice settings, patients initiating LTRA monotherapy have about twice the adherence as patients initiating ICS or ILBA monotherapy. Because adherence to treatment is a critical component of treatment response, it is important to consider this factor in the prescription of oral vs. inhaled asthma medications.

Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial

BACKGROUND Mepolizumab, an anti-interleukin-5 monoclonal antibody approved as add-on therapy to standard of care for patients with severe eosinophilic asthma, has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo. We aimed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life (HRQOL). METHODS We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial (MUSCA) in 146 hospitals or research centres in 19 countries worldwide. Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines. Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years. We randomly assigned participants (1:1) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo, plus standard of care, every 4 weeks for 24 weeks (the final dose was given at week 20). We did the randomisation using an interactive voice response system and a centralised, computer-generated, permuted-block design of block size six. The two treatments were identical in appearance and administered in a masked manner; patients, investigators, other site staff and the entire study team including those assessing outcomes data were also masked to group assignment. The primary endpoint was the mean change from baseline in the St Georges Respiratory Questionnaire (SGRQ) total score at week 24 in the modified intention-to-treat (modified ITT) population (analysed according to their randomly assigned treatment). Safety was assessed in all patients who received at least one dose of trial medication (analysed according to the actual treatment received). This trial is registered with ClinicalTrials.gov, number NCT02281318. FINDINGS We recruited patients between Dec 11, 2014, and Nov 20, 2015, and the study was undertaken between Dec 11, 2014, and June 10, 2016. The modified ITT population comprised 274 patients assigned to mepolizumab 100 mg and 277 assigned to placebo. Mepolizumab versus placebo showed significant improvements at week 24 from baseline in SGRQ total score (least squares mean [SE] change from baseline -15·6 (1·0) vs -7·9 (1·0), a treatment difference of -7·7 (95% CI -10·5 to -4·9; p<0·0001). No deaths occurred during the study. 192 (70%) of 273 patients who received mepolizumab and 207 (74%) of 278 who received placebo reported at least one on-treatment adverse event, the most common of which were headache (in 45 [16%] given mepolizumab vs 59 [21%] given placebo) and nasopharyngitis (in 31 [11%] given mepolizumab vs 46 [17%] given placebo). 15 (5%) and 22 (8%) patients had an on-treatment serious adverse event in the mepolizumab and placebo groups, respectively; the most common was asthma in both groups (in three [1%] given mepolizumab vs nine [3%] given placebo). INTERPRETATION Mepolizumab was associated with significant improvements in HRQOL in patients with severe eosinophilic asthma, and had a safety profile similar to that of placebo. These results add to and support the use of mepolizumab as a favourable add-on treatment option to standard of care in patients with severe eosinophilic asthma. FUNDING GlaxoSmithKline.

Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials

BackgroundSymptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT – Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms.MethodsThis study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset.ResultsIn each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearmans rho; p < 0.01, all comparisons listed here): FEV1% predicted (-0.19, -0.14, -0.15); St. Georges Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (-0.30, -0.14) and incremental shuttle walk (ISWT) (-0.18) tests. Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity. RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p < 0.0001). RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p < 0.0001). Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed.ConclusionsResults suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials.Trial registrationMPEX: NCT00739648; AZ1: NCT00949975; AZ 2: NCT01023516

Intermittent or daily montelukast versus placebo for episodic asthma in children

BACKGROUND No standard, optimal treatment exists for severe intermittent (ie, episodic) asthma in children. However, evidence suggests that both daily and episode-driven montelukast are effective for this phenotype. OBJECTIVE To assess the regimen-related efficacy of montelukast in treating pediatric episodic asthma. METHODS A multicenter, randomized, double-blind, double-dummy, parallel-group, 52-week study was performed in children 6 months to 5 years of age comparing placebo with two regimens of montelukast 4 mg: (1) daily; or (2) episode-driven for 12 days beginning with signs/symptoms consistent with imminent cold or breathing problem. The main outcome measure was the number of asthma episodes (symptoms requiring treatment) culminating in an asthma attack (symptoms requiring physician visit, emergency room visit, corticosteroids, or hospitalization). RESULTS Five hundred eighty-nine patients were randomized to daily montelukast, 591 to intermittent montelukast, and 591 to placebo. Compared with placebo, no significant difference was seen between daily montelukast (P = .510) or intermittent montelukast (P = .884) in the number of asthma episodes culminating in an asthma attack over 1 year. Daily montelukast reduced symptoms over the 12-day treatment period of asthma episodes compared with placebo (P = .045). Beta-agonist use was reduced with both daily (P = .048) and intermittent montelukast (P = .028) compared with placebo. However, because of prespecified rules for multiplicity adjustments (requiring a positive primary endpoint), statistical significance for secondary endpoints cannot be concluded. All treatments were well tolerated. CONCLUSIONS Montelukast did not reduce the number of asthma episodes culminating in an asthma attack over 1 year in children 6 months to 5 years of age, although numerical improvements occurred in some endpoints.

Measuring respiratory symptoms in clinical trials of COPD: reliability and validity of a daily diary

Background Although respiratory symptoms are characteristic features of COPD, there is no standardised method for quantifying their severity in stable disease. Objective To evaluate the EXACT-Respiratory Symptom (E-RS) measure, a daily diary comprising 11 of the 14 items in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT). Methods Qualitative: patient focus group and interviews to address content validity. Quantitative: secondary data analyses to test reliability and validity. Results Qualitative: n=84; mean (SD) age 65 (10) years, FEV1 1.2(0.4) L; 44% male. Subject descriptions of their respiratory symptoms were consistent with E-RS content and structure. Quantitative: n=188; mean (SD) age 66 (10) years, FEV1 1.2(0.5) L; 50% male. Factor analysis (FA) showed 3 subscales: RS-Breathlessness, RS-Cough & Sputum, and RS-Chest Symptoms; second-order FA supported a general factor and total score. Reliability (total and subscales): 0.88, 0.86, 0.73, 0.81; 2-day test-retest ICC: 0.90, 0.86, 0.87, 0.82, respectively. Validity: Total scores correlated significantly (p < 0.0001) with SGRQ Total (r=0.75), Symptoms (r=0.66), Activity (r=0.57), Impact (r=0.70) scores; subscale correlations were also significant (r=0.26, p < 0.05 (RS-Chest Symptoms with Activity) to r=0.69, p < 0.0001 (RS-Cough & Sputum with Symptoms). RS-Breathlessness correlated with rescue medication use (r=0.32, p < 0.0001), clinician-reported mMRC (r=0.33, p < 0.0001), and FEV1% predicted (r=-0.17, p < 0.05). E-RS scores differentiated groups based on chronic bronchitis diagnosis (p < 0.01–0.001), smoking status (p < 0.05–0.001), and rescue medication use (p < 0.05–0.0001). Conclusions Results suggest the RS-Total is a reliable and valid instrument for evaluating respiratory symptom severity in stable COPD. Further study of sensitivity to change is warranted.

Outcomes Associated with Initiation of Different Controller Therapies in a Medicaid Asthmatic Population: A Retrospective Data Analysis

Background. Outcomes in asthmatic patients may vary depending on the controller medication used. Observational studies of outcomes of asthma therapy are needed to understand the implications of choice of controller in different populations. Objectives. To determine whether there are differences in health care use and costs of asthma treatment in asthma patients treated with montelukast compared with fluticasone proponiate 44 µg. Method. Using data from the North Carolina Medicaid program, we compared continuously enrolled asthmatic patients starting either fluticasone propionate 44 µg (FP44), an inhaled corticosteroid (ICS) (n = 312), or montelukast 5 and 10 mg, an oral leukotriene modifier (LM) (n = 398) between the years 1998 and 1999. A secondary analysis compared continuously enrolled asthmatic patients already using ICS as controller therapy initiating either salmeterol (long-acting β-agonist) (n = 97) or montelukast (n = 101) in the year 1998. Patients were followed for 1 year pre- and postcontroller or additional controller initiation for health care service use, medication refill patterns, and costs. Results. There were no significant differences in the adjusted asthma-related health care costs between the montelukast and FP44 groups. In both groups, physician visits were significantly higher in year 2 (p < 0.01) than in year 1. We found montelukast users to be more adherent with prescription refills (using measures of medication possession) even after allowing for a wider adherence range for FP (RR = 2.53; 95% CI = 1.50–4.26), although patients using montelukast were more likely than patients with fluticasone to switch controller pharmacotherapy (RR = 1.53; 95% CI = 1.12–2.09). Similarly, there were no differences in health care service use and costs between the montelukast and salmeterol groups, with the exception of a 33% reduction (p < 0.01) in number of inhaled corticosteroid refills in the second year in the salmeterol group. Conclusion. There were no cost and major health care use differences between the two primary or secondary controller therapies in the postinitiation year. Although FP was associated with lower rate of controller switch, montelukast use was associated with significantly better treatment adherence in patients with treatment persistence in this population of Medicaid-enrolled asthmatic patients. The addition of salmeterol as additional controller was associated with a significant decrease in inhaled corticosteroid use, suggesting decreased adherence in patients on the two-drug regimen.

Seasonal patterns in health care use and pharmaceutical claims for asthma prescriptions for preschool- and school-aged children.

BACKGROUND In children, hospitalization for asthma is reported to have a distinct seasonal pattern with peaks coincident with the start of school. Although guidelines indicate that asthma controller medications should be used daily, there is limited information on actual seasonal patterns of medication use. OBJECTIVE To describe seasonal patterns of asthma-related health care use and asthma controller and reliever medication claims in children. METHODS An ecological analysis was conducted of data collected from records for children aged 2 to 12 years from 2002 through 2004 from an automated research database of insurance claims from a large US health care plan. Seasonal patterns for health care use and estimates of prescription asthma controller and reliever use were determined for preschool-aged children (aged 2-5 years) and school-aged children (aged 6-12 years). Rates were constructed by week; deviations from annual mean rates were used to determine peaks in use. Results were confirmed using Poisson regression models, modeling for rates within age group, with factors for week, year, and regions. RESULTS Emergency department and outpatient visits and hospitalizations were lowest during summer; rates increased beginning in September, peaking in October or November. Asthma controller and reliever medication claims increased beginning in September, peaking in December. Rates also were elevated in February. CONCLUSIONS The data suggest that children who reduce their asthma medications during the summer do not resume taking medications until signs or symptoms of asthma worsen. The summer hiatus and other factors may contribute to seasonal increases in health care use and in asthma medication prescriptions, particularly in the fall.

Congenital malformations among infants born to women receiving montelukast, inhaled corticosteroids, and other asthma medications

0 5 min Epinephrine 1:1000, 0.3 mL SQ PF 420 Loratadine, 10 mg po 10 min Prednisone, 50 mg po BP 102/50, HR 88, RR 18 15 min BP 102/60 17 min Epinephrine 1:1000, 0.3 mL SQ Loratadine, 10 mg PF 420 25 min BP 102/58, PF 440 27 min Epinephrine 1:1000, 0.3 mL SQ BP 102/64, HR 96 37 min Hep-Lock placed with 18-gauge needle 42 min BP 112/72, HR 102, PF 430 47 min Epinephrine 1:1000, 0.3 mL SQ 70 min Epinephrine 1:1000, 0.3 mL SQ BP 142/78, HR 70, PF 460 74 min Diphenhydramine, 25 mg po 87 min BP 138/88, HR 86, PF 460 104 min BP 142/90, HR 90, PF 460 122 min BP 146/90, HR 80, PF 460 150 min Admitted to ward BP 142/90, HR 82, PF 450

Key Concepts of Migraine Postdrome: A Qualitative Study to Develop a Post‐Migraine Questionnaire

(Headache 2011;51:105‐117)

The asthma disease activity score: a discriminating, responsive measure predicts future asthma attacks.

BACKGROUND Classifying asthma severity or activity has evolved, but there are no published weighted composite measures of asthma disease activity that account for the relative importance of the many individual clinical variables that are widely used. OBJECTIVES We sought to develop a weighted and responsive measure of asthma disease activity. METHODS Discriminant and multiple regression analyses based on 2 previously conducted clinical trials were used to develop the Asthma Disease Activity Score (ADAS-6). RESULTS The ADAS-6 demonstrated content validity because its components assess different manifestations of asthma: FEV(1) (percent predicted), Asthma Quality of Life Questionnaire-Symptom domain, rescue β-agonist use, nocturnal awakenings, peak expiratory flow diurnal variability, and rescue β-agonist use diurnal variability. The ADAS-6 demonstrated cross-sectional and longitudinal validity. It was discriminating: it distinguished levels of disease activity and response to different treatment intensities (P < .0001). Similar results were obtained with an independent clinical trial. The ADAS-6 was highly responsive to treatment effects, with a standardized effect size exceeding that of other widely used outcome measures. Using ADAS-6 as the primary end point in the montelukast pivotal trials would have significantly reduced the sample size needed to detect a comparable change in outcome. Furthermore, increments in the ADAS-6 predicted the risk of future asthma attacks. A simplified Asthma Disease Activity Score 4-variable version (ADAS-4) demonstrated similar measurement properties. CONCLUSIONS The ADAS-6 and ADAS-4 are novel, weighted, and responsive measures of asthma disease activity. Use of these measures in clinical trials might better separate treatment effects, predict future asthma attacks, and substantially reduce sample size.