Baseline characteristics and secondary medication adherence among Medicare patients diagnosed with transthyretin amyloid cardiomyopathy and/or receiving tafamidis prescriptions: A retrospective analysis of a Medicare cohort.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed, life-threatening condition that mostly affects older persons. In May 2019, regulatory approval of tafamidis provided the first pharmacologic treatment of ATTR-CM. In the pivotal phase 3 Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), 97.2% of patients were classified as adherent (defined as taking ≥ 80% of scheduled doses). Given its recent approval, there is limited real-world evidence examining patient adherence to tafamidis. OBJECTIVE: To evaluate adherence patterns, demographics, and clinical characteristics of patients in the United States receiving tafamidis prescriptions through Medicare. Secondarily, we aimed to evaluate concomitant medications filled by this patient population. METHODS: We conducted a retrospective cohort study of US Medicare claims data, limited by the Health Insurance Portability and Accountability Act of 1996, in adult patients with an adjudicated pharmacy claim for tafamidis (tafamidis free acid 61-mg capsule once daily or tafamidis meglumine four 20-mg capsules once daily) between May 1, 2019, and June 30, 2021. Gaps in therapy were measured using day gaps between prescription refills and continuous measure of medication gaps. Implementation adherence was assessed through modified medication possession ratio (MPRm), medication refill adherence (MRA), and proportion of days covered (PDC). Patients were grouped based on Medicare coverage. Patients were analyzed by subgroups based on age and at the zip code level, via distressed communities index quartiles and rural-urban tiers. RESULTS: A total of 3,558 patients who received a prescription fill of a tafamidis formulation were identified using Medicare Fee-for-Service (FFS) and Medicare Advantage (MA) claims data from May 1, 2019, to June 30, 2021. The characteristics of this patient population were consistent with published literature, as 98.6% were older than 65 years, 53.4% were between 75 years and 84 years, and 81.5% were male. In the patient population receiving tafamidis refills, adherence was high across all 3 measures, with mean MPRm greater than 90% and mean MRA greater than 80%, across all age groups. Mean PDC adherence rates were 79% or more across all age groups. Concomitant medications were generally indicated for heart failure and thrombosis. Among monotherapy groups with similar demographic makeup, adherence was significantly higher among users of tafamidis free acid vs tafamidis meglumine (P < 0.0001 across all mean adherence measures). CONCLUSIONS: Our results demonstrate that real-world adherence to tafamidis in the Medicare population is high, regardless of age, zip code-level socioeconomic quartile, or geography. Adherence was higher among patients receiving tafamidis free acid, suggesting that the enhanced convenience of a single capsule once daily may positively contribute to adherence among patients with ATTR-CM. DISCLOSURES: Darrin Benjumea is an employee of Genesis Research who has been contracted by Pfizer, Inc., for involvement in this study. Andrew Peterson is an employee of University of the Sciences who has been contracted by Pfizer, Inc., for involvement in this study. Zach Bredl is an employee of Care Journey who has been contracted by Pfizer, Inc., for involvement in this study. Anuja Roy, Nick Marchant, Jose Alvir, Rahul Bhambri, Jason Kemner, and Bhash Parasuraman are employees of Pfizer, Inc., and own stock and/or stock options. This study was supported by Pfizer, Inc.

Baseline Characteristics and Secondary Medication Adherence Patterns Among Patients Receiving Tafamidis Prescriptions: A Retrospective Analysis Using a National Specialty Pharmacy Dispensing Database.

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a serious, underrecognized condition, which leads to heart failure and early mortality if left untreated. Until recently, heart transplantation was the only treatment for ATTR-CM. Regulatory approval of tafamidis transformed treatment for patients. In the phase 3 Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), which established the safety and efficacy of tafamidis, medication adherence was high with 97.2% of patients taking ≥80% of scheduled doses. Evidence of real-world adherence to cardiology drugs demonstrates low adherence and suboptimal outcomes; however, real-world adherence to tafamidis has not been investigated. The main objective of this study was to describe adherence patterns of patients filling tafamidis in the Symphony Health database. Methods: This retrospective analysis of the Symphony Health Solutions claims database used secondary adherence measures, including modified medication possession ratio (MPRm), days between fills adherence rate, and compliance rate, to assess adherence patterns of 2020 patients filling tafamidis free acid 61-mg capsules or tafamidis meglumine 4x20-mg capsules from June 1, 2019 to August 31, 2020. Results: Patients receiving a tafamidis formulation had characteristics consistent with the expected patient population; 71.6% were aged 75-84 years, 83.2% were male, and the highest proportion resided in the Northeast region (30.5%) of the United States. Adherence for tafamidis was high, as 75% to 100% of the patients across subgroups met or exceeded the commonly defined adherence threshold of 80%. Median number of refills ordered and received was six refills per patient. Most patients received refills with no gap (n=1633) or a gap <30 days (n=1267/1317 patients). Adherence was high across follow-up time, sex, and age subgroups. Adherence varied by geographic region, with the Northeast being significantly higher than the Midwest (mean MPRm 94.41% vs 88.21%, p=0.0007). Conclusion: These results provide evidence that real-world adherence to tafamidis in patients with ATTR-CM is high.

EGFR mutation testing in patients with advanced non-small cell lung cancer: a comprehensive evaluation of real-world practice in an East Asian tertiary hospital.

INTRODUCTION: Guidelines for management of non-small cell lung cancer (NSCLC) strongly recommend EGFR mutation testing. These recommendations are particularly relevant in Asians that have higher EGFR mutation prevalence. This study aims to explore current testing practices, logistics of testing, types of EGFR mutation, and prevalence of EGFR mutations in patients with advanced NSCLC in a large comprehensive cancer center in Korea. METHODS: Our retrospective cohort included 1,503 NSCLC patients aged ≥18 years, with stage IIIB/IV disease, who attended the Samsung Medical Center in Seoul, Korea, from January 2007 through July 2010. Trained oncology nurses reviewed and abstracted data from electronic medical records. RESULTS: This cohort had a mean age (SD) of 59.6 (11.1) years, 62.7% were males, and 52.9% never-smokers. The most common NSCLC histological types were adenocarcinoma (70.5%) and squamous cell carcinoma (18.0%). Overall, 39.5% of patients were tested for EGFR mutations. The proportion of patients undergoing EGFR testing during January 2007 through July 2008, August 2008 through September 2009, and October 2009 through July 2010 were 23.3%, 38.3%, and 63.5%, respectively (P<0.001). The median time elapsed between cancer diagnoses and receiving EGFR testing results was 21 days. EGFR testing was most frequently ordered by oncologists (57.7%), pulmonologists (31.9%), and thoracic surgeons (6.6%). EGFR testing was more commonly requested for women, younger patients, stage IV disease, non-smokers, and adenocarcinoma histology. Of 586 cases successfully tested for EGFR mutations, 209 (35.7%) were positive, including 118 cases with exon 19 deletions and 62 with L858R mutations. EGFR mutation positive patients were more likely to be female, never-smokers, never-drinkers and to have adenocarcinoma. CONCLUSIONS: In a large cancer center in Korea, the proportion of EGFR testing increased from 2007 through 2010. The high frequency of EGFR mutation positive cases warrants the need for generalized testing in Asian NSCLC patients.

Real world impact of epidermal growth factor receptor mutation status on treatment patterns in patients with non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation status is an important predictor of the efficacy of EGFR tyrosine kinase inhibitor (TKI) therapy in patients with non-small cell lung cancer (NSCLC). We evaluated the real impact of EGFR mutation status on chemotherapy patterns of NSCLC patients. PATIENTS AND METHODS: This is a retrospective cohort study of consecutive advanced NSCLC patients attended at the Samsung Medical Centre in Seoul, Korea, from January 2007 through July 2010. EGFR mutation was analyzed by direct sequencing testing. RESULTS: Among 1164 patients treated during the study period, 166 (14.3%) were EGFR mutation positive, 275 (23.6%) were mutation negative, and 723 (62.1%) had mutation status unknown. Overall, 605 (52%) received TKI therapy as a first-, second-, or third-line therapy. The proportions of patients receiving TKI therapy among those with positive, negative and unknown EGFR mutation status were 88.0, 46.5, and 45.8%, respectively. After adjustment for other factors, patients with a positive EGFR mutation status (odds ratio [OR] 7.88, 95% CI 4.58, 13.57), and those who were female (OR 2.83, 95% CI 2.04, 3.92) or had poor performance status (OR 1.58, 95% CI 1.13, 2.22) were significantly more likely to receive TKI treatment. Furthermore, the temporal relationship between EGFR mutation reporting and initiation of TKI therapy significantly differed by EGFR mutation status. CONCLUSION: EGFR mutation status significantly affected the chemotherapy patterns in advanced NSCLC. More widespread EGFR testing and the use of faster and more sensitive mutation tests will result in more timely and appropriate use of TKI therapy in advanced NSCLC.

Pain in castration-resistant prostate cancer with bone metastases: a qualitative study.

BACKGROUND: Bone metastases are a common painful and debilitating consequence of castration-resistant prostate cancer (CPRC). Bone pain may predict patients' prognosis and there is a need to further explore CRPC patients' experiences of bone pain in the overall context of disease pathology. Due to the subjective nature of pain, assessments of pain severity, onset and progression are reliant on patient assessment. Patient reported outcome (PRO) measures, therefore, are commonly used as key endpoints for evaluating the efficacy of CRPC treatments. Evidence of the content validity of leading PRO measures of pain severity used in CRPC clinical trials is, however, limited. METHODS: To document patients' experience of CRPC symptoms including pain, and their impact on health-related quality of life (HRQL), semi-structured in-depth qualitative interviews were conducted with 17 patients with CRPC and bone metastases. The content validity of the Present Pain Intensity (PPI) scale from the McGill Pain Questionnaire (MPQ), and the 'Average Pain' and 'Worst Pain' items of the Brief Pain Inventory Short-Form (BPI-SF) was also assessed. RESULTS: Patients with CRPC and bone metastases present with a constellation of symptoms that can have a profound effect on HRQL. For patients in this study, bone pain was the most prominent and debilitating symptom associated with their condition. Bone pain was chronic and, despite being generally well-managed by analgesic medication, instances of breakthrough cancer pain (BTcP) were common. Cognitive debriefing of the selected PRO measures of pain severity highlighted difficulties among patients in understanding the verbal response scale (VRS) of the MPQ PPI scale. There were also some inconsistencies in the way in which the BPI-SF 'Average Pain' item was interpreted by patients. In contrast, the BPI-SF 'Worst Pain' item was well understood and interpreted consistently among patients. CONCLUSIONS: Study findings support the importance of PRO measures of pain severity as key endpoints for evaluating the efficacy of treatments for CRPC, particularly for patients with bone metastases where episodes of BTcP are common. Qualitative evidence from CRPC patients supports the content validity of the BPI-SF ''Worst Pain' item and promotes use of this item for measuring pain severity in this population.

Once- vs twice-daily budesonide/formoterol in 6- to 15-year-old patients with stable asthma.

OBJECTIVE: To assess efficacy/tolerability of once-daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide pMDI (primary) and twice-daily budesonide/formoterol (secondary) in children/adolescents with asthma stabilized with twice-daily budesonide/formoterol. METHODS: This 12-week multicenter, double-blind randomized controlled study (www.clinicaltrials.gov identifier NCT00646321) included 521 patients aged 6 to 15 years with mild/moderate persistent asthma. Patients stabilized during a 4- to 5-week run-in with twice-daily budesonide/formoterol pMDI 40/4.5 microgx2 inhalations (160/18 microg daily) received twice-daily budesonide/formoterol pMDI 40/4.5 microgx2 inhalations (160/18 microg daily), once-daily budesonide/formoterol pMDI 80/4.5 microgx2 inhalations (160/9 microg daily; evening), or once-daily budesonide pMDI 80 microgx2 inhalations (160 microg daily; evening). RESULTS: Once- or twice-daily budesonide/formoterol was more effective than budesonide for evening peak expiratory flow (primary variable) at the end of the 24-hour once-daily dosing interval (P

The safety and clinical benefit of budesonide/formoterol pressurized metered-dose inhaler versus budesonide alone in children.

Few studies have evaluated inhaled corticosteroid (ICS)/long-acting beta(2)-adrenergic agonist combination therapy in asthmatic children. This study was designed to evaluate the safety (primary) and clinical benefits (secondary) of budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide dry powder inhaler (DPI) in children with persistent asthma. This was a 26-week, multicenter, randomized, open-label U.S. study of 187 children 6-11 years of age previously receiving ICS. After 1 week of usual ICS therapy, subjects received twice-daily budesonide/formoterol pMDI 160/4.5 micrograms x 2 inhalations (320/9 micrograms; n = 124) or budesonide DPI 200 micrograms x 2 inhalations (400 micrograms [320 micrograms delivered ex-mouthpiece]; n = 63). Budesonide/formoterol and budesonide were well tolerated with a similar incidence of adverse events (AEs) (84.6% and 85.7%, respectively), most of mild or moderate intensity. Treatment-related AE incidence was low (5.4%) and similar across groups (budesonide/formoterol, 4.9%; budesonide, 6.3%). No clinically important treatment differences were observed for 12-lead electrocardiograms, hematology, serum glucose and potassium, and 24-hour urinary cortisol. Compared with budesonide, budesonide/formoterol decreased health care use (urgent care visits and interference with daily activities [child] or work [caregiver]; p < or = 0.012) and improved health-related quality of life (Pediatric Asthma Quality of Life Questionnaire [standardized] and Pediatric Asthma Caregiver Quality of Life Questionnaire overall scores; p < or = 0.006) and pulmonary function (predose forced expiratory volume in 1 second and forced expiratory flow during the middle half of exhalation; p < or = 0.007). In this 26-week study of asthmatic children (6-11 years), safety profiles were similar and clinical benefits were greater with budesonide/formoterol than with budesonide.

Comparison of patient-reported outcomes during treatment with adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler versus fixed-dose fluticasone propionate/salmeterol dry powder inhaler in patients with asthma.

OBJECTIVE: Assessment of patient-reported outcomes is important in evaluating the impact of asthma treatment. This study was conducted to compare effects of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler with fixed-dose fluticasone propionate/salmeterol dry powder inhaler regimens on patient-reported outcomes in patients aged > or =18 years with moderate to severe asthma. METHODS: In this phase III, randomized, open-label study, 1225 patients were randomized 2:1 to fixed-dose budesonide/formoterol 160/4.5 microg x 2 inhalations (320/9 mug) twice daily or fixed-dose fluticasone propionate/salmeterol 250/50 microg twice daily for 1 month. In the subsequent 6 months, patients receiving fixed-dose fluticasone propionate/salmeterol continued therapy, whereas those receiving fixed-dose budesonide/formoterol were randomized 1:1 to fixed-dose or adjustable-dose budesonide/formoterol (adjustable from 320/9 microg twice daily to 320/9 microg once daily or 640/18 microg twice daily). RESULTS: Mean improvements from baseline to end of treatment in the Asthma Quality of Life Questionnaire (standardized) overall and individual domain scores and the Asthma Control Questionnaire score were clinically important (> or =0.5 points) for all treatments. Patients in both budesonide/formoterol groups reported greater treatment satisfaction on the Asthma Treatment Satisfaction Measure questionnaire than patients in the fluticasone propionate/salmeterol dry powder inhaler group for the attributes of timely relief of symptoms (p < or = .037) and feel medication working (p < or = .020). Onset of Effect Questionnaire scores showed a greater percentage of patients perceiving onset of effect with budesonide/formoterol regimens versus fixed-dose fluticasone propionate/salmeterol (p < or = .002). CONCLUSIONS: Treatment regimens did not differ regarding improvements in asthma-specific quality of life and asthma control. Questions related to perceived rate of onset and feeling medication working in the Asthma Treatment Satisfaction Measure and Onset of Effect Questionnaire generally elicited somewhat more favorable responses with budesonide/formoterol pressurized metered-dose inhaler regimens versus fixed-dose fluticasone propionate/salmeterol dry powder inhaler.

Development of the asthma treatment satisfaction measure.

OBJECTIVE: Study aims were to develop and assess the measurement properties of a four-part treatment satisfaction measure for patients with asthma. The Asthma Treatment Satisfaction Measure (ATSM) incorporates specific attributes representing patient expectations, treatment preferences, self-reported treatment outcomes, and overall treatment satisfaction. This paper describes patients' ability to detect change in their satisfaction with asthma therapies using the ATSM. METHODS: Adult patients with chronic asthma requiring a change in their asthma controller medications were recruited from sites in the US and Canada. Interviews were conducted with 22 patients to elicit areas important to patients in asthma treatment for measurement of satisfaction, providing the basis for the four-part questionnaire that was then tested for clarity. An additional 105 patients participated in the validation study and completed the first two parts of the ATSM (expectations and importance of treatment) at their initial visit (baseline) prior to a change in treatment. Parts 3 and 4 (treatment outcomes and treatment satisfaction) were completed after 4 weeks on the new treatment. A daily diary was completed by patients at home between visits. During clinical visits, patients also completed the Asthma Specific Quality of Life Questionnaire Standardized version assessing HRQL (AQLQ(S)), the Asthma Control Questionnaire 6-item version (ACQ-6), a 9-item asthma symptom checklist, items assessing symptom severity, and a single item overall rating of satisfaction (numerical analog scale between 0 and 10). Derived total satisfaction scores were compared to scores produced by the single global treatment satisfaction item using score variation and distribution plots. RESULTS: Qualitative results identified 11 key attributes of asthma treatment. Internal consistency for the expectations, outcomes, and satisfaction parts of the measures (11 items each) were 0.73, 0.82 and 0.95, respectively. ATSM scores were able to discriminate between control and lack of control measured by ACQ-6 scores (F = 30.09; p < 0.001); between improvement, no change, or worsening of symptoms using the 4-week diary (F = 7.05; p < 0.001); between mild, moderate and severe levels of self-reported severity of asthma (F = 2.07; p < 0.001); and levels of self-reported health status (F = 5.96; p < 0.001). Compared to the single overall satisfaction item, the ATSM satisfaction score demonstrated a broader and more normal distribution. Irrespective of the variety of treatment regimens being changed from and changed to in the normal care setting, 4 of the 11 attributes still detected statistically significant differences in (p < 0.05) levels of patient satisfaction related to their new asthma treatment regimen. CONCLUSION: By augmenting a satisfaction rating with the constructs that help define satisfaction with treatment (expectation, importance and actual treatment experience), the ATSM scores demonstrated greater ability to detect changes in treatment and provide a potentially useful measurement system for pharmacologic evaluation. This study was conducted using a normal care setting to identify patients undergoing a change in treatment. Therefore, the main limitations were the inability to control for efficacy of treatment, and a relatively small sample. Several individual ATSM satisfaction scores were able to detect significant levels of patient satisfaction related to their treatment, while the global satisfaction scores were unable to detect any significant differences.

Efficacy and tolerability of once-daily budesonide/formoterol pressurized metered-dose inhaler in adults and adolescents with asthma previously stable with twice-daily budesonide/ formoterol dosing.

BACKGROUND: The goal of asthma therapy is to control symptoms using minimal pharmacologic intervention. OBJECTIVE: To evaluate the efficacy and tolerability of once-daily budesonide/formoterol vs once-daily budesonide in patients stable with twice-daily budesonide/formoterol. METHODS: This double-blind, 12-week study enrolled 619 patients 12 years and older with mild to moderate asthma. After 4 to 5 weeks of twice-daily budesonide/formoterol pressurized metered-dose inhaler (pMDI), 80/4.5 microg x 2 inhalations (320/18 microg/d), stable patients were randomized 1:1:1:1 to 2 inhalations twice daily of budesonide/formoterol pMDI, 80/4.5 microg (320/18 microg/d), or 2 inhalations once daily (evening) of budesonide/formoterol pMDI, 160/4.5 microg or 80/4.5 microg (320/9 microg or 160/9 microg/d), or budesonide pMDI, 160 microg (320 microg/d). RESULTS: All budesonide/formoterol groups maintained significantly more favorable evening predose forced expiratory volume in 1 second (FEV1), morning peak expiratory flow (PEF), daytime/nighttime asthma symptoms, nighttime rescue medication use, and rescue medication-free days vs budesonide. Variables evaluated during the end of the once-daily dosing interval (evening predose FEV1, evening PEF, daytime asthma symptoms, and daytime rescue medication use) significantly favored twice-daily budesonide/formoterol vs all treatments. Twice-daily budesonide/formoterol demonstrated significantly more favorable results for symptom-free and asthma control days vs all treatments and awakening-free nights vs budesonide. Asthma Quality of Life Questionnaire and Asthma Control Questionnaire results significantly favored twice-daily budesonide/formoterol vs budesonide (P < or = .018). All treatments were well tolerated. CONCLUSIONS: Pulmonary function and asthma control were more effectively maintained with all budesonide/formoterol regimens vs once-daily budesonide and with twice-daily budesonide/formoterol at twice the daily formoterol dose vs both once-daily budesonide/formoterol doses.

Optimal recall periods for patient-reported outcomes: challenges and potential solutions.

OBJECTIVES: As the role and importance of patient-reported outcomes (PROs) increase, the validity and reliability of PRO measures come under greater scientific and regulatory scrutiny. One key issue is selecting the 'most appropriate' recall period for capturing PROs in clinical trials. This paper draws on survey research, health-specific literature, and results from clinical trials to summarize factors that can influence recall and provide guidance on selecting an optimal recall period. METHODS: We conducted a systematic review of six databases and additional literature drawn from bibliographies of the selected articles. RESULTS: Six major factors can influence recall; these can be classified into two broad areas: characteristics of the recalled phenomenon (recency, attributes, complexity) and context or meaning of the recalled phenomenon (salience, patient experience, mood). Results of different recall periods for three classes of PROs are presented: health behaviors, symptoms, and health-related quality of life. We present findings on the effect of alternative recall periods for three commonly used PROs. Finally, we propose a heuristic model to link the concept under investigation with an optimal recall period. CONCLUSIONS: No single recall period is best for all measures or all phenomena. The recall period must correspond to the characteristics of the phenomenon of interest and the purpose of the assessment. Recall period is an issue of internal validity. An incorrect recall period introduces measurement error that may reduce the chances of detecting a treatment effect. Researchers should consider recall period as seriously as they do other measurement properties.

Patient-reported outcomes in adults with moderate to severe asthma after use of budesonide and formoterol administered via 1 pressurized metered-dose inhaler.

BACKGROUND: Patient-reported outcomes (PROs) are important for evaluating asthma therapy. OBJECTIVE: To evaluate PROs in adults with moderate to severe persistent asthma receiving budesonide and formoterol administered via 1 pressurized metered-dose inhaler (pMDI). METHODS: This 12-week, double-blind, double-dummy, placebo-controlled, multicenter study randomized 596 patients 12 years or older to budesonide/formoterol pMDI 160/4.5 microg x 2 inhalations (320/9 microg); budesonide pMDI 160 microg x 2 inhalations (320 microg) + formoterol dry powder inhaler (DPI) 4.5 microg x 2 inhalations (9 microg); budesonide pMDI 160 microg x 2 inhalations (320 microg); formoterol DPI 4.5 microg x 2 inhalations (9 microg); or placebo, each twice daily, after 2 weeks of budesonide pMDI 80 microg x 2 inhalations (160 microg) twice daily. PROs were assessed in 553 patients 18 years or older using the standardized Asthma Quality of Life Questionnaire (AQLQ[S]), Medical Outcomes Survey (MOS) Sleep Scale, Patient Satisfaction With Asthma Medication (PSAM) questionnaire, diary data, and global assessments. RESULTS: Patients receiving budesonide/formoterol reported significantly greater improvements from baseline on the AQLQ(S) and asthma control variables (based on symptoms and rescue medication use; all P < .001) vs placebo. Clinically important improvements (increase of > or = 0.5 points) from baseline to end of treatment in AQLQ(S) overall scores were achieved by 43.6% of patients receiving budesonide/formoterol vs 22.6% of patients receiving placebo (P = .001). The MOS Sleep Scale scores generally showed no differences among treatment groups. Patients receiving budesonide/formoterol had significantly greater PSAM questionnaire scores and better outcomes on physician-patient global assessments at end of treatment vs placebo (all P < or = .001). CONCLUSION: Significantly greater improvements in health-related quality of life and asthma control and greater treatment satisfaction were observed with budesonide/formoterol pMDI vs placebo.

Development and validation of an onset of effect questionnaire for patients with asthma.

A maintenance medication that patients with asthma can feel working shortly after administration could reinforce daily treatment and improve satisfaction, adherence, and outcomes. This study was performed to develop and test a measure assessing patient perception and satisfaction with feeling an asthma medication working right away. Three studies were conducted to develop and evaluate the measure. Study 1 involved qualitative patient interviews to understand the concept of feeling a medication working right away and developed the assessment method and item pool (n = 64). Study 2 examined item clarity and content validity through cognitive interviews (n = 39). Study 3 tested reliability and validity through secondary analyses of data from adults participating in a 12-week, multicenter, double-blind, placebo-controlled phase III trial of mild to moderate persistent asthma (n = 245). A five-item weekly diary, the Onset of Effect Questionnaire, was developed with two items selected as primary: one evaluating whether patients feel their medication working right away and one assessing satisfaction with how quickly they feel their medication begin to work. These items showed 1-week reproducibility (phi = 0.77; 0.70; p < 0.0001), construct validity (relationship with improvement in 15-minute postdose forced expiratory volume in 1 second [FEV(1); p < 0.0001 and symptom severity] p < 0.001) and predictive validity (response after 1 week of treatment predicted 2-week 15-minute postdose FEV(1) [p < 0.0001], Asthma Quality of Life Questionnaire symptom domain [p < 0.05], and Patient Satisfaction with Asthma Medication overall perception of medication [p < 0.0001] and asthma relief subscales [p < 0.0001]). Results suggest that the items are reliable and valid and may be used as end points in clinical trials involving similar patient populations.

Onset of effect of budesonide and formoterol administered via one pressurized metered-dose inhaler in patients with asthma previously treated with inhaled corticosteroids.

BACKGROUND: Onset of bronchodilation of budesonide/formoterol in one pressurized metered-dose inhaler (pMDI) has not been evaluated in asthma. OBJECTIVE: To evaluate time to onset of clinically significant bronchodilation (> or = 15% improvement in forced expiratory volume in 1 second) and patient-perceived onset of effect (OE) in patients previously receiving inhaled corticosteroids. METHODS: In two 12-week studies, patients 12 years and older with moderate to severe (study 1; n = 596) and mild to moderate (study 2; n = 480) persistent asthma received budesonide/formoterol pMDI, budesonide pMDI plus formoterol dry powder inhaler (study 1 only), budesonide pMDI, formoterol dry powder inhaler, or placebo. Postdose time to 15% or greater improvement in forced expiratory volume in 1 second and patient-perceived OE (assessed in a subset of patients 18 years and older [study 1, n=553; study 2, n=405]) were evaluated [corrected] RESULTS: More budesonide/formoterol-treated patients achieved onset of clinically significant bronchodilation within 15 minutes (median, 13 minutes) of administration at randomization vs those taking budesonide or placebo (P < .001). More patients receiving budesonide/formoterol vs budesonide and placebo reported feeling their study medication begin to work right away (P < or = .004; end of week 1). Similar results (P < .001) were observed for patient satisfaction with how quickly they felt their medication begin to work (except budesonide/formoterol vs budesonide, study 1 [P = .073]). Time to onset of clinically significant bronchodilation and patient-perceived OE of budesonide/formoterol and formoterol were similar. CONCLUSION: Budesonide/formoterol demonstrated a more rapid onset of clinically significant bronchodilation and a greater percentage of patients who perceived their medication working right away vs budesonide or placebo.

Comparison of adjustable- and fixed-dose budesonide/formoterol pressurized metered-dose inhaler and fixed-dose fluticasone propionate/salmeterol dry powder inhaler in asthma patients.

BACKGROUND: The adjustable-dose budesonide/formoterol dry powder inhaler (DPI) has demonstrated similar or greater asthma control with less inhaled corticosteroid compared with the fixed-dose budesonide/formoterol DPI. OBJECTIVE: We sought to evaluate the efficacy, tolerability, and resource use of maintenance therapy with the adjustable-dose budesonide/formoterol pressurized metered-dose inhaler versus the fixed-dose budesonide/formoterol pressurized metered-dose inhaler and the fixed-dose fluticasone propionate/salmeterol DPI. METHODS: This was a randomized, open-label, multicenter study of patients (N = 1225) 12 years and older with moderate-to-severe persistent asthma. After 10 to 14 days of current therapy, patients were randomized 2:1 to fixed-dose budesonide/formoterol (160/4.5 microg x 2 inhalations [320/9 microg] twice daily) or fixed-dose fluticasone propionate/salmeterol (250/50 microg x 1 inhalation twice daily) for 1 month (treatment period 1), after which, the fixed-dose fluticasone propionate/salmeterol group continued therapy and the fixed-dose budesonide/formoterol group was randomized 1:1 to fixed-dose budesonide/formoterol or adjustable-dose budesonide/formoterol (adjustable from 2 inhalations [320/9 microg] twice daily to 2 inhalations [320/9 microg] once daily or 4 inhalations [640/18 microg] twice daily) for 6 months (treatment period 2). RESULTS: There were no significant between-group differences in asthma exacerbations (primary variable), asthma symptoms, or lung function during the 7-month treatment period. Less study drug (inhalations per day, P < .001) was used with adjustable-dose versus fixed-dose budesonide/formoterol. All treatments were well tolerated. CONCLUSIONS: Adjustable-dose and fixed-dose budesonide/formoterol showed no differences in asthma control or tolerability versus fixed-dose fluticasone propionate/salmeterol.

Can managed care organizations partner with manufacturers for comparative effectiveness research?

OBJECTIVE: To describe 2 published pragmatic or practical clinical trials (PCTs) as case studies illustrating successful partnerships between managed care organizations (MCOs) and pharmaceutical manufacturers. STUDY DESIGN: In today's environment, there is increasing concern about the comparative effectiveness of medical interventions. Various opinion leaders and stakeholders lament the dearth of such evidence and are calling for the public and private sectors to invest up to billions of dollars to create better comparative evidence. METHODS: We selected 2 PCTs conducted at different points in the drug life cycle to highlight strengths, limitations, and policy implications. The phase IV study compared fluoxetine hydrochloride vs 2 generic tricyclic antidepressants in selected primary care clinics of a health maintenance organization from 1992 through 1994. The phase IIIb study compared daily budesonide via dry powder inhaler vs triamcinolone acetonide metered-dose inhaler in adult patients with persistent asthma in 25 MCOs from 1995 through 1998. RESULTS: Both PCTs were successfully sponsored and funded by pharmaceutical manufacturers in collaboration with MCOs and provided potentially useful evidence of real-world effectiveness and evidence of value to healthcare decision makers. CONCLUSIONS: Industry-sponsored PCTs in managed care are feasible when manufacturer and MCO incentives align and can provide real-world evidence of comparative effectiveness and value for money. These trials can be conducted successfully in the phase IIIb and phase IV environments.

The effect of budesonide and formoterol in one pressurized metered-dose inhaler on patient-reported outcomes in adults with mild-to-moderate persistent asthma.

OBJECTIVE: To determine the effects of budesonide and formoterol administered via one pressurized metered-dose inhaler (budesonide/formoterol pMDI) on patient-reported outcomes (PROs) and to determine the contributions of budesonide and formoterol to those effects in adults with asthma. RESEARCH DESIGN AND METHODS: A 12-week, randomized, double-blind, double-dummy, placebo-controlled, multicenter study was conducted in 480 patients aged > or = 12 years with mild-to-moderate persistent asthma. After a 2-week run-in period during which current asthma therapy was discontinued, patients were randomized to receive two inhalations twice daily of budesonide/formoterol pMDI 80/4.5 microg (160/9 microg), budesonide pMDI 80 microg (160 microg), formoterol via dry powder inhaler (DPI) 4.5 microg (9 microg), or placebo. MAIN OUTCOME MEASURES: Analyses included a subpopulation of 405 patients aged > or = 18 years. PROs included the standardized Asthma Quality of Life Questionnaire (AQLQ(S)), the Medical Outcomes Study (MOS) Sleep Scale, the Patient Satisfaction with Asthma Medication (PSAM) questionnaire, and asthma control variables (recorded via electronic diaries), such as asthma symptoms, rescue medication use, and nighttime awakenings due to asthma. Patient and physician global assessments were collected at the end of the study. RESULTS: Patients aged > or = 18 years receiving budesonide/formoterol pMDI reported significantly greater improvements from baseline in AQLQ overall and domain scores, MOS Sleep Scale domain scores, and asthma control variables than patients receiving placebo (p < or = 0.033). Improvements from baseline in AQLQ(S) overall and domain scores, daily asthma symptoms scores, percentage of symptom-free days, percentage of rescue medication-free days, and percentage of asthma control days were significantly greater in patients receiving budesonide/formoterol pMDI versus formoterol DPI (p < or = 0.042). Patients receiving budesonide/formoterol pMDI reported significantly greater PSAM scores than did patients in all other treatment arms (p < or = 0.004). Study limitations may include the fact that the formoterol-alone arm used a different device and formulation than the other active arms as well as the absence of a treatment arm with budesonide and formoterol administered concomitantly in separate inhalers. In addition, these results may not be generalized to all patients with asthma, as this analysis included only patients aged > or = 18 years. CONCLUSIONS: Patients receiving treatment with budesonide/formoterol pMDI experienced significantly greater improvements from baseline in asthma-related quality of life, quality of sleep, and asthma control and greater satisfaction with treatment than patients receiving placebo. The combination of budesonide and formoterol in one pMDI is beneficial in improving how a patient feels and functions as a result of treatment.

Relationship between symptom change, objective tumor measurements, and performance status during chemotherapy for advanced lung cancer.

PURPOSE: Our objective was to identify which symptoms of advanced lung cancer are most likely to change with objective tumor measurements (progressions and responses) or changes in performance status (PS). PATIENTS AND METHODS: Eighty patients with advanced non-small-cell lung cancer were studied during the first 12 weeks of chemotherapy. Symptoms were assessed weekly through telephone administration of the Functional Assessment of Cancer Therapy-Lung Symptom Index-12. Data on PS were collected from patients every 3 weeks. Symptom reports were mapped onto clinical events (progression or response as determined by clinicians) and PS assessments. RESULTS: Disease progression and declining PS were associated with worsening of several symptoms. Pain, shortness of breath, cough, weight loss, and appetite loss worsened most from before to after progression. Patients with an objective response to chemotherapy reported more fatigue and difficulty breathing at response than before response. However, unlike patients who experienced progression, patients responding to chemotherapy never or rarely complained of clinically significant pain, weight loss, cough, chest tightness, nausea, or confusion before, during, or after response. With the exception of bother with side effects of treatment, confusion, and difficulty breathing, symptoms tracked fairly closely over the 12 weeks with changes in PS. Declining PS was associated with considerably more symptom worsening than unchanged or improved PS, independent of treatment response. CONCLUSION: These data can help the clinician identify symptoms of lung cancer most reliably associated with objective responses and perceived changes in functional status during chemotherapy. Symptom self-reports could be used by clinicians to monitor patient status and possibly inform treatment modification.

Patient-reported outcomes: instrument development and selection issues.

At its most elemental, patient-reported outcomes (PRO) assessment involves asking the patients questions and evaluating their answers. Instrument developers need to be clear about what they want to know, from whom they want to know it and why, whether what they learned is credible, and whether they can interpret what they learned in the context of the research objectives. Because credible instrument development is neither inexpensive nor technically trivial, researchers must first determine that no available measure meets their research objectives. We suggest that the tasks of either reviewing current instruments or developing new ones originate from the same basic premise: PRO assessment requires a well-articulated conceptual framework. Once defined in the context of the research objectives, the conceptual framework needs to be adapted to the population of interest. We discuss how qualitative methods enrich the conceptual framework and facilitate the technical measurement tasks of item development, testing, and reduction. We recognize that PRO assessment stands at a technological crossroads with the increasingly frequent application of "modern" psychometric methods and discuss how innovations such as item banks and computer-adaptive testing will influence PRO instrument development. Although items are the essential building blocks for instruments, scales are the primary unit of analysis for PRO assessment, and we discuss methods for scoring and combining them. Finally, PRO assessment is meaningless if the key figure chooses not to cooperate. We consider how respondent burden influences the quality of PRO assessment.