A new protocol for exercise testing in COPD; improved prediction algorithm for WMAX and validation of the endurance test in a placebo-controlled double bronchodilator study.

BACKGROUND: Two new protocols have been developed for bicycle exercise testing in chronic obstructive pulmonary disease (COPD) with an individualized cardiopulmonary exercise test (ICPET) and subsequent customized endurance test (CET), which generate less interindividual spread in endurance time compared with the standard endurance test. Main objectives of this study were to improve the prediction algorithm for WMAX for the ICPET and validate the CET by examining treatment effects on exercise performance of indacaterol/glycopyrronium (IND/GLY) compared with placebo. METHODS: COPD patients, with forced expiratory volume in 1 s (FEV1) 40-80% predicted, were recruited. Pooled baseline data from two previous studies (n = 38) were used for the development of an improved WMAX prediction algorithm. Additional COPD patients (n = 14) were recruited and performed the ICPET, using the new prediction formula at visit 1. Prior to the CET at visits 2 and 3, they were randomized to a single dose of IND/GLY (110/50 µg) or placebo. RESULTS: The improved multiple regression algorithm for WMAX includes diffusing capacity for carbon monoxide (DLCO), FEV1, sex, age and height and correlated to measured WMAX (R2 = 0.89 and slope = 0.89). Treatment with IND/GLY showed improvement in endurance time versus placebo, mean 113 s [95% confidence interval (CI): 6-220], p = 0.037, with more prominent effect in patients with FEV1 < 70% predicted. CONCLUSION: The two new protocols for ICPET (including the new improved algorithm) and CET were retested with consistent results. In addition, the CET showed a significant and clinically relevant prolongation of endurance time for IND/GLY versus placebo in a small number of patients.

Reduced Variability of Endurance Time in New Protocols for Exercise Tests in COPD.

Purpose: For exercise testing of COPD patients, a standard endurance test (ET) with constant workload is recommended. The test suffers from large inter-individual variability and need for large sample sizes in order to evaluate treatment effects. Methods: A new protocol for ET in COPD was designed. In contrast to the standard ET, the new ET involved an increasing workload in order to reduce the standard deviation of endurance time. Two new ETs were compared with the standard ET. In Study A, the new ET started at 75% of the patient's maximum workload (WMAX) and increased stepwise with 3%/2 min until exhaustion. Study B started at 70% of WMAX and increased linearly with 1%/min. Results: In Study A, that included 15 patients, the standard deviation and range for endurance time and work capacity were narrower for the new versus the standard ET. However, the higher mean workload at end and the low mean work capacity relative to the standard ET indicated that the stepwise increase was too aggressive. In Study B, that included 18 patients, with a modified protocol, the averages for endurance time, workload at end and work capacity were similar for new and standard ET, while the standard deviations and ranges for endurance time and work capacity were kept more narrow in the new ET. The variances for endurance time were not equal between the standard ET and the two new ETs (p<0.05 for both according to Levene's test). Conclusion: The new ET reduced the number of patients with extreme endurance times (short and long) compared to the standard test. The new test showed a significant lower variance for endurance time, which potentially can lead to fewer patients needed in comparative studies. The overall best results were observed with a low linear increase during endurance.

A new maximal bicycle test using a prediction algorithm developed from four large COPD studies.

Background: Maximum exercise workload (WMAX) is today assessed as the first part of Cardiopulmonary Exercise testing. The WMAX test exposes patients with COPD, often having cardiovascular comorbidity, to risks. Our research project was initiated with the final aim to eliminate the WMAX test and replace this test with a predicted value of WMAX, based on a prediction algorithm of WMAX derived from multicentre studies. Methods: Baseline data (WMAX, demography, lung function parameters) from 850 COPD patients from four multicentre studies were collected and standardized. A prediction algorithm was prepared using Random Forest modelling. Predicted values of WMAX were used in a new WMAX test, which used a linear increase in order to reach the predicted WMAX within 8 min. The new WMAX test was compared with the standard stepwise WMAX test in a pilot study including 15 patients with mild/moderate COPD. Results: The best prediction algorithm of WMAX included age, sex, height, weight, and six lung function parameters. FEV1 and DLCO were the most important predictors. The new WMAX test had a better correlation (R2 = 0.84) between predicted and measured WMAX than the standard WMAX test (R2 = 0.66), with slopes of 0.50 and 0.46, respectively. The results from the new WMAX test and the standard WMAX test correlated well. Conclusion: A prediction algorithm based on data from four large multicentre studies was used in a new WMAX test. The prediction algorithm provided reliable values of predicted WMAX. In comparison with the standard WMAX test, the new WMAX test provided similar overall results.

Safety of formoterol in asthma clinical trials: an update.

Use of long-acting ß-agonists (LABAs) in asthma remains controversial, and large safety trials are in progress. We have previously reported safety outcomes with formoterol in 117 AstraZeneca asthma trials (78,339 patients, 92% using inhaled corticosteroids) completed by December 2006, and have now added 32 trials with formoterol (26,124 patients, 100% using inhaled corticosteroids) completed by December 2011. The primary dataset of 79 randomised controlled trials includes 94,684 patients, 67,380 of whom were exposed to formoterol, while the complete dataset comprises 149 trials and 104,463 patients. There were no new asthma-related deaths in the expanded primary dataset, with eight asthma-related deaths among formoterol-randomised patients and two among non-LABA-randomised patients (relative risk 1.13, 95% CI 0.23-10.9), and 15 versus nine cardiac-related deaths (relative risk 0.47, 95% CI 0.19-1.22). Nonfatal asthma-related serious adverse events were significantly reduced with formoterol (relative risk 0.63, 95% CI 0.53-0.75), as were discontinuations due to adverse events. Examining 40 trials with direct formoterol versus non-LABA comparisons, Mantel-Haenszel relative risk for asthma-related death was 2.75 (95% CI 0.52-14.4) and for serious adverse events 0.83 (95% CI 0.68-1.02). We conclude that this enlarged dataset indicates no increased risk of asthma-related deaths among patients exposed to formoterol compared with non-LABA treatments, although the wide confidence interval precludes certainty.

Risks of pneumonia in patients with asthma taking inhaled corticosteroids.

RATIONALE: Inhaled corticosteroids (ICS) are the mainstay of asthma treatment. Studies in chronic obstructive pulmonary disease reported increased rates of pneumonia with ICS. Concerns exist about an increased pneumonia risk in patients with asthma taking ICS. OBJECTIVES: To evaluate the risks of pneumonia in patients with asthma taking ICS. METHODS: A retrospective analysis evaluated studies of the ICS budesonide in asthma. The primary data set were all double-blind, placebo-controlled trials lasting at least 3 months, involving budesonide (26 trials, n = 9,067 for budesonide; n = 5,926 for the comparator) sponsored by AstraZeneca. A secondary data set evaluated all double-blind trials lasting at least 3 months but without placebo control (60 trials, n = 33,496 for budesonide, n = 2,773 for fluticasone propionate). Cox proportional hazards regression modeling was used to estimate the relative effect of ICS on pneumonia adverse events (AEs) or serious adverse events (SAEs). MEASUREMENTS AND MAIN RESULTS: In the primary data set, the occurrence of pneumonia AEs was 0.5% (rate 10.0 events/1,000 patient-years [TPY]) for budesonide and 1.2% (19.3 per TPY) for placebo (hazard ratio, 0.52; 95% confidence interval, 0.36-0.76; P < 0.001); the occurrence of pneumonia SAEs was 0.15% (2.9 per TPY) for budesonide and 0.13% (2.1 per TPY) for placebo (hazard ratio, 1.29; 95% confidence interval, 0.53-3.12; P = 0.58). In the secondary data set, the percentage of patients reporting pneumonia AEs was 0.70% (12.7 per TPY), whereas the percentage of patients reporting pneumonia SAEs was 0.17% (3.1 per TPY). There was no increased risk with higher budesonide doses or any difference between budesonide and fluticasone. CONCLUSIONS: There is no increased risk of pneumonia in patients with asthma, identified as an AE or SAE, in clinical trials using budesonide.

Safety of formoterol in patients with asthma: combined analysis of data from double-blind, randomized controlled trials.

BACKGROUND: Concerns exist that regular long-acting beta(2)-adrenergic agonist (LABA) therapy may increase the risk of serious asthma-related events. OBJECTIVE: To assess risks of formoterol-containing versus non-LABA treatment by using a large asthma database. METHODS: This analysis included all blind, parallel-arm, randomized, active-controlled and/or placebo-controlled AstraZeneca-sponsored asthma studies with formoterol-containing and non-LABA comparator arms. Serious adverse events were assessed for inclusion in all-cause death, asthma-related death, asthma-related intubation, and asthma-related hospitalization categories by using blind adjudication. Data were combined across trials; relative risk (RR) was assessed by using Mantel-Haenszel methods. RESULTS: Data were from 13,542 formoterol-randomized and 9968 non-LABA patients 4 years or older (42 trials), of whom 93% and 89%, respectively, received inhaled corticosteroid as part of randomized treatment or allowed medication. Incidence of all-cause death was low (n=3 and n=4, respectively), with numerically lower all-cause deaths/1000 patient-treatment years in the formoterol-treated group (0.53) versus the non-LABA group (0.82) (RR, 0.64; 95% confidence interval [CI], 0.14-2.92). No asthma-related deaths and 1 asthma-related intubation (formoterol-treated group) occurred. Asthma-related hospitalizations/1000 patient-treatment years were lower numerically in the formoterol-treated group (12.1) versus the non-LABA group (16.4) (RR, 0.73; 95% CI, 0.54-1.01), with fewer study discontinuations in the formoterol-treated group (12.7% vs 15.4%, respectively; RR, 0.79; 95% CI, 0.74-0.85). Relative to non-LABA, increasing daily formoterol dose (>/=4.5, 9, 18, 36 mug) did not increase the rate or incidence of asthma-related hospitalization. CONCLUSION: No evidence of increased risk of asthma-related hospitalization, no asthma-related deaths, and a low incidence of all-cause death and asthma-related intubation were seen with formoterol-containing versus non-LABA treatment.

Safety of budesonide/formoterol maintenance and reliever therapy in asthma trials.

BACKGROUND: The safety of long-acting beta(2)-agonists (LABAs) in asthma is debated. This study examined the safety of the inhaled corticosteroid (ICS)/LABA combination budesonide/formoterol dry powder inhaler used as maintenance and reliever therapy versus combination treatments based on guideline recommendations. METHODS: Safety data from six double-blind, randomised clinical trials (RCTs) in asthma where budesonide/formoterol was used as maintenance and reliever therapy for at least 6 months were reviewed (N=14 346). All-cause mortality and asthma-related serious adverse events (SAEs) (co-primary endpoints), overall and cardiac SAEs, and discontinuations due to adverse events (DAEs) were assessed. Estimated Mantel-Haenszel (MH) relative risks (RR) with this regimen versus comparators were calculated. RESULTS: There was no increase in all-cause mortality with budesonide/formoterol maintenance and reliever therapy (four deaths [0.07%] versus nine [0.10%]; pooled MH RR 0.70, 95% confidence interval [CI] 0.21-2.30). Asthma-related SAEs were reduced with budesonide/formoterol maintenance and reliever therapy: 41 (0.73%) versus 121 (1.38%); pooled MH RR 0.59, 95% CI 0.42-0.85. All-cause and asthma-related DAEs were also reduced with budesonide/formoterol maintenance and reliever therapy: pooled MH RR 0.60 (95% CI 0.46-0.79) and 0.43 (0.28-0.68), respectively. Overall and cardiac-related SAEs were comparable between treatment groups: pooled MH RR 0.96 (95% CI 0.82-1.14) and 1.26 (0.72-2.22), respectively. CONCLUSION: Budesonide/formoterol dry powder inhaler maintenance and reliever therapy was well tolerated in RCTs versus fixed-dose alternatives and not associated with increased risk of death or cardiac-related SAEs and DAEs, and asthma-related SAEs and DAEs were significantly reduced. Given the limitations of RCTs, particularly exclusion of patients with co-morbidities, ongoing surveillance is appropriate.

Budesonide and the risk of pneumonia: a meta-analysis of individual patient data.

BACKGROUND: Concern is continuing about increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD) who use inhaled corticosteroids. We aimed to establish the effects of inhaled budesonide on the risk of pneumonia in such patients. METHODS: We pooled patient data from seven large clinical trials of inhaled budesonide (320-1280 mug/day), with or without formoterol, versus control regimen (placebo or formoterol alone) in patients with stable COPD and at least 6 months of follow-up. The primary analysis compared treatment groups for the risk of pneumonia as an adverse event or serious adverse event during the trial or within 15 days of the trial end. Cox proportional hazards regression was used to analyse the data on an intention-to-treat basis. Data were adjusted for patients' age, sex, smoking status, body-mass index, and postbronchodilator percent of predicted forced expiratory volume in 1 s (FEV(1)). FINDINGS: We analysed data from 7042 patients, of whom 3801 were on inhaled budesonide and 3241 were on control treatment, with 5212 patient-years of exposure to treatment. We recorded no significant difference between treatment groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs 3% [n=103]; adjusted hazard ratio 1.05, 95% CI 0.81-1.37) or a serious adverse event (1% [n=53] vs 2% [n=50]; 0.92, 0.62-1.35), or for time to pneumonia as an adverse event (log-rank test 0.94) or a serious adverse event (0.61). Increasing age and decreasing percent of predicted FEV(1) were the only two variables that were significantly associated with occurrence of pneumonia as an adverse event or a serious adverse event. INTERPRETATION: Budesonide treatment for 12 months does not increase the risk of pneumonia in patients with COPD during that time and therefore is safe for clinical use in such patients. FUNDING: Michael Smith Foundation for Health Research.

Outcome of pregnancy in a randomized controlled study of patients with asthma exposed to budesonide.

BACKGROUND: Budesonide is the only inhaled corticosteroid to be given a category B pregnancy rating by the US Food and Drug Administration, based on observational data from the Swedish Medical Birth Registry. However, data from large randomized controlled trials are lacking. OBJECTIVE: To compare pregnancy outcomes among patients with recent-onset mild-to-moderate persistent asthma receiving low-dose budesonide vs placebo. METHODS: In a randomized, double-blind, placebo-controlled trial, 7241 patients aged 5 to 66 years with mild-to-moderate persistent asthma for less than 2 years and no previous regular corticosteroid therapy received once-daily budesonide or placebo via dry powder inhaler in addition to their usual asthma medication for 3 years. This trial was followed by a 2-year open-label treatment period. The daily dose of budesonide was 400 microg for adults. The study included 2473 females aged 15 to 50 years at randomization. Pregnancy was not an exclusion criterion (except for U.S. patients). RESULTS: Of 319 pregnancies reported, 313 were analyzed. Healthy children were delivered in 81% and 77% of all pregnancies in the budesonide and placebo groups, respectively. Of the 196 pregnancies reported by participants taking budesonide, 38 (19%) had adverse outcomes: 23 (12%) had miscarriages, 3 (2%) had congenital malformations, and 12 (6%) had other outcomes. Of the 117 pregnancies reported in the placebo group, 27 (23%) had adverse outcomes: 11 (9%) had miscarriages, 4 (3%) had congenital malformations, and 12 (10%) had other outcomes. CONCLUSIONS: Treatment with low-dose inhaled budesonide in females with mild-to-moderate persistent asthma does not seem to affect the outcome of pregnancy.