A randomized controlled trial of glycopyrrolate administered by metered dose inhaler in patients with uncontrolled asthma despite ICS/LABA treatment.

OBJECTIVE: To evaluate the efficacy and safety of three doses of glycopyrrolate metered dose inhaler (GP MDI) in patients with uncontrolled asthma despite treatment with inhaled corticosteroid/long-acting ß2-agonists (ICS/LABA) with or without tiotropium, to characterize the benefit of triple therapy. METHOD: This phase II/III, double-blind study randomized patients to 24 weeks' treatment with twice-daily GP MDI 36 µg, 18 µg, 9 µg, or placebo MDI (all delivered via Aerosphere inhalers), or once-daily open-label tiotropium 2.5 µg. Patients continued their own ICS/LABA regimen throughout the study. The primary endpoint was change from baseline in forced expiratory volume in 1 s (FEV1) area under the curve from 0 - 4 h (AUC0 - 4) at Week 24. Secondary endpoints included patient questionnaires to measure asthma control or symptoms. Safety was also assessed. RESULTS: The primary analysis (modified intent-to-treat) population included 1066 patients. The primary study endpoint was not met (changes from baseline in FEV1 AUC0 - 4 at Week 24 were 294 mL, 284 mL, 308 mL, 240 mL, and 347 mL for GP MDI 36 µg, GP MDI 18 µg, GP MDI 9 µg, placebo, and open-label tiotropium, respectively). There were no significant differences between treatment and placebo in secondary endpoints at Week 24. Post-hoc analyses using post-bronchodilator FEV1 as the baseline measurement, or averaging values across multiple baseline visits, showed a dose-related response to GP MDI. The incidence of adverse events was low and similar across treatments. CONCLUSION: Although this study did not meet its primary endpoint, post hoc analyses identified a dose-related response to GP MDI when alternative definitions of baseline FEV1 were used in the analyses.

A Randomized, Double-Blind, Double-Dummy Study of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Relative to Umeclidinium/Vilanterol Dry Powder Inhaler in COPD.

INTRODUCTION: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, is the only approved fixed-dose combination long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) delivered via MDI. Direct comparisons of GFF MDI versus other LAMA/LABAs have not previously been performed. We assessed the efficacy and safety of GFF MDI relative to umeclidinium/vilanterol dry powder inhaler (UV DPI) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). METHODS: In this phase IIIb randomized, double-blind, double-dummy, multicenter, 24-week study, patients received GFF MDI 18/9.6 µg (equivalent to glycopyrronium/formoterol fumarate dihydrate 14.4/10 µg; two inhalations per dose, twice-daily; n = 559) or UV DPI 62.5/25 µg (one inhalation, once-daily; n = 560). Primary endpoints were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and peak change from baseline in FEV1 within 2 h post-dose, both over 24 weeks. Additional lung function, symptom and safety endpoints were also assessed. RESULTS: For the primary endpoints, GFF MDI was non-inferior to UV DPI (using a margin of - 50 mL) for peak FEV1 (least squares mean [LSM] difference - 3.4 mL, 97.5% confidence interval [CI] - 32.8, 25.9) but not for trough FEV1 (LSM difference - 87.2 mL; - 117.0, - 57.4). GFF MDI was nominally superior to UV DPI for onset of action (p < 0.0001) and was nominally non-inferior to UV DPI for all symptom endpoints (Transition Dyspnea Index focal score, Early Morning/Night-Time Symptoms COPD instrument scores, and COPD Assessment Test score). Exacerbation and safety findings were similar between groups. CONCLUSIONS: Over 24 weeks of treatment, GFF MDI was non-inferior to UV DPI for peak FEV1, but not for morning pre-dose trough FEV1. GFF MDI had a faster onset of action versus UV DPI. There were no clinically meaningful differences between treatments in symptom endpoints. Both treatments were well tolerated with similar safety profiles. TRIAL REGISTRATION: NCT03162055 (Clinicaltrials.gov) FUNDING: AstraZeneca.

Serious Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone.

BACKGROUND: Concerns remain about the safety of adding long-acting ß2-agonists to inhaled glucocorticoids for the treatment of asthma. In a postmarketing safety study mandated by the Food and Drug Administration, we evaluated whether the addition of formoterol to budesonide maintenance therapy increased the risk of serious asthma-related events in patients with asthma. METHODS: In this multicenter, double-blind, 26-week study, we randomly assigned patients, 12 years of age or older, who had persistent asthma, were receiving daily asthma medication, and had had one to four asthma exacerbations in the previous year to receive budesonide-formoterol or budesonide alone. Patients with a history of life-threatening asthma were excluded. The primary end point was the first serious asthma-related event (a composite of adjudicated death, intubation, and hospitalization), as assessed in a time-to-event analysis. The noninferiority of budesonide-formoterol to budesonide was defined as an upper limit of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The primary efficacy end point was the first asthma exacerbation, as assessed in a time-to-event analysis. RESULTS: A total of 11,693 patients underwent randomization, of whom 5846 were assigned to receive budesonide-formoterol and 5847 to receive budesonide. A serious asthma-related event occurred in 43 patients who were receiving budesonide-formoterol and in 40 patients who were receiving budesonide (hazard ratio, 1.07; 95% confidence interval [CI], 0.70 to 1.65]); budesonide-formoterol was shown to be noninferior to budesonide alone. There were two asthma-related deaths, both in the budesonide-formoterol group; one of these patients had undergone an asthma-related intubation. The risk of an asthma exacerbation was 16.5% lower with budesonide-formoterol than with budesonide (hazard ratio, 0.84; 95% CI, 0.74 to 0.94; P=0.002). CONCLUSIONS: Among adolescents and adults with predominantly moderate-to-severe asthma, treatment with budesonide-formoterol was associated with a lower risk of asthma exacerbations than budesonide and a similar risk of serious asthma-related events. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01444430 .).

BCG scar and tuberculin reactivity in children and adults.

Bacille Calmette-Guérin (BCG) vaccination generally leads to scar formation and tuberculin skin test (TST) reactivity. This study aimed at analysing these 2 parameters and their correlation in a setting with a low prevalence of tuberculosis. Retrospectively, we analysed 314 children and 390 adults living in Sweden and known from records or individual recall to have undergone BCG vaccination. A BCG scar was present in 161 (51%) of the children and in 340 (87%) of the adults. Among children with a scar, 94 (58%) were TST-positive (>or=6 mm) compared to 23 (15%) of 154 children lacking a visible scar. Among adults with a scar, 258 (76%) were TST- positive compared to 23 (46%) of 50 with no scar. Out of 152 non-vaccinated adults, 142 (94.4%) were TST-negative. When 175 TST-negative health care students were BCG-vaccinated in a prospective part of the study, 174 (99%) were found to develop a scar. In essence, the study showed a positive correlation between scar presence and TST reactivity. Furthermore, BCG vaccination of adults in the present setting resulted in consistent scar formation, while scar prevalence in previously vaccinated children was low.

Primary vaccination and revaccination of young adults with BCG: a study using immunological markers.

Questions have been raised about the effectiveness of Bacille Calmette-Guérin (BCG) vaccination against tuberculosis (TB) in adults. We therefore analysed the immune response after BCG vaccination in primary-vaccinated and revaccinated young adults. 31 tuberculin skin test (TST) negative healthy students were BCG-vaccinated; 15 were primary-vaccinated and 16 revaccinated. Tuberculin-induced lymphocyte transformation (LT) and cytokine production of peripheral blood mononuclear cells were studied before BCG vaccination, as well as after 2 months and 1 y. In the primary-vaccinated as well as the revaccinated group the LT response increased after 2 months and remained significantly higher than baseline values after 1 y. In both groups the interferon-gamma (IFN-gamma) levels increased significantly after 2 months and the increase was maintained after 1 y. LT increased more in the revaccinated group than in the primary-vaccinated group, while the increase in IFN-gamma response did not differ between the 2 groups. Both primary vaccination and revaccination of TST negative young adults caused a significant increase in the T-helper 1-type immune response, suggesting a protective effect against TB. The present in vitro results thus support the policy in several low-endemic countries of primary vaccination as well as revaccination of young adults at risk of TB exposure.