Ubaldo J. Martin

Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial.

Background: Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid (ICS) is recommended in patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler (DPI) in a 1-year study and when administered via the hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) in a 6-month study.Objective: This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD.Methods: This was a 12-month, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled, multicentre study (NCT00206167) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US, Europe and Mexico. After 2 weeks of treatment based on previous therapy (ICSs, short-acting bronchodilators allowed), patients received one of the following treatments twice daily: budesonide/formoterol pMDI 160/4.5 μg × two inhalations (320/9 μg); budesonide/formoterol pMDI 80/4.5 μg × two inhalations (160/9 μg); formoterol DPI 4.5 μg × two inhalations (9 μg); or placebo.Main outcome measures: The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV1) and 1-hour post-dose FEV1.Results: Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1 versus formoterol (p = 0.008), and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo (p < 0.001). The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo (p ≤ 0.004). Both budesonide/formoterol doses were more effective than placebo (p ≤ 0.006) for controlling dyspnoea and improving health status (St George’s Respiratory Questionnaire). All treatments were generally well tolerated. The incidence of pneumonia was not different for active (3.4–4.0%) and placebo (5.0%) groups.Conclusions: Budesonide/formoterol pMDI (320/9 μg and 160/9 μg) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD. Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co-primary variables compared with formoterol DPI 9 μg. Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo.

Efficacy and Safety of Budesonide and Formoterol in One Pressurized Metered-Dose Inhaler in Patients with Moderate to Very Severe Chronic Obstructive Pulmonary Disease

AbstractBackground: The combination of an inhaled corticosteroid (ICS) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease (COPD) who have frequent exacerbations. Budesonide/formoterol dry powder inhaler (DPI) has demonstrated efficacy and tolerability in patients with COPD. Objective: To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) in patients with COPD. Methods: This was a 6-month, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicentre study (NCT00206154) of 1704 patients aged ≥40 years with moderate to very severe COPD conducted in 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa. After 2 weeks of treatment based on previous therapy (ICSs and short-acting bronchodilators allowed during the run-in period), patients received one of the following treatments administered twice daily: budesonide/formoterol pMDI 160/4.5 μg × two inhalations (320/9 μg); budesonide/formoterol pMDI 80/4.5 μg × two inhalations (160/9 μg); budesonide pMDI 160 μg × two inhalations (320 μg) plus formoterol DPI 4.5 μg × two inhalations (9 μg); budesonide pMDI 160 μg × two inhalations (320 μg); formoterol DPI 4.5 μg × two inhalations (9 μg); or placebo. Main outcome measures: The co-primary efficacy variables were pre-dose forced expiratory volume in 1 second (FEV1) and 1-hour post-dose FEV1. Results: Budesonide/formoterol 320/9 μg demonstrated significantly greater improvements in pre-dose FEV1 versus formoterol (p = 0.026; pre-specified primary comparator) and 1-hour post-dose FEV1 versus budesonide (p < 0.001; pre-specified primary comparator); budesonide/formoterol 160/9 μg demonstrated significantly greater improvements versus budesonide (p < 0.001) for 1-hour post-dose FEV1 but not versus formoterol for pre-dose FEV1. Dyspnoea (measured using the Breathlessness Diary) and health-related quality-of-life (HR-QOL) scores (based on the St George’s Respiratory Questionnaire total score) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide, formoterol and placebo (p ≤ 0.044 for all). Although not powered a priori for comparisons, the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and/or hospitalization was numerically (20–25%) lower with the budesonide-containing treatments (0.710–0.884) versus formoterol (1.098) and placebo (1.110). This result was driven by the exacerbations requiring treatment with oral corticosteroids (79–120 events). The number of exacerbations resulting in hospitalization was very low across treatment groups (11–22); the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 μg (0.158) versus other treatment groups (0.081–0.108) except budesonide/formoterol 160/9 μg (0.139), and for budesonide/formoterol 160/9 μg versus formoterol (0.081) [p ≤ 0.05]. All treatments were generally well tolerated. The incidence of individual non-fatal serious adverse events was similar across all treatment groups, except COPD, which was highest in the budesonide/formoterol 320/9 μg group (6.1%) and lowest in the budesonide (3.6%) and formoterol (3.9%) groups, with a range of 4.3–4.6% in the budesonide/formoterol 160/9 μg, budesonide plus formoterol and placebo groups. Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo. There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo. Conclusions: Budesonide/formoterol pMDI 320/9 μg demonstrated significantly greater efficacy for pulmonary function on both co-primary endpoints versus the pre-specified comparators (formoterol DPI 9 μg for pre-dose FEV1 and budesonide pMDI 320 μg for 1-hour post-dose FEV1). Budesonide/formoterol pMDI 160/9 μg demonstrated significantly greater efficacy for 1-hour post-dose FEV1 versus budesonide pMDI 320 μg. Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo. Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo.

Effect of budesonide/formoterol pMDI on COPD exacerbations: A double-blind, randomized study

BACKGROUND Treatment with an inhaled corticosteroid (ICS) and long-acting bronchodilator is recommended for severe/very severe chronic obstructive pulmonary disease (COPD) patients with repeated exacerbations. This randomized, double-blind, double-dummy, parallel-group, 12-month multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler (pMDI) on COPD exacerbations. METHODS Following a 2-week run-in during which COPD patients aged ≥40 years with an exacerbation history discontinued medications except ICSs, 1219 patients were randomized 1:1:1 to twice-daily budesonide/formoterol pMDI 320/9 μg, budesonide/formoterol pMDI 160/9 μg, or formoterol dry powder inhaler 9 μg. An exacerbation was defined as COPD worsening requiring oral corticosteroids and/or hospitalization. A post hoc analysis, with antibiotic treatment added to the exacerbation definition, was also performed. RESULTS Budesonide/formoterol 320/9 and 160/9 reduced exacerbation rates (number per patient-treatment year) by 34.6% and 25.9%, respectively, versus formoterol (p ≤ 0.002). Budesonide/formoterol 320/9 prolonged time to first exacerbation versus formoterol, corresponding to a 21.2% reduction in hazard ratio (0.788 [95% CI: 0.639, 0.972]; p = 0.026). Exacerbation rates (number per patient-treatment year) including antibiotic treatment (post hoc analysis) were reduced by 25.9% and 18.7% with budesonide/formoterol 320/9 and 160/9, respectively, versus formoterol (p ≤ 0.023). Both budesonide/formoterol doses were well tolerated with safety profiles similar to formoterol. Pneumonia adverse events occurred in 6.4%, 4.7%, and 2.7% of patients in the budesonide/formoterol 320/9, 160/9, and formoterol groups. CONCLUSIONS Over 12 months, both budesonide/formoterol doses reduced the exacerbation rate (defined with or without antibiotic treatment) versus formoterol. Budesonide/formoterol pMDI is an appropriate treatment for reducing exacerbations in COPD patients with a history of exacerbations. (NCT00419744).

Bronchodilator Reversibility in COPD

COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The diagnosis of COPD is based on spirometric evidence of airways obstruction following bronchodilator administration. Although it used to be commonly believed that patients with COPD have largely irreversible airflow obstruction, evidence now suggests that a considerable proportion of patients exhibit clinically significant bronchodilator reversibility. The complexity and inherent variability of a patients acute response to a bronchodilator and the lack of a standardized procedure for assessing bronchodilator reversibility have led to significant confusion surrounding this concept. Although bronchodilator reversibility commonly is defined based on thresholds for improvement in FEV(1), lung volume-based measures of pulmonary function may be of particular importance in patients with severe COPD. The usefulness of acute reversibility to short-acting bronchodilators in predicting a patients long-term response to bronchodilator maintenance therapy is also unclear, although most studies suggest that a lack of acute response to short-acting bronchodilators does not preclude a beneficial long-term response to maintenance bronchodilator treatment. This review outlines recent findings about the prevalence and usefulness of bronchodilator reversibility in patients with COPD based on the available literature and proposes areas of future research.

ADRB2 Polymorphisms and Budesonide/Formoterol Responses in COPD

BACKGROUND Effects of β(2)-adrenergic receptor gene (ADRB2) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials. We aimed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD. METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I (NCT00206167) or the 6-month trial II (NCT00206154) were randomly assigned to bid budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9 μg or 160/9 μg, budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg (trial II), budesonide pMDI 320 μg (trial II), formoterol dry powder inhaler 9 μg, or placebo. The effect of Gly16Arg on predose FEV(1) and 1-h postdose FEV(1), exacerbations, diary variables, and adverse events were analyzed. RESULTS No significant interaction between genotype and treatment response was observed for predose (P ≥ .197) or postdose FEV(1) (P ≥ .125) in either pharmacogenetic study (n = 2,866). The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups (both studies). Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment. CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD.

Long-term safety and asthma control measures with a budesonide/formoterol pressurized metered-dose inhaler in African American asthmatic patients: A randomized controlled trial

BACKGROUND Information surrounding the long-term safety of combination inhaled corticosteroid/long-acting β(2)-adrenergic agonist medications in African American asthmatic patients is limited. OBJECTIVE We sought to assess safety and asthma control with a budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide over 1 year in African American patients. METHODS This 52-week, randomized, double-blind, parallel-group, multicenter, phase 3B safety study (NCT00419952) was conducted in 742 self-reported African American patients 12 years or older with moderate-to-severe asthma previously receiving medium- to high-dose inhaled corticosteroids. After 2 weeks using a 320 μg twice-daily budesonide pMDI, patients were randomized 1:1 to 320/9 μg twice-daily budesonide/formoterol pMDI or 320 μg twice-daily budesonide pMDI. RESULTS Both treatments were well tolerated. Asthma exacerbation incidence and rate (per patient-treatment year) were lower with budesonide/formoterol versus budesonide (incidence, 7.7% vs 14.0% [P= .006]; rate ratio, 0.615 [P= .002]). Time to first asthma exacerbation was longer (P= .018) with budesonide/formoterol versus budesonide. The most common adverse events, regardless of study drug relationship, were headache (9.5% and 7.7%), nasopharyngitis (6.9% and 8.0%), sinusitis (4.0% and 6.3%), and viral upper respiratory tract infection (5.8% and 4.4%) for budesonide/formoterol and budesonide, respectively. Serious adverse events occurred in 12 and 15 patients, respectively; none were considered drug related. No substantial or unexpected patterns of abnormalities were observed in laboratory, electrocardiographic, or Holter monitoring assessments. Hospitalization caused by asthma exacerbation occurred in 0 and 4 patients in the budesonide/formoterol and budesonide groups, respectively. Pulmonary function and asthma control measures generally favored budesonide/formoterol. CONCLUSIONS In this population budesonide/formoterol pMDI was well tolerated over 12 months, with a safety profile similar to that of budesonide; the asthma exacerbation rate was reduced by 38.5% versus budesonide.

Budesonide/Formoterol Pressurized Metered-Dose Inhaler versus Budesonide: A Randomized Controlled Trial in Black Patients with Asthma

Objective. Concerns exist that responses to long-acting β2-adrenergic agonists in black patients may differ from the general population. The efficacy and safety of budesonide/formoterol (BUD/FM) pressurized metered-dose inhaler (pMDI) versus budesonide dry powder inhaler (BUD DPI) were evaluated in adolescent and adult black asthma patients. Methods. This 12-week, randomized, double-blind, multicenter, phase IV US study was conducted in 311 self-reported black patients aged ≥12 years with moderate to severe persistent asthma, previously receiving medium- to high-dose inhaled corticosteroid. After 2 weeks on BUD 90 μg × 2 inhalations twice daily (bid), symptomatic patients were randomized to BUD/FM 160/4.5 μg × 2 inhalations bid or BUD 180 μg × 2 inhalations bid. Results. Improvement in predose forced expiratory volume in 1 second from baseline to the treatment mean (primary variable) was greater with BUD/FM versus BUD (0.16 vs. 0.07 L; p = .008); this effect was also observed at weeks 2, 6, and end of treatment (p ≤ .032). Greater improvements (p < .001) in peak expiratory flow with BUD/FM versus BUD were seen at first measurement and maintained during 12 weeks (morning: 25.34 vs. 7.53 L/minute, respectively; evening: 21.61 vs. 7.67 L/minute, respectively); greater improvements in daily asthma symptom score and rescue medication use were also observed (p ≤ .039). Both treatments were well tolerated, with similar safety profiles. Conclusions. In this population of black asthma patients, BUD/FM pMDI resulted in greater improvements in pulmonary function and asthma control versus BUD DPI, with similar safety profiles.

Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology

ABSTRACT This gamma scintigraphy imaging study was the first to assess pulmonary and extrathoracic deposition and regional lung deposition patterns of a radiolabelled long‐acting muscarinic antagonist/long‐acting &bgr;2‐agonist fixed‐dose combination glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 &mgr;g (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 &mgr;g), delivered by pressurized metered dose inhaler (pMDI) using novel co‐suspension delivery technology. In this Phase I, randomized, single‐centre, single‐blind, single‐dose, two‐treatment, crossover, placebo‐controlled study (PT003020), 10 healthy male adults received two actuations of GFF pMDI (7.2/5.0 &mgr;g per actuation) and placebo pMDI (containing phospholipid‐based porous particles without active pharmaceutical ingredient), both radiolabelled with 99mTc, up to 5 MBq per actuation. Gamma scintigraphy images of lungs, stomach, head and neck were recorded. In addition, images of the actuators after use, collected mouth washings and exhalation filters were acquired. On average, 38.4% of the emitted dose of radiolabelled GFF pMDI, and 32.8% of radiolabelled placebo pMDI, was deposited in the lungs. The percentage emitted dose detected in the oropharyngeal and stomach regions was 61.4% and 66.9% for radiolabelled GFF pMDI and placebo pMDI, respectively. For both treatments, ≤0.25% of the emitted dose was detected in the exhalation filter. The normalized outer/inner ratio was 0.57 and 0.59 for radiolabelled GFF pMDI and placebo pMDI, respectively, and the standardized central/peripheral ratio was 1.85 and 1.94 respectively, indicating delivery of both co‐suspension delivery technology formulations throughout the airways. There were no new or unexpected safety findings. In conclusion, both formulations were efficiently and uniformly deposited in the lungs with similar regional deposition patterns, oropharyngeal and stomach deposition, exhalation fraction and actuator‐recovered dose. Graphical abstract Figure. No Caption available.

24-h bronchodilation and inspiratory capacity improvements with glycopyrrolate/formoterol fumarate via co-suspension delivery technology in COPD

BackgroundSymptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control. We report the results of two phase IIIb crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 μg delivered using innovative co-suspension delivery technology) administered twice daily.MethodsPatients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks’ treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only). Lung function was assessed over 24 h on day 29 of each treatment period. The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV1AUC0–24). Other outcomes included change from baseline in average daily rescue medication use over the treatment period. In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity.ResultsGFF MDI treatment significantly increased FEV1AUC0–24 versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV1AUC versus placebo for hours 0–12 and 12–24. In PT003011, improvements with GFF MDI versus tiotropium in FEV1AUC were greater during hours 12–24 compared to 0–12 h. GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (−0.84 [p<0.0001] and −1.11 [p=0.0054] puffs/day in PT003011 and PT003012, respectively), and versus tiotropium in PT003011 (−0.44 [p=0.017] puffs/day). A post-hoc pooled analysis showed patients treated with GFF MDI were more likely to achieve a >15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29). There were no significant safety/tolerability findings.ConclusionsGFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI.Trial registrationPearl Therapeutics, Inc.; www.clinicaltrials.gov; NCT02347072 and NCT02347085. Registered 21 January 2015.

Baseline Symptom Score Impact on Benefits of Glycopyrrolate/Formoterol Metered Dose Inhaler in COPD

BACKGROUND: The clinical severity of COPD is currently categorized by symptom burden and exacerbation risk. Previous 24‐week phase III trials (NCT01854645 and NCT01854658) that demonstrated better improvement of lung function with glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) (an MDI fixed‐dose of GFF 18/9.6 &mgr;g) over individual monocomponent MDIs included a cross‐section of patients with moderate to very severe airflow limitation and a broad range of COPD symptoms. METHODS: These post hoc analyses of pooled data investigated whether baseline symptom burden, assessed using the COPD Assessment Test (CAT) score, impacted GFF MDI‐associated improvements in lung function, health status, rescue medication use, and exacerbation risk. RESULTS: In 3,699 patients, improvement in FEV1 at week 24 between the GFF MDI and monocomponent MDIs and a placebo MDI was similar in magnitude regardless of baseline CAT score. In contrast, the magnitude of mean difference in the St. Georges Respiratory Questionnaire total score for GFF MDI vs monocomponent MDIs and the placebo MDI increased with increasing baseline CAT scores. Likewise, reduced rescue medication use and lower exacerbation risk were more pronounced in GFF MDI groups with a higher baseline symptom burden. CONCLUSIONS: Beneficial effects of GFF MDI on health status, rescue medication use, and exacerbation risk in symptomatic patients with COPD increased as a function of baseline symptom burden, whereas lung function benefits were independent. These data suggest a greater clinical benefit from dual bronchodilators in symptomatic patients than in patients without symptoms. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01854645 and NCT01854658; URL: www.clinicaltrials.gov.