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Formoterol pMDI
Abstracts S153
J ALLERGY CLIN IMMUNOL VOLUME 121, NUMBER 2
588
Budesonide/Formoterol Combination Reduces Production of IL-5 and RANTES from Mononuclear Cells but Not Adhesion of Activated Eosinophils M. Nagata, T. Soma, Y. Takaku, T. Kobayashi, K. Hagiwara, M. Kanazawa; Saitama Medical University, Saitama, JAPAN. RATIONALE: Budesonide (BUD)/formoterol (FOR) combination (SymbicortÒ) for both maintenance and reliever therapy (SMART) results in the reduction in asthma exacerbations as compared with traditional fixed dosing regimens. The use of combination therapy during the early stage of asthma exacerbation may intervenes the development of subsequent airway inflammation. The objective of the study was to evaluate whether the use of BUD/FOR at the early stage of cell activation can modify the adhesion of eosinophils or production of cytokines from mononuclear cells. METHODS: Eosinophils isolated from human peripheral blood were pretreated with either BUD (0.1 mM), FOR (0.1 mM), or BUD/FOR for 30 min at 378C and stimulated with IL-5, LTD4, or PMA. The adhesion of eosinophils was evaluated using an EPO assay. Peripheral blood mononuclear cells (PBMC) were treated with BUD (0.1 mM), FOR (0.1 mM), or BUD/FOR either 15 min or 4 hr following the stimulation with a combination of ionomycin and PMA. The concentrations of IL-5 and RANTES in the culture supernatants of PBMC were examined by ELISA. RESULTS: Neither BUD, FOR, nor BUD/FOR combination modified eosinophil adhesion induced by IL-5, LTD4, or PMA. By contrast, BUD/ FOR combination significantly reduced the productions of IL-5, RANTES, and TNF-a by PBMC (N 5 6, p < 0.001), only when these compounds were added 15 min, but not 4 hr, following the stimulation of the cells. CONCLUSIONS: Inhalant BUD/FOR at early stage of exacerbation of asthma may suppress the progression of allergic inflammatory cascade via its inhibitory effect on mononuclear cells and hence prevents the development of severe asthma exacerbations. Funding: Saitama Medical University
589
Safety of Once-Daily (qd) Budesonide and Formoterol Administered via One Pressurized Metered-Dose Inhaler (pMDI) in Adults and Adolescents With Asthma Previously Stable With Twice-Daily (bid) Budesonide/Formoterol pMDI C. LaForce1, E. M. Kerwin2, J. J. Oppenheimer3, C. J. Miller4, P. Vervaet4, L. O’Dowd4, M. Goldman4; 1University of North Carolina School of Medicine and North Carolina Clinical Research, Raleigh, NC, 2Clinical
Research Institute of Southern Oregon, PC, Medford, OR, 3Pulmonary and Allergy Associates, Springfield, NJ, 4AstraZeneca, Wilmington, DE. RATIONALE: To evaluate the tolerability of budesonide/formoterol pMDI qd in patients previously stabilized on budesonide/formoterol pMDI bid. METHODS: This was a randomized, double-blind, 12-week study (D5896C00001) of 619 patients 12 years with mild to moderate asthma. After 4-5 weeks on budesonide/formoterol pMDI 80/4.5mg 32 inhalations bid (320/18mg daily), patients with stable asthma were randomized to budesonide/formoterol pMDI 80/4.5mg 32 inhalations bid (320/18mg daily), budesonide/formoterol pMDI 160/4.5mg 32 inhalations qd (320/9mg daily; evening), budesonide/formoterol pMDI 80/4.5mg 32 inhalations qd (160/ 9mg daily; evening), or budesonide pMDI 160mg 32 inhalations qd (320mg daily; evening). Adverse events (AEs), clinical laboratory evaluations, vital signs, and physical examinations were assessed. RESULTS: All treatments were generally well tolerated. Most AEs (62.9%) were mild intensity. Discontinuations due to AEs were low and similar among treatments. Two patients (1.3%) in the budesonide/ formoterol bid and 3 (1.9%) in the lower-dose budesonide/formoterol qd groups had serious AEs. There were no serious drug-related AEs. The percentage of patients with any drug-related AE was low, but numerically higher in the budesonide/formoterol bid (7.7%) and lower-dose qd (6.4%) groups versus the higher-dose qd budesonide/formoterol (3.3%) and budesonide (2.0%) groups. Two patients discontinued because of drugrelated AEs: 1 patient each in the budesonide/formoterol bid (headache) and higher-dose budesonide/formoterol qd (anxiety and restlessness) groups. No clinically significant findings were observed in clinical laboratory values (including serum glucose and potassium), vital signs (heart rate, blood pressure), or physical examinations for any budesonide/ formoterol group versus budesonide. CONCLUSIONS: All budesonide/formoterol pMDI treatments were well tolerated, with safety profiles similar to that of budesonide. Funding: AstraZeneca
590
Long-Term Safety of Bronchial Thermoplasty: Extended Follow-Up Out to 5 Years G. Cox1, J. Miller1, S. Goodwin2, J. Fitzgerald3, L. Hui3, S. Lam3; 1 McMaster University, Hamilton, ON, CANADA, 2St. Joseph’s Healthcare Hamilton, Hamilton, ON, CANADA, 3Vancouver General Hospital, Vancouver, BC, CANADA. INTRODUCTION: Bronchial thermoplasty (BT) is a novel bronchoscopic procedure designed to control asthma by reducing the mass of airway smooth muscle. The first 16 patients with asthma to undergo BT recently completed follow-up out to 5 years. The long-term safety findings for Year 2 and beyond are presented. METHODS: The Feasibility Study enrolled 16 adults with stable asthma (no asthma medication changes in prior 6 weeks), post-bronchodilator FEV1 of >65% predicted, and a methacholine PC20 of <8 mg/ml. All patients were evaluated annually for 5 years post-treatment. To assess longterm safety, adverse event (AE) and spirometry data were collected. Qualitative comparisons of annual CT scans against Baseline CT’s were also performed. RESULTS: Total number of respiratory AEs during Years 2, 3, 4, and 5 were 18 (mild 5 5; moderate 5 12; severe 5 1), 25 (mild 5 9; moderate 5 15; severe 5 1), 14 (mild 5 7; moderate 5 7; severe 5 0), and 22 (mild 5 9; moderate 5 13; severe 5 0), respectively. There were no hospitalizations related to the patients’ asthma in the study, including this follow-up period. Pre-bronchodilator FEV1 %predicted was 87.2, 83.8, 82.6 and 86.3 for Years 2-5, respectively, compared to a baseline of 82.4. There was no evidence of any clinically significant changes in the airways including stenosis or bronchiectasis post-BT based on comparison of CT scans taken at Baseline and annually for 5 years after BT. CONCLUSIONS: The absence of any qualitative (based on CT scans), functional (based on spirometry) and clinical complications in 5 years post-BT suggests this procedure has a satisfactory safety profile over the long-term. Funding: Asthmatx
MONDAY
budesonide/formoterol pMDI 80/4.5mg 32 inhalations bid (320/18mg daily), budesonide/formoterol pMDI 160/4.5mg 32 inhalations qd (320/9mg daily; evening), budesonide/formoterol pMDI 80/4.5mg 32 inhalations qd (160/9mg daily; evening), or budesonide pMDI 160mg 32 inhalations qd (320mg daily; evening). Evening predose FEV1 (primary variable, measured at the end of qd dosing interval) and predose morning and evening PEF were measured. RESULTS: All budesonide/formoterol treatments were significantly (P .016) more effective than budesonide for evening predose FEV1. Evening PEF was significantly (P .004) higher for bid and higher-dose qd budesonide/formoterol than budesonide. All budesonide/formoterol treatments were significantly (P < .001) more effective than budesonide for morning PEF (measured halfway through qd dosing interval), with no significant differences among budesonide/formoterol groups. Changes from baseline in evening predose FEV1 significantly (P 5 .031) favored higher-dose versus lower-dose qd budesonide/formoterol. Changes from baseline in evening predose FEV1 and evening PEF (measured at the end of qd dosing interval) significantly (P <.001) favored budesonide/formoterol bid versus budesonide/formoterol qd. CONCLUSIONS: Budesonide/formoterol qd (320/9mg and 160/9mg daily) and bid (320/18mg daily) were more effective at maintaining pulmonary function versus budesonide qd (320mg daily). Budesonide/ formoterol bid, at twice the daily formoterol dose, was more effective than budesonide/formoterol qd, regardless of the budesonide dose. Funding: AstraZeneca
J ALLERGY CLIN IMMUNOL VOLUME 121, NUMBER 2
588
Budesonide/Formoterol Combination Reduces Production of IL-5 and RANTES from Mononuclear Cells but Not Adhesion of Activated Eosinophils M. Nagata, T. Soma, Y. Takaku, T. Kobayashi, K. Hagiwara, M. Kanazawa; Saitama Medical University, Saitama, JAPAN. RATIONALE: Budesonide (BUD)/formoterol (FOR) combination (SymbicortÒ) for both maintenance and reliever therapy (SMART) results in the reduction in asthma exacerbations as compared with traditional fixed dosing regimens. The use of combination therapy during the early stage of asthma exacerbation may intervenes the development of subsequent airway inflammation. The objective of the study was to evaluate whether the use of BUD/FOR at the early stage of cell activation can modify the adhesion of eosinophils or production of cytokines from mononuclear cells. METHODS: Eosinophils isolated from human peripheral blood were pretreated with either BUD (0.1 mM), FOR (0.1 mM), or BUD/FOR for 30 min at 378C and stimulated with IL-5, LTD4, or PMA. The adhesion of eosinophils was evaluated using an EPO assay. Peripheral blood mononuclear cells (PBMC) were treated with BUD (0.1 mM), FOR (0.1 mM), or BUD/FOR either 15 min or 4 hr following the stimulation with a combination of ionomycin and PMA. The concentrations of IL-5 and RANTES in the culture supernatants of PBMC were examined by ELISA. RESULTS: Neither BUD, FOR, nor BUD/FOR combination modified eosinophil adhesion induced by IL-5, LTD4, or PMA. By contrast, BUD/ FOR combination significantly reduced the productions of IL-5, RANTES, and TNF-a by PBMC (N 5 6, p < 0.001), only when these compounds were added 15 min, but not 4 hr, following the stimulation of the cells. CONCLUSIONS: Inhalant BUD/FOR at early stage of exacerbation of asthma may suppress the progression of allergic inflammatory cascade via its inhibitory effect on mononuclear cells and hence prevents the development of severe asthma exacerbations. Funding: Saitama Medical University
589
Safety of Once-Daily (qd) Budesonide and Formoterol Administered via One Pressurized Metered-Dose Inhaler (pMDI) in Adults and Adolescents With Asthma Previously Stable With Twice-Daily (bid) Budesonide/Formoterol pMDI C. LaForce1, E. M. Kerwin2, J. J. Oppenheimer3, C. J. Miller4, P. Vervaet4, L. O’Dowd4, M. Goldman4; 1University of North Carolina School of Medicine and North Carolina Clinical Research, Raleigh, NC, 2Clinical
Research Institute of Southern Oregon, PC, Medford, OR, 3Pulmonary and Allergy Associates, Springfield, NJ, 4AstraZeneca, Wilmington, DE. RATIONALE: To evaluate the tolerability of budesonide/formoterol pMDI qd in patients previously stabilized on budesonide/formoterol pMDI bid. METHODS: This was a randomized, double-blind, 12-week study (D5896C00001) of 619 patients 12 years with mild to moderate asthma. After 4-5 weeks on budesonide/formoterol pMDI 80/4.5mg 32 inhalations bid (320/18mg daily), patients with stable asthma were randomized to budesonide/formoterol pMDI 80/4.5mg 32 inhalations bid (320/18mg daily), budesonide/formoterol pMDI 160/4.5mg 32 inhalations qd (320/9mg daily; evening), budesonide/formoterol pMDI 80/4.5mg 32 inhalations qd (160/ 9mg daily; evening), or budesonide pMDI 160mg 32 inhalations qd (320mg daily; evening). Adverse events (AEs), clinical laboratory evaluations, vital signs, and physical examinations were assessed. RESULTS: All treatments were generally well tolerated. Most AEs (62.9%) were mild intensity. Discontinuations due to AEs were low and similar among treatments. Two patients (1.3%) in the budesonide/ formoterol bid and 3 (1.9%) in the lower-dose budesonide/formoterol qd groups had serious AEs. There were no serious drug-related AEs. The percentage of patients with any drug-related AE was low, but numerically higher in the budesonide/formoterol bid (7.7%) and lower-dose qd (6.4%) groups versus the higher-dose qd budesonide/formoterol (3.3%) and budesonide (2.0%) groups. Two patients discontinued because of drugrelated AEs: 1 patient each in the budesonide/formoterol bid (headache) and higher-dose budesonide/formoterol qd (anxiety and restlessness) groups. No clinically significant findings were observed in clinical laboratory values (including serum glucose and potassium), vital signs (heart rate, blood pressure), or physical examinations for any budesonide/ formoterol group versus budesonide. CONCLUSIONS: All budesonide/formoterol pMDI treatments were well tolerated, with safety profiles similar to that of budesonide. Funding: AstraZeneca
590
Long-Term Safety of Bronchial Thermoplasty: Extended Follow-Up Out to 5 Years G. Cox1, J. Miller1, S. Goodwin2, J. Fitzgerald3, L. Hui3, S. Lam3; 1 McMaster University, Hamilton, ON, CANADA, 2St. Joseph’s Healthcare Hamilton, Hamilton, ON, CANADA, 3Vancouver General Hospital, Vancouver, BC, CANADA. INTRODUCTION: Bronchial thermoplasty (BT) is a novel bronchoscopic procedure designed to control asthma by reducing the mass of airway smooth muscle. The first 16 patients with asthma to undergo BT recently completed follow-up out to 5 years. The long-term safety findings for Year 2 and beyond are presented. METHODS: The Feasibility Study enrolled 16 adults with stable asthma (no asthma medication changes in prior 6 weeks), post-bronchodilator FEV1 of >65% predicted, and a methacholine PC20 of <8 mg/ml. All patients were evaluated annually for 5 years post-treatment. To assess longterm safety, adverse event (AE) and spirometry data were collected. Qualitative comparisons of annual CT scans against Baseline CT’s were also performed. RESULTS: Total number of respiratory AEs during Years 2, 3, 4, and 5 were 18 (mild 5 5; moderate 5 12; severe 5 1), 25 (mild 5 9; moderate 5 15; severe 5 1), 14 (mild 5 7; moderate 5 7; severe 5 0), and 22 (mild 5 9; moderate 5 13; severe 5 0), respectively. There were no hospitalizations related to the patients’ asthma in the study, including this follow-up period. Pre-bronchodilator FEV1 %predicted was 87.2, 83.8, 82.6 and 86.3 for Years 2-5, respectively, compared to a baseline of 82.4. There was no evidence of any clinically significant changes in the airways including stenosis or bronchiectasis post-BT based on comparison of CT scans taken at Baseline and annually for 5 years after BT. CONCLUSIONS: The absence of any qualitative (based on CT scans), functional (based on spirometry) and clinical complications in 5 years post-BT suggests this procedure has a satisfactory safety profile over the long-term. Funding: Asthmatx
MONDAY
budesonide/formoterol pMDI 80/4.5mg 32 inhalations bid (320/18mg daily), budesonide/formoterol pMDI 160/4.5mg 32 inhalations qd (320/9mg daily; evening), budesonide/formoterol pMDI 80/4.5mg 32 inhalations qd (160/9mg daily; evening), or budesonide pMDI 160mg 32 inhalations qd (320mg daily; evening). Evening predose FEV1 (primary variable, measured at the end of qd dosing interval) and predose morning and evening PEF were measured. RESULTS: All budesonide/formoterol treatments were significantly (P .016) more effective than budesonide for evening predose FEV1. Evening PEF was significantly (P .004) higher for bid and higher-dose qd budesonide/formoterol than budesonide. All budesonide/formoterol treatments were significantly (P < .001) more effective than budesonide for morning PEF (measured halfway through qd dosing interval), with no significant differences among budesonide/formoterol groups. Changes from baseline in evening predose FEV1 significantly (P 5 .031) favored higher-dose versus lower-dose qd budesonide/formoterol. Changes from baseline in evening predose FEV1 and evening PEF (measured at the end of qd dosing interval) significantly (P <.001) favored budesonide/formoterol bid versus budesonide/formoterol qd. CONCLUSIONS: Budesonide/formoterol qd (320/9mg and 160/9mg daily) and bid (320/18mg daily) were more effective at maintaining pulmonary function versus budesonide qd (320mg daily). Budesonide/ formoterol bid, at twice the daily formoterol dose, was more effective than budesonide/formoterol qd, regardless of the budesonide dose. Funding: AstraZeneca