Budesonide/Formoterol Therapy in Asthma
Budesonide/Formoterol Therapy in Asthma
Between July 2009 and August 2010, a total of 1022 eligible asthma patients were enrolled from 51 study centres across China, India, Indonesia, Thailand and Taiwan. Amongst them, 862 (84.3%) patients entered into the study treatment period. There were 407 males and 455 females with mean age (± SD) of 44.7 ± 13.7 years. Together, they have had asthma for a mean duration of 10.73 ± 12.03 years, and the majority of these patients (69%) were being treated with Salbutamol (393 patients; 45.6%) or combination of Fluticason and Salmeterol (202 patients; 23.4%), while the rest were treated with various other asthma medications. Most patients were also on concomitant ICS. At entry to this study, 719 patients (83.4%) were on ICS, with 525 patients (60.9%) on LABA plus ICS, and 135 patients (15.7%) on SABA plus ICS.
Of the patients who entered into the study treatment period, 66 (7.7%) of them discontinued from the study for various reasons, which include adverse events (15 patients), pregnancy (1 patient), self-withdrawal (13 patients), deviations from study protocol (6 patients), incorrect enrolment (8 patients) and lost to follow-up (23 patients). The 862 patients who took at least one dose of the investigational drug, budesonide/formoterol, formed the set of subjects for analysis of both the efficacy and safety outcomes of this study (Table 1). The demographic and baseline characteristics of the subjects in the full analysis set are summarised in Table 2.
Change in ACQ-5 Score From Baseline at Regional Level. At the regional level, patients' asthma control significantly improved during treatment with budesonide/formoterol maintenance and reliever therapy. This is reflected by the consistent reduction in mean overall ACQ-5 score from baseline to 4, 8, and 12 weeks of the therapy (Figure 2 and Table 3). A significant decrease in ACQ-5 score was evident from 4 weeks post-initiation of treatment with budesonide/formoterol maintenance and reliever therapy, indicating early onset of improvement in asthma control. During the treatment period, overall mean ACQ-5 score improved significantly by 0.58 ± 0.93 (95% CI, 0.51 to 0.64; P < 0.0001). Clinically important improvement in ACQ-5 score (change ≥ MID of 0.5) was observed by 8 weeks of treatment. During treatment, 48.2% of the patients experienced improvement in symptoms, while only 8.8% experienced worsening of symptoms.
(Enlarge Image)
Figure 2.
Mean ACQ-5 scores following initiation of treatment with budesonide/formoterol maintenance and reliever therapy (regional level). * denotes significant difference from baseline level. Visit 2 = baseline.
Change in ACQ-5 Score From Baseline at Country/Area Level. Significant reduction in mean ACQ-5 score of patients was observed in all 5 participating countries during the period they were treated with budesonide/formoterol maintenance and reliever therapy (P < 0.0001 to P = 0.0089), indicating significant improvements in asthma control across the region during the treatment (Figure 3 and Table 4). Statistically significant changes were observed from as early as 4 weeks after initiation of the treatment. However, the quantum of change in ACQ-5 scores differed significantly between study populations in the various countries/areas (P < 0.0001); the change was highest amongst the study population in Indonesia, followed by that of those in India, China, Thailand and Taiwan. Improvement in asthma control reached clinical importance (change in ACQ-5 score ≥ MID of 0.5) only in the study populations in China, India and Indonesia; in China and Indonesia, clinically important improvement in ACQ-5 score was achieved by 4 weeks post-initiation of treatment with budesonide/formoterol maintenance and reliever therapy.
(Enlarge Image)
Figure 3.
Mean Change in ACQ-5 scores from baseline to treatment period (by country/area). * denotes significant difference from baseline level.
Asthma Symptom Score, Days With Awakening(s) During the Night, Inhalations of Medications, Asthma-control and Asthma Symptom-free Days. Patients' mean asthma symptom score was significantly reduced (P < 0.0001) while they were on treatment with budesonide/formoterol maintenance and reliever therapy. From run-in to treatment period, night- and day-time symptom score improved by 0.32 ± 0.54 (95% CI, 0.28 to 0.35) and 0.30 ± 0.52 (95% CI, 0.27 to 0.34), respectively. The percentage of days with awakening(s) due to asthma symptoms during the night was reduced by 11.09 ± 26.13% (95% CI, 9.34 to 12.85%; P < 0.0001), while the percentage of asthma-control and symptom-free days increased by 20.90 ± 34.40% (95% CI, 18.59 to 23.21%) and 23.89 ± 34.62% (95% CI, 21.56 to 26.21%), respectively (P < 0.0001).
During the run-in period, the number of inhalations (mean ± SD) of as-needed medications was 0.57 ± 0.88 inhalations during night-time and 0.65 ± 1.04 inhalations during day-time. The corresponding numbers of night-time and day-time inhalations during treatment period was 0.27 ±0.44 and 0.36 ± 0.56 inhalations, respectively. Along with that, the number of inhalations of as-needed reliever medications for night- and day-time was significantly reduced by 0.30 ± 0.82 (95% CI, 0.24 to 0.35) inhalations and 0.30 ± 0.97 (95% CI, 0.23 to 0.36) inhalations, respectively (P < 0.0001). Concurrently, the percentage of as-needed medication free days increased by 11.90 ± 44.65% (95% CI, 8.90 to 14.89%; P < 0.0001). During the period patients were on budesonide/formoterol maintenance and reliever therapy, only 1 patient (0.1%) had used SABA concomitantly for relief of symptoms.
Change in Forced Expiratory Volume in One Second (FEV1) From Baseline Level. Patients' lung function improved during treatment with budesonide/formoterol maintenance and reliever therapy. This was reflected by a significant increase in FEV1 G-mean value from baseline level as early as 4 weeks post-initiation of treatment (P < 0.0001), indicating an early onset in recovery of impaired lung function (Figure 4 and Table 5). At baseline, mean FEV1 (mean ± SD) was 1.96 ± 0.76 L and G-mean FEV1 (G-mean ± CV%) was 1.82 ± 40.78 L. During the 12 weeks of treatment, the overall increase in mean FEV1 from baseline was 0.17 ± 0.35 (95% CI, 0.15 - 0.20) L; the corresponding increase in G-mean FEV1 was 1.10 ± 19.33 (95% CI, 1.08 - 1.11) L (P < 0.0001).
(Enlarge Image)
Figure 4.
G-mean FEV1change from Visit 2 (baseline) and 95% CI.
Change in AQLQ-S Domains and Overall Scores From Baseline (Regional Level). During treatment with budesonide/formoterol maintenance and reliever therapy, patients' overall AQLQ-S score improved by 0.70 ± 0.89 (95% CI, 0.64 to 0.76) from baseline level (P < 0.0001), demonstrating a significant overall improvement in patients' quality of life across the region. Significant improvement was evident from as early as 4 weeks into the therapy, and the improvement continued throughout the treatment period (Table 6). Clinically important change (difference ≥ MID of 0.5) was evident from 8 weeks post-initiation of budesonide/formoterol maintenance and reliever therapy. While 52.9% of the patients experienced improvement in everyday functioning and well-being, only 5.1% of them experienced worsened conditions. Overall scores for symptoms, activity limitations, emotion function and response to environmental stimuli were likewise significantly increased during the treatment period (P < 0.0001), with significant improvement seen from as early as 4 weeks after initiation of treatment with budesonide/formoterol maintenance and reliever therapy.
Change in AQLQ-S Domains and Overall Scores From Baseline (Country/Area Level). Statistically significant improvement in overall AQLQ-S score was observed in all 5 participating countries/areas during treatment with budesonide/formoterol maintenance and reliever therapy (P < 0.0001 to P = 0.0002). Significant improvements from baseline levels were observed by 4 weeks of treatment (P < 0.0001 to P = 0.0252). The quantum of change however differed significantly between the populations studied in the various countries/areas (P < 0.0001); the change from baseline level was greatest in the study population in Indonesia, followed by that of those in India, China, Thailand and Taiwan. Clinically important change (difference ≥ MID of 0.5) in AQLQ-S score was observed only in Indonesia, Thailand, China and India. Significant improvements in individual domains (symptoms, activity limitations, emotional function and response to environmental stimuli) measured during treatment were also observed in all the study populations in the 5 countries/area.
Amongst the 862 patients included in the safety analysis, 171 patients (19.8%) reported adverse events, and 12 patients (1.4%) reported serious adverse events. The most frequently reported adverse events were nasopharyngitis (3.4%), followed by upper respiratory tract infection (3.2%), and asthma exacerbation (1.4%). The majority (130 of 171) of the adverse events were of mild intensity. Thirteen patients (1.5%) had their study medication discontinued because of adverse events. Serious adverse events were uncommon, with only 15 events reported in 12 patients, 8 of which were considered severe in intensity, and one of them was life threatening. There were 3 cases of palpitations, the causality of which were judged by the investigator as possibly related to budesonide/formoterol maintenance and reliever therapy. Two of the serious adverse events, an asthma exacerbation and a myocardial infarction, resulted in death. Both deaths were however considered unrelated to budesonide/formoterol maintenance and reliever therapy.
Results
Patients' Demographics and Baseline Characteristics
Between July 2009 and August 2010, a total of 1022 eligible asthma patients were enrolled from 51 study centres across China, India, Indonesia, Thailand and Taiwan. Amongst them, 862 (84.3%) patients entered into the study treatment period. There were 407 males and 455 females with mean age (± SD) of 44.7 ± 13.7 years. Together, they have had asthma for a mean duration of 10.73 ± 12.03 years, and the majority of these patients (69%) were being treated with Salbutamol (393 patients; 45.6%) or combination of Fluticason and Salmeterol (202 patients; 23.4%), while the rest were treated with various other asthma medications. Most patients were also on concomitant ICS. At entry to this study, 719 patients (83.4%) were on ICS, with 525 patients (60.9%) on LABA plus ICS, and 135 patients (15.7%) on SABA plus ICS.
Of the patients who entered into the study treatment period, 66 (7.7%) of them discontinued from the study for various reasons, which include adverse events (15 patients), pregnancy (1 patient), self-withdrawal (13 patients), deviations from study protocol (6 patients), incorrect enrolment (8 patients) and lost to follow-up (23 patients). The 862 patients who took at least one dose of the investigational drug, budesonide/formoterol, formed the set of subjects for analysis of both the efficacy and safety outcomes of this study (Table 1). The demographic and baseline characteristics of the subjects in the full analysis set are summarised in Table 2.
Assessments of Impact on Patients' Asthma Control
Change in ACQ-5 Score From Baseline at Regional Level. At the regional level, patients' asthma control significantly improved during treatment with budesonide/formoterol maintenance and reliever therapy. This is reflected by the consistent reduction in mean overall ACQ-5 score from baseline to 4, 8, and 12 weeks of the therapy (Figure 2 and Table 3). A significant decrease in ACQ-5 score was evident from 4 weeks post-initiation of treatment with budesonide/formoterol maintenance and reliever therapy, indicating early onset of improvement in asthma control. During the treatment period, overall mean ACQ-5 score improved significantly by 0.58 ± 0.93 (95% CI, 0.51 to 0.64; P < 0.0001). Clinically important improvement in ACQ-5 score (change ≥ MID of 0.5) was observed by 8 weeks of treatment. During treatment, 48.2% of the patients experienced improvement in symptoms, while only 8.8% experienced worsening of symptoms.
(Enlarge Image)
Figure 2.
Mean ACQ-5 scores following initiation of treatment with budesonide/formoterol maintenance and reliever therapy (regional level). * denotes significant difference from baseline level. Visit 2 = baseline.
Change in ACQ-5 Score From Baseline at Country/Area Level. Significant reduction in mean ACQ-5 score of patients was observed in all 5 participating countries during the period they were treated with budesonide/formoterol maintenance and reliever therapy (P < 0.0001 to P = 0.0089), indicating significant improvements in asthma control across the region during the treatment (Figure 3 and Table 4). Statistically significant changes were observed from as early as 4 weeks after initiation of the treatment. However, the quantum of change in ACQ-5 scores differed significantly between study populations in the various countries/areas (P < 0.0001); the change was highest amongst the study population in Indonesia, followed by that of those in India, China, Thailand and Taiwan. Improvement in asthma control reached clinical importance (change in ACQ-5 score ≥ MID of 0.5) only in the study populations in China, India and Indonesia; in China and Indonesia, clinically important improvement in ACQ-5 score was achieved by 4 weeks post-initiation of treatment with budesonide/formoterol maintenance and reliever therapy.
(Enlarge Image)
Figure 3.
Mean Change in ACQ-5 scores from baseline to treatment period (by country/area). * denotes significant difference from baseline level.
Asthma Symptom Score, Days With Awakening(s) During the Night, Inhalations of Medications, Asthma-control and Asthma Symptom-free Days. Patients' mean asthma symptom score was significantly reduced (P < 0.0001) while they were on treatment with budesonide/formoterol maintenance and reliever therapy. From run-in to treatment period, night- and day-time symptom score improved by 0.32 ± 0.54 (95% CI, 0.28 to 0.35) and 0.30 ± 0.52 (95% CI, 0.27 to 0.34), respectively. The percentage of days with awakening(s) due to asthma symptoms during the night was reduced by 11.09 ± 26.13% (95% CI, 9.34 to 12.85%; P < 0.0001), while the percentage of asthma-control and symptom-free days increased by 20.90 ± 34.40% (95% CI, 18.59 to 23.21%) and 23.89 ± 34.62% (95% CI, 21.56 to 26.21%), respectively (P < 0.0001).
During the run-in period, the number of inhalations (mean ± SD) of as-needed medications was 0.57 ± 0.88 inhalations during night-time and 0.65 ± 1.04 inhalations during day-time. The corresponding numbers of night-time and day-time inhalations during treatment period was 0.27 ±0.44 and 0.36 ± 0.56 inhalations, respectively. Along with that, the number of inhalations of as-needed reliever medications for night- and day-time was significantly reduced by 0.30 ± 0.82 (95% CI, 0.24 to 0.35) inhalations and 0.30 ± 0.97 (95% CI, 0.23 to 0.36) inhalations, respectively (P < 0.0001). Concurrently, the percentage of as-needed medication free days increased by 11.90 ± 44.65% (95% CI, 8.90 to 14.89%; P < 0.0001). During the period patients were on budesonide/formoterol maintenance and reliever therapy, only 1 patient (0.1%) had used SABA concomitantly for relief of symptoms.
Change in Forced Expiratory Volume in One Second (FEV1) From Baseline Level. Patients' lung function improved during treatment with budesonide/formoterol maintenance and reliever therapy. This was reflected by a significant increase in FEV1 G-mean value from baseline level as early as 4 weeks post-initiation of treatment (P < 0.0001), indicating an early onset in recovery of impaired lung function (Figure 4 and Table 5). At baseline, mean FEV1 (mean ± SD) was 1.96 ± 0.76 L and G-mean FEV1 (G-mean ± CV%) was 1.82 ± 40.78 L. During the 12 weeks of treatment, the overall increase in mean FEV1 from baseline was 0.17 ± 0.35 (95% CI, 0.15 - 0.20) L; the corresponding increase in G-mean FEV1 was 1.10 ± 19.33 (95% CI, 1.08 - 1.11) L (P < 0.0001).
(Enlarge Image)
Figure 4.
G-mean FEV1change from Visit 2 (baseline) and 95% CI.
Assessment of Impact on Patients' Quality of Life
Change in AQLQ-S Domains and Overall Scores From Baseline (Regional Level). During treatment with budesonide/formoterol maintenance and reliever therapy, patients' overall AQLQ-S score improved by 0.70 ± 0.89 (95% CI, 0.64 to 0.76) from baseline level (P < 0.0001), demonstrating a significant overall improvement in patients' quality of life across the region. Significant improvement was evident from as early as 4 weeks into the therapy, and the improvement continued throughout the treatment period (Table 6). Clinically important change (difference ≥ MID of 0.5) was evident from 8 weeks post-initiation of budesonide/formoterol maintenance and reliever therapy. While 52.9% of the patients experienced improvement in everyday functioning and well-being, only 5.1% of them experienced worsened conditions. Overall scores for symptoms, activity limitations, emotion function and response to environmental stimuli were likewise significantly increased during the treatment period (P < 0.0001), with significant improvement seen from as early as 4 weeks after initiation of treatment with budesonide/formoterol maintenance and reliever therapy.
Change in AQLQ-S Domains and Overall Scores From Baseline (Country/Area Level). Statistically significant improvement in overall AQLQ-S score was observed in all 5 participating countries/areas during treatment with budesonide/formoterol maintenance and reliever therapy (P < 0.0001 to P = 0.0002). Significant improvements from baseline levels were observed by 4 weeks of treatment (P < 0.0001 to P = 0.0252). The quantum of change however differed significantly between the populations studied in the various countries/areas (P < 0.0001); the change from baseline level was greatest in the study population in Indonesia, followed by that of those in India, China, Thailand and Taiwan. Clinically important change (difference ≥ MID of 0.5) in AQLQ-S score was observed only in Indonesia, Thailand, China and India. Significant improvements in individual domains (symptoms, activity limitations, emotional function and response to environmental stimuli) measured during treatment were also observed in all the study populations in the 5 countries/area.
Safety
Amongst the 862 patients included in the safety analysis, 171 patients (19.8%) reported adverse events, and 12 patients (1.4%) reported serious adverse events. The most frequently reported adverse events were nasopharyngitis (3.4%), followed by upper respiratory tract infection (3.2%), and asthma exacerbation (1.4%). The majority (130 of 171) of the adverse events were of mild intensity. Thirteen patients (1.5%) had their study medication discontinued because of adverse events. Serious adverse events were uncommon, with only 15 events reported in 12 patients, 8 of which were considered severe in intensity, and one of them was life threatening. There were 3 cases of palpitations, the causality of which were judged by the investigator as possibly related to budesonide/formoterol maintenance and reliever therapy. Two of the serious adverse events, an asthma exacerbation and a myocardial infarction, resulted in death. Both deaths were however considered unrelated to budesonide/formoterol maintenance and reliever therapy.