Safety and Efficacy of Proprietary Glycopyrronium MDI in COPD
A total of 73 subjects were screened for the study. Of these 25 (34.2%) were not eligible because of the reversibility criteria. Of those eligible, 33 study patients were enrolled in this study (Figure 1). No patients meeting the entry criteria were taking leukotriene inhibitors (zafirlukast, montelukast, zileuton) or cromoglycate and nedocromil. Two study patients were withdrawn due to rescue medication use during a test day. The majority of study patients were male (58%) and Caucasian (97%). Other demographic and baseline clinical characteristics are shown in Table 1. The intent-to-treat/safety population (N = 33) included all study patients who were randomized and received at least one dose of study treatment and was used for demographic and safety analyses. A modified intent-to-treat (mITT) population (n = 30) that excluded 3 randomized study patients due to protocol violations (rescue medication use) was used for PK and efficacy analyses.
(Enlarge Image)
Figure 1.
Study patient disposition; reports the overall enrollment, allocation, and follow-up for study patients. Two patients were excluded for both failed FEV1 reversibility and a failed ECG, making the total number of patients who failed screening 40.
Primary Efficacy Variable. The mean change in FEV1 from test-day baseline over time is illustrated in Figure 2. All 4 doses of GP MDI demonstrated statistically superior efficacy compared with Placebo MDI (P < 0.001) for peak change in FEV1 (Table 2). There was a clear dose ordering of the peak FEV1 response, with the 115.2 μg dose presenting the greatest difference from placebo (248 mL). TIO 18 μg also demonstrated statistically superior efficacy compared with Placebo MDI (P < 0.001) for peak change in FEV1.
(Enlarge Image)
Figure 2.
Mean (±standard error) change from baseline in FEV1over 24 hours by treatment; represents the results for the peak change in FEV1(the primary efficacy endpoint) as well as the change in FEV1from test-day baseline over time.
Secondary Efficacy Variables. Each of the GP MDI doses exhibited a statistically significantly greater (P ≤ 0.049) mean change from test-day baseline compared with Placebo MDI for 12- and 24-hour tFEV1, FEV1 AUC0–12, FEV1 AUC0–24, and FEV1 AUC12–24, with the single exception of the GP MDI 28.8 μg comparison for the 24-hour tFEV1 (P = 0.059) (Figure 3). GP MDI demonstrated a more rapid onset of action compared with TIO 18 μg, with median time to ≥10% improvement in FEV1 of 0.5 hours or less for all doses of GP MDI evaluated, compared with approximately 1 hour for TIO 18 μg.
(Enlarge Image)
Figure 3.
Adjusted Mean (±standard error) change from baseline in FEV1parameters relative to placebo; provides a concise depiction of the mean change from baseline in peak FEV1, 12-hour FEV1, FEV1AUC0–12, 24 hour FEV1, FEV1AUC0–24, FEV1AUC12–24.
Mean plasma glycopyrronium concentrations over time are presented in Figure 4. Overall, exposure (both maximum plasma concentration [Cmax] and AUC) increased in a proportional manner with dose (Table 3). Cmax was reached rapidly (usually within 6 minutes of dosing). Apparent oral clearance and volume of distribution appeared relatively consistent across doses.
(Enlarge Image)
Figure 4.
Mean plasma glycopyrronium concentrations over time.
The most frequently reported AE was dry mouth (Table 4). All other AEs were reported only once or twice during the study and were distributed across the treatments. Dry mouth was also the most frequently reported drug-related AE. The only other AEs besides dry mouth reported as being drug-related were dyspnea (GP MDI 28.8 μg, 1 study patient) and paradoxical bronchospasm, defined as a reduction in FEV1 of >20% from test-day baseline with associated symptoms of wheezing, shortness of breath or cough (GP MDI 115.2 μg, 1 patient; mild in severity on the day following treatment). No patient experienced an SAE during the study, and no study patient discontinued due to an AE. Changes in hematology, clinical chemistry, vital signs, physical examination findings, and ECGs were small, and no treatment-related trends were observed.
Results
Disposition and Baseline Characteristics
A total of 73 subjects were screened for the study. Of these 25 (34.2%) were not eligible because of the reversibility criteria. Of those eligible, 33 study patients were enrolled in this study (Figure 1). No patients meeting the entry criteria were taking leukotriene inhibitors (zafirlukast, montelukast, zileuton) or cromoglycate and nedocromil. Two study patients were withdrawn due to rescue medication use during a test day. The majority of study patients were male (58%) and Caucasian (97%). Other demographic and baseline clinical characteristics are shown in Table 1. The intent-to-treat/safety population (N = 33) included all study patients who were randomized and received at least one dose of study treatment and was used for demographic and safety analyses. A modified intent-to-treat (mITT) population (n = 30) that excluded 3 randomized study patients due to protocol violations (rescue medication use) was used for PK and efficacy analyses.
(Enlarge Image)
Figure 1.
Study patient disposition; reports the overall enrollment, allocation, and follow-up for study patients. Two patients were excluded for both failed FEV1 reversibility and a failed ECG, making the total number of patients who failed screening 40.
Efficacy
Primary Efficacy Variable. The mean change in FEV1 from test-day baseline over time is illustrated in Figure 2. All 4 doses of GP MDI demonstrated statistically superior efficacy compared with Placebo MDI (P < 0.001) for peak change in FEV1 (Table 2). There was a clear dose ordering of the peak FEV1 response, with the 115.2 μg dose presenting the greatest difference from placebo (248 mL). TIO 18 μg also demonstrated statistically superior efficacy compared with Placebo MDI (P < 0.001) for peak change in FEV1.
(Enlarge Image)
Figure 2.
Mean (±standard error) change from baseline in FEV1over 24 hours by treatment; represents the results for the peak change in FEV1(the primary efficacy endpoint) as well as the change in FEV1from test-day baseline over time.
Secondary Efficacy Variables. Each of the GP MDI doses exhibited a statistically significantly greater (P ≤ 0.049) mean change from test-day baseline compared with Placebo MDI for 12- and 24-hour tFEV1, FEV1 AUC0–12, FEV1 AUC0–24, and FEV1 AUC12–24, with the single exception of the GP MDI 28.8 μg comparison for the 24-hour tFEV1 (P = 0.059) (Figure 3). GP MDI demonstrated a more rapid onset of action compared with TIO 18 μg, with median time to ≥10% improvement in FEV1 of 0.5 hours or less for all doses of GP MDI evaluated, compared with approximately 1 hour for TIO 18 μg.
(Enlarge Image)
Figure 3.
Adjusted Mean (±standard error) change from baseline in FEV1parameters relative to placebo; provides a concise depiction of the mean change from baseline in peak FEV1, 12-hour FEV1, FEV1AUC0–12, 24 hour FEV1, FEV1AUC0–24, FEV1AUC12–24.
PK
Mean plasma glycopyrronium concentrations over time are presented in Figure 4. Overall, exposure (both maximum plasma concentration [Cmax] and AUC) increased in a proportional manner with dose (Table 3). Cmax was reached rapidly (usually within 6 minutes of dosing). Apparent oral clearance and volume of distribution appeared relatively consistent across doses.
(Enlarge Image)
Figure 4.
Mean plasma glycopyrronium concentrations over time.
Safety
The most frequently reported AE was dry mouth (Table 4). All other AEs were reported only once or twice during the study and were distributed across the treatments. Dry mouth was also the most frequently reported drug-related AE. The only other AEs besides dry mouth reported as being drug-related were dyspnea (GP MDI 28.8 μg, 1 study patient) and paradoxical bronchospasm, defined as a reduction in FEV1 of >20% from test-day baseline with associated symptoms of wheezing, shortness of breath or cough (GP MDI 115.2 μg, 1 patient; mild in severity on the day following treatment). No patient experienced an SAE during the study, and no study patient discontinued due to an AE. Changes in hematology, clinical chemistry, vital signs, physical examination findings, and ECGs were small, and no treatment-related trends were observed.
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