There may be no advantage to using the long-acting muscarinic antagonist glycopyrronium (GP) metered dose inhaler (MDI) 28.8 µg compared with a GP MDI 14.4 µg for the treatment of chronic obstructive pulmonary disease, according to data published in Respiratory Research.
Researchers conducted a randomized double-blind 7-day chronic-dosing, 3-period incomplete block, cross-over study (ClinicalTrials.gov Identifier: NCT01350128) to determine the safety and efficacy of a GP MDI delivered via a cosuspension delivery MDI as a part of a larger study as it moves toward a phase 3 clinical trial.
A total of 103 individuals were randomly assigned to 72 different treatment sequences, with each sequence including 3 of 6 treatment groups: 2 doses of a GP MDI and either placebo MDI or ipratropium MDI: GP MDI 28.8 µg, 14.4 µg, 7.2 µg, and 3.6 µg ex-actuator delivered as 2 actuations twice daily; placebo MDI delivered as 2 actuations twice daily; and open-label ipratropium bromide MDI 34 µg as the active control delivered as 2 actuations, 4 times daily.
If necessary, participants were allowed to use albuterol sulfate 90 µg for COPD symptom relief during all treatment periods. The primary efficacy end point of the study was the forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 12 hours (AUC 0-12) relative to baseline on day 7.
Three treatment groups were formed: intention to treat (ITT; n=103), in which individuals received at least 1 dose of the studied medication and completed baseline and postbaseline data; modified intention to treat (mITT; n=91), which included individuals who completed at least 2 treatment periods, with at least 1 predose assessment on day 7; and the per protocol group (PP; n=68), which included individuals in the ITT group who completed all 3 treatment periods, with spirometry data of at least 11.5 hours on day 7.
All 4 treatment GP MDI treatments were superior to the placebo MDI on day 7 in terms of the primary efficacy end point, when FEV1 was compared with baseline in the mITT group. Least squares mean differences compared with placebo for each of the GP MDI treatment demonstrated a range from 0.121 to 0.191 L (all P <.0001), and all GP MDI treatments were noninferior to treatment with ipratropium MDI. Finally, a smaller treatment effect was only seen with GP MDI 7.2 µg compared with GP MDI 3.6 µg (least squares mean difference: −0.071 L; P =.0127).
Statistically significant superiority for all secondary efficacy end points was seen in only GP MDI 28.8 µg and 14.4 µg when compared with placebo MDI, with the exception of GP MDI 14.4 µg in regard to proportion of patients achieving ≥12% improvement in FEV1. Secondary end points measure on day 7 found GP MDI 28.8 µg, 14.4 µg, and 3.6 µg to have a greater mean change from baseline in morning predose FEV1 and at 12-hour postdose trough FEV1 compared with GP MDI 7.2 µg (least squares mean differences, 0.065 L to 0.078 L; P ≤.0373).
Regarding the safety profile of these drug doses, 45 individuals (43.7%) reported at least 1 treatment-emergent adverse event, with the most common being dry mouth (11.7%), followed by cough and headache (5.8% and 3.9%, respectively). There were no unexpected safety findings and no clinically relevant differences among the treatment groups, and all doses were well tolerated in participants.
Researchers concluded that there were statistically significant and clinically relevant increases in FEV1 AUC0-12 for all doses of GP MDI when compared with placebo MDI twice daily and open-label ipratropium MDI 34 µg 4 times daily. All were found to be well tolerated with no safety concerns, as the only adverse effect was dry mouth, which has already been established as a common adverse effect with long-acting muscarinic antagonist therapy. These findings support the use of GP MDI 14.4 µg twice daily for future phase 3 clinical studies.
Kerwin EM, Spangenthal S, Kollar C, St Rose E, Reisner C. A phase IIb randomized, chronic-dosing, incomplete block, cross-over study of glycopyrronium, delivered via metered dose inhaler, compared with a placebo and an active control in patients with moderate-to-severe COPD [published online March 5, 2018]. Respir Res. doi:10.1186/s12931-018-0739-6