A Dose-Ranging Study of Epinephrine Hydrofluroalkane Metered-Dose Inhaler (Primatene® MIST) in Subjects with Intermittent or Mild-to-Moderate Persistent Asthma

Abstract

Background: Two sequential single-dose crossover dose-ranging studies were performed to evaluate the clinical efficacy and safety profile of epinephrine hydrofluroalkane (HFA) metered-dose inhaler (MDI) formulation at various doses in subjects with asthma. Methods: In these multicenter, multiarm, double-blinded, or evaluator-blinded studies, subjects were randomized to receive the epinephrine HFA (Primatene® MIST HFA) MDI medication at doses ranging from 90 to 440 μg/dose, as well as to a placebo (PLA) control and an active control of epinephrine CFC (chlorofluorocarbon) MDI (Primatene® MIST CFC) at 220 μg/inhalation. Results: Spirometry testing for FEV1 (Forced Expiratory Volume in one second) demonstrated statistically significant improvements over PLA for epinephrine HFA MDI at all doses above 125 μg, as the amount out of the actuator (i.e., mouthpiece). The efficacy results for epinephrine HFA MDI in the dose range of 125-250 μg were also comparable to epinephrine CFC MDI (220 μg/inh). Safety assessments demonstrated minimal safety concerns for all treatment groups. No notable safety differences were observed between the studied doses of epinephrine HFA MDI and the active control formulation of epinephrine CFC MDI. Conclusion: The findings indicate that epinephrine HFA MDI provided clinically significant bronchodilator efficacy with minimal safety concerns in a dose range of 125-250 μg. These findings confirmed the optimal treatment doses of 125-250 μg that were appropriate for use in longer term 12 and 26 week chronic dosing studies of epinephrine HFA MDI for patients with intermittent or mild to moderate persistent asthma. Clinical trials registration number: NCT01025648.

Keywords: asthma; dose–response; efficacy; inhaled epinephrine; metered-dose inhalers.

Conflict of interest statement

Dr. Edward M. Kerwin served on advisory boards, speaker panels, consultants, or received travel reimbursement from Novartis, AstraZeneca, Amphastar, Forest, Pearl, Sunovion, Teva, Theravance, Mylan, GSK, Boehringer Ingelheim, and Cipla, outside the submitted work. Dr. Donald P. Tashkin reports personal fees from Amphastar Pharmaceuticals, personal fees from AstraZeneca, outside the submitted work. Dr. Thomas R Murphy and Dr. George W. Bensch have no conflicts of interest to disclose. Dr. Jack Y. Zhang, Dr. Mary Z. Luo, and Tony Marrs are employees of Amphastar Pharmaceuticals, Inc. at the time of study and article preparation.

Figures

FIG. 1.

Primary endpoint of Epi-HFA versus Doses: AUC of %ΔFEV1: The two period moving average of Epi-HFA is shown with Standard Error Bars shown for each data point. The two green dash lines indicate the dose range that has been approved by the FDA. AUC, area under the curve; FEV1, Forced Expiratory Volume in one second; HFA, hydrofluroalkane.

FIG. 2.

(a–d) Dose–response curves for four secondary endpoints. The two period moving average of Epi-HFA is shown with Standard Error Bars shown for each data point. The two green dash lines indicate the dose range that has been approved by the FDA.

FIG. 3.

Zero to 6 hour spirometry results of Study A1: %ΔFEV1 Curves for Moderate Dose Study (250–440 μg/dose). All Epi-HFA doses tested in this study were well above PLA. The 2 × 125 μg showed greatest improvements in FEV1. PLA, placebo.

FIG. 4.

Zero to 6 hour spirometry results of Study A2. %ΔFEV1 Curves for Low-Dose Study (90–250 μg/dose). All Epi-HFA doses showed superiority to PLA, but the lowest Epi-HFA, 90 μg (Arm T1) showed minimal bronchodilation over PLA. 2 × 90 (180 μg) showed greatest improvements in FEV1.