Dose-Ranging and Cumulative Dose Studies of Albuterol Sulfate MDI in Co-Suspension Delivery™ Technology (AS MDI; PT007) in Patients with Asthma: the ASPEN and ANTORA Trials

Christy Cappelletti, Andrea Maes, Kimberly Rossman, Michael Gillen, Craig LaForce, Edward M Kerwin, Colin Reisner, Christy Cappelletti, Andrea Maes, Kimberly Rossman, Michael Gillen, Craig LaForce, Edward M Kerwin, Colin Reisner

Abstract

Background and objectives: Co-suspension Delivery™ Technology has been developed for the administration of albuterol sulfate pressurised inhalation suspension via metered-dose inhaler (AS MDI, PT007). We assessed the efficacy and safety of AS MDI versus Proventil® in order to determine the optimal dose of AS MDI to take to Phase III clinical trials.

Methods: ASPEN (NCT03371459) and ANTORA (NCT03364608) were Phase II, randomised, crossover, multicentre studies of AS MDI versus Proventil® in patients with persistent asthma. In ASPEN, 46 patients received cumulative-dose treatments (90 μg/inhalation using 1 + 1 + 2 + 4 + 8 inhalations at 30-minute intervals) in 1 of 2 possible sequences: AS MDI/Proventil or Proventil/AS MDI. In ANTORA, 86 patients were randomised to one of 10 treatment sequences of AS MDI (90 μg or 180 μg), placebo MDI, or Proventil (90 μg or 180 μg). The primary endpoints were baseline-adjusted forced expiratory volume in 1 second (FEV1) 30 minutes after each cumulative dose (ASPEN) and change from baseline in FEV1 area under the curve from 0 to 6 h (ANTORA). Safety was assessed in both studies.

Results: In ASPEN, AS MDI was equivalent to Proventil (within pre-specified bounds of ± 200 mL) following cumulative doses of albuterol up to 1440 μg for the primary endpoint. In ANTORA, 90 μg and 180 μg doses of AS MDI and Proventil were significantly superior to placebo MDI (p < 0.0001), and AS MDI was non-inferior to Proventil at both doses, based on a margin of 100 mL. No new safety concerns were identified.

Conclusion: The effects of albuterol delivered via AS MDI and Proventil on bronchodilation were equivalent, supporting the selection of AS MDI 180 µg to be taken into Phase III clinical trials, either alone or in combination with an inhaled corticosteroid.

Trial registration number: ASPEN (NCT03371459); Date of registration: 29/12/2017. ANTORA (NCT03364608); Date of registration: 15/12/2017.

Conflict of interest statement

AM, CC, CR, KR and MG are employees of, and own stock in, AstraZeneca. CLF has received payments from 4D Pharma PLC, Amphastar, Boehringer Ingelheim, Bond Avillion 2 Development LP, Bosch Healthcare Solutions GmbH, Cipla Ltd, GlaxoSmithKline, Knopp Biosciences LLC, Novartis Research and Development, Romark, Sanofi US Services Inc, Teva Pharmaceuticals Ltd and Vorso Corp. EK has performed consulting, served on advisory boards, and received travel reimbursement from Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Novartis, Sunovion and Theravance. He has conducted multicentre clinical research trials for some 40 pharmaceutical companies.

Figures

Fig. 1
Fig. 1
Adjusted mean change from baseline in FEV1 (± SE) (L) 30 minutes after each cumulative dose and 6 h after the final cumulative dose (mITT analysis population) in the ASPEN study. Arrows indicate when each of the 5 doses was given. AS albuterol sulfate, FEV1 forced expiratory volume in 1 second, MDI metered-dose inhaler, mITT modified intent-to-treat, SE standard error
Fig. 2
Fig. 2
Mean (± SE) plasma albuterol concentration-time profile (pharmacokinetic analysis set) in the ASPEN study. Arrows indicate when each of the 5 doses was given. AS albuterol sulfate, MDI metered-dose inhaler, mITT modified intent-to-treat, SE standard error
Fig. 3
Fig. 3
Mean change from baseline in FEV1 (L) over time (mITT analysis set) in the ANTORA study. Error bars represent SE. AS albuterol sulfate, FEV1 forced expiratory volume in 1 second, MDI metered-dose inhaler, mITT modified intent-to-treat, SE standard error

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