AMPLIFY: a randomized, Phase III study evaluating the efficacy and safety of aclidinium/formoterol vs monocomponents and tiotropium in patients with moderate-to-very severe symptomatic COPD

Sanjay Sethi, Edward Kerwin, Henrik Watz, Gary T Ferguson, Robert M Mroz, Rosa Segarra, Eduard Molins, Diana Jarreta, Esther Garcia Gil, Sanjay Sethi, Edward Kerwin, Henrik Watz, Gary T Ferguson, Robert M Mroz, Rosa Segarra, Eduard Molins, Diana Jarreta, Esther Garcia Gil

Abstract

Background: AMPLIFY assessed the efficacy and safety of aclidinium bromide/formoterol fumarate (AB/FF) vs its monocomponents and tiotropium (TIO) in patients with moderate-to-very severe symptomatic COPD (NCT02796677).

Methods: In this 24-week, Phase III, double-dummy, active-controlled study, symptomatic patients (COPD Assessment Test score ≥10) were randomized to twice-daily AB/FF 400/12 µg, AB 400 µg, or FF 12 µg, or once-daily TIO 18 µg. Co-primary endpoints were change from baseline at week 24 in 1-hour morning post-dose FEV1 (AB/FF vs AB) and in pre-dose (trough) FEV1 (AB/FF vs FF). Non-inferiority of AB vs TIO in pre-dose FEV1 was also an objective. Normalized area under the curve (AUC)0-3/3 h FEV1 and nighttime and early morning symptoms were also assessed. A subgroup participated in a 24-hour serial spirometry sub-study.

Results: A total of 1,594 patients were randomized; 566 entered the sub-study. At week 24, 1-hour post-dose FEV1 significantly improved with AB/FF vs AB, FF, and TIO (84, 84, and 92 mL; all P<0.0001). AB/FF significantly improved trough FEV1 vs FF (55 mL, P<0.001) and AB was non-inferior to TIO. AB/FF significantly improved AUC0-3/3 h FEV1 vs all comparators (P<0.0001) and provided significant improvements in early morning symptoms vs TIO. The 24-hour spirometry demonstrated significantly greater improvements with AB/FF in AUC12-24/12 h vs all comparators, and in AUC0-24/24 h vs FF or TIO at week 24.

Conclusion: In patients with moderate-to-very severe symptomatic COPD, twice-daily AB/FF significantly improved lung function vs monocomponents and TIO, and early morning symptom control vs TIO.

Keywords: 24-hour lung function; LABA; LAMA; aclidinium bromide; bronchodilators.

Conflict of interest statement

Disclosure SS has received grants from AstraZeneca, Dey, and Pearl Therapeutics. He has received personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cempra, CSL Behring, Forest, GlaxoSmithKline, Merck, Pearl Therapeutics, Pulmonx, Reckitt Benckiser, Sunovion, and Theravance. EK has served on advisory boards, speaker panels, or received travel reimbursement from Amphastar, AstraZeneca, GlaxoSmithKline, Mylan, Novartis, Oriel, Pearl Therapeutics, Sunovion, Teva, and Theravance. He has conducted multicenter clinical trials for ~ 40 pharmaceutical companies. HW has received honoraria for consultancies, lectures, and travel support to attend scientific congresses from Almirall, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Takeda. His institution received investigator fees for participation in clinical trials from Almirall, AstraZeneca, Bayer Health Care, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Roche, Sanofi Aventis, and Takeda. GTF reports consulting and advisory board participation for AstraZeneca, Boehringer Ingelheim, Forest Laboratories, Novartis, Pearl Therapeutics, Sunovion, and Verona Pharma; consulting fees from Receptos; speaking engagements for AstraZeneca, Boehringer Ingelheim, Forest Laboratories, GlaxoSmithKline, Pearl Therapeutics, and Sunovion; and research grants from AstraZeneca, Boehringer Ingelheim, Forest Laboratories, GlaxoSmithKline, Novartis, Pearl Therapeutics, Sanofi, Sunovion, and Theravance Biopharma. RMM has received consulting fees, speaker’s fees, and travel expenses from Boehringer Ingelheim and has also received compensation for participating in advisory boards for Almirall, AstraZeneca, Boehringer Ingelheim, and Novartis. Furthermore, RMM has received compensation for participation in multicenter clinical trials in the past 5 years from several companies including Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Merck Sharp & Dohme, Mundipharma, Novartis, Pearl, Roche, and Takeda. RS, EM, DJ, and EGG are employees of AstraZeneca PLC, Barcelona, Spain. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Study design. Abbreviations: AB, aclidinium bromide; BID, twice daily; FF, formoterol fumarate; QD, once daily; TIO, tiotropium.
Figure 2
Figure 2
CONSORT flowchart. Abbreviations: AB, aclidinium bromide; FF, formoterol fumarate; TIO, tiotropium.
Figure 3
Figure 3
Change from baseline in 1-hour post-dose FEV1 at week 24, ITT population (co-primary endpoint). Notes: ****P<0.0001. Data are least squares means ± standard error. Abbreviations: AB, aclidinium bromide; FF, formoterol fumarate; ITT, intent-to-treat; TIO, tiotropium.
Figure 4
Figure 4
Change from baseline in trough FEV1 at week 24, ITT population (co-primary endpoint). Notes: ***P<0.001. Data are least squares means ± standard error. Abbreviations: AB, aclidinium bromide; FF, formoterol fumarate; ITT, intent-to-treat; TIO, tiotropium.
Figure 5
Figure 5
Change from baseline in FEV1 over 3 hours post-dose and AUC0–3/3 h on (A) day 1 and (B) at week 24, ITT population. Notes: *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001 vs all other treatments. #P<0.01 vs FF. ‡P<0.0001. Data are least squares means ± standard error. Abbreviations: AB, aclidinium bromide; AUC, area under the curve; FF, formoterol fumarate; ITT, intent-to-treat; TIO, tiotropium.
Figure 6
Figure 6
Severity of (A) NiSCI and (B) EMSCI over 24 weeks, ITT population. Notes: *P<0.05. Data are least squares means ± standard error. Abbreviations: AB, aclidinium bromide; EMSCI, Early-Morning Symptoms of COPD Instrument; FF, formoterol fumarate; ITT, intent-to-treat; NiSCI, Nighttime Symptoms of COPD Instrument; TIO, tiotropium.
Figure 7
Figure 7
Change from baseline in FEV1 over 24 hours post-dose (A) on day 1 and (B) at week 24, sub-study ITT population. Notes: *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001 for AB/FF vs all other treatments. #P<0.05; ##P<0.01; ###P<0.001; ####P<0.0001 for AB/FF vs FF and TIO. ‡‡‡‡P<0.0001 for AB/FF vs AB and TIO. §P<0.05; §§P<0.01; §§§P<0.001 for AB/FF vs FF. Data are least squares means ± standard error. Abbreviations: AB, aclidinium bromide; FF, formoterol fumarate; ITT, intent-to-treat; TIO, tiotropium bromide.
Figure 8
Figure 8
Change from baseline in normalized (A) AUC0–12/12 h, (B) AUC12–24/12 h, and (C) AUC0–24/24 h FEV1 at week 24, sub-study ITT population. Notes: *P<0.05; ***P<0.001; ****P<0.0001. Data are least squares means ± standard error. Abbreviations: AB, aclidinium bromide; AUC, area under the curve; FF, formoterol fumarate; ITT, intent-to-treat; TIO, tiotropium bromide.
Figure 9
Figure 9
Severity of (A) NiSCI and (B) EMSCI over 24 weeks, sub-study ITT population. Notes: *P<0.05. Data are least squares means ± standard error. Abbreviations: AB, aclidinium bromide; EMSCI, Early Morning Symptoms of COPD Instrument; FF, formoterol fumarate; ITT, intent-to-treat; NiSCI, Nighttime Symptoms of COPD Instrument; TIO, tiotropium bromide.

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Source: PubMed

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