Clinical potential of aclidinium bromide in chronic obstructive pulmonary disease

Figures & data

Table 1 Overview of Phase II, Phase III, and long-term trials of aclidinium in COPD

Study acronym and reference	Study treatments	N	Duration (weeks)	Key efficacy results treated vs placebo, respectively: impact on trough and peak FEV1	Key safety results: most common AEs (>10% patients in any group); cardiac AEs, anticholinergic AEs
BID dosing studies
Phase II Fuhr et al^Citation29 NCT0868231	Aclidinium 400 μg BID Placebo Tiotropium 18 μg QD	30	2	Change from baseline in FEV1 AUC0–12/12h at Day 15 vs placebo • Aclidinium 400 μg: 221 mL (P<0.0001) • Tiotropium 18 μg: 244 mL (P<0.0001)	Adverse events reported by seven patients receiving aclidinium, eight receiving placebo, and three receiving tiotropium Most common AE was COPD exacerbation (three patients all receiving placebo)
Phase II Singh et al^Citation30 NCT1120093	Aclidinium 100, 200, 400 μg BID Placebo Formoterol 12 μg BID	79	1	Change from baseline in FEV1 AUC0–12 at Day 7 vs placebo • Aclidinium 100 μg: 154 mL (P<0.0001) • Aclidinium 200 μg: 176 mL (P<0.0001) • Aclidinium 400 μg: 208 mL (P<0.0001) • Formoterol 12 μg: 210 mL (P<0.0001)	The safety profile of aclidinium was comparable to placebo
ACCORD COPD I (Phase III) Kerwin et al^Citation31 NCT0891462	Aclidinium 200 μg BID Aclidinium 400 μg BID Placebo	185 190 186	12	Trough FEV1 change from baseline vs placebo • 200 μg: 86 mL (95% CI 45–127; P≤0.0001) • 400 μg: 124 mL (95% CI 83–164; P≤0.0001) Peak FEV1 change from baseline vs placebo • 200 μg: 146 mL (95% CI 101–190; P≤0.0001) • 400 μg: 192 mL (95% CI 148–236; P≤0.0001)	Aclidinium 200 μg: no event >10% (COPD exacerbation, 9.2%); <2% cardiac and anticholinergic AEs Aclidinium 400 μg: no event >10% (COPD exacerbation, 7.4%); <2% cardiac and anticholinergic AEs Placebo: COPD exacerbation (12.4%); <2% cardiac and anticholinergic AEs
ATTAIN (Phase III) Jones et al^Citation32 NCT1001494	Aclidinium 200 μg BID Aclidinium 400 μg BID Placebo	277 269 272	24	Trough FEV1 change from baseline vs placebo • 200 μg: 99 mL (P<0.0001) • 400 μg: 128 mL (P<0.0001) Peak FEV1 change from baseline vs placebo • 200 μg: 185 mL (P<0.0001) • 400 μg: 209 mL (P<0.0001)	Aclidinium 200 μg: COPD exacerbation (15.9%), headache (10.8%), nasopharyngitis (11.6%); <1% cardiac and anticholinergic AEs Aclidinium 400 μg: COPD exacerbation (14.1%), headache (12.3%), nasopharyngitis (11.2%); <2% cardiac and <1% anticholinergic AEs Placebo: COPD exacerbation (20.5%), headache (8.1%), nasopharyngitis (8.4%); <2% cardiac and anticholinergic AEs
ACCORD COPD II (Phase III) Rennard et al^Citation33 NCT1045161	Aclidinium 200 μg BID Aclidinium 400 μg BID Placebo	182 178 184	12	Trough FEV1 change from baseline vs placebo • 200 μg: 51 mL (P<0.05) • 400 μg: 72 mL (P<0.05) Peak FEV1 change from baseline vs placebo • 200 μg: 115 mL (P<0.0001) • 400 μg: 125 mL (P<0.0001)	Aclidinium 200 μg, and 400 μg had a similar AE profile to placebo, with a similar number of patients in each group experiencing a severe AE or an AE leading to discontinuation. Exacerbation of COPD was the only AE reported in more than 5% of patients in any treatment group, occurring in 11.5% of placebo group, 8.7% of aclidinium 200 μg group, and 13.0% of aclidinium 400 μg group <2% cardiac AEs; <2% anticholinergic AEs
ACCORD COPD I extension D’Urzo et al^Citation35 NCT0970268	Aclidinium 200 μg BID Aclidinium 400 μg BID (patients previously receiving placebo re-randomized to one of the two aclidinium doses)	291	52	Improvements in peak and trough FEV achieved during the lead-in phase were maintained to the end of the extension phase (Week 64) Improvements from baseline in trough FEV1 in patients receiving aclidinium throughout • 200 μg: 62–127 mL • 400 μg: 56–140 mL Improvements from baseline in peak FEV1 in patients receiving aclidinium throughout • 200 μg: 213 mL • 400 μg: 219 mL	Aclidinium 200 μg: COPD exacerbation (25.5%); <2% cardiac and <3.5% anticholinergic AEsbr(/)Aclidinium 400 μg: COPD exacerbation (21.7%); <2% cardiac and <3.5% anticholinergic AEs
LAS-MD-35 (Phase III) Gelb et al^Citation34 NCT1044459	Aclidinium 200 μg BID(br)Aclidinium 400 μg BID	312 293	52	Trough FEV1 change from baseline at Week 52 (maximal values during the study) • 200 μg: 34 mL (62 mL) • 400 μg: 72 mL (101 mL) Peak FEV1 change from baseline at Week 52 (maximal values during the study): • 200 μg: 185 mL (226 mL) • 400 μg: 214 mL (235 mL)	Aclidinium 200 μg: COPD exacerbation (19.3%); <2% cardiac and <3.5% anticholinergic AEs Aclidinium 400 μg: COPD exacerbation (19.9%); <2% cardiac and <3.5% anticholinergic AEs
LAS39 (Phase IIIb) Beier et al^Citation36 NCT1462929	Aclidinium 400 μg BID Tiotropium 18 μg QD Placebo	171 158 85	6	Difference from placebo in change from baseline in FEV1 AUC0–24 • Aclidinium 400 μg BID: 150 mL (P<0.0001) • Tiotropium 18 μg QD: 140 mL (P<0.0001) Difference from placebo in change from baseline in FEV1 AUC12–24 • 400 μg aclidinium BID: 160 mL (P<0.0001) • 18 μg tiotropium QD: 123 mL (P<0.0001)	AE incidence (28.0% overall) was similar between treatment groups, with few patients experiencing anticholinergic AEs (<1.5%, any group)
QD dosing studies
Phase II Chanez et al^Citation37	Aclidinium 25, 50,100, 200 or 400 μg QD Tiotropium 18 μg QD Placebo	464	4	Difference from placebo in change from baseline in trough FEV1 at Day 29 • Aclidinium 200 μg QD: 148 mL (P=0.006) • Aclidinium 400 μg QD: 128 mL (P=0.018) • Tiotropium 18 μg QD: 161 mL (P=0.003)	Aclidinium was well tolerated, with no dose-dependent effect on EKG, laboratory parameters or AEs
Phase II Joos et al^Citation38	Aclidinium 100, 300 or 900 μg QD Placebo	17	Single doses	Mean area under the FEV1 curve (0–24 h time interval) was 1.58 L for placebo and 1.73 L, 1,79 L, and 1.82 L for 100, 300, and 900 μg aclidinium, respectively (P<0.001 vs placebo for all aclidinium doses)	Well tolerated, no anticholinergic side effects reported, no clinical effect on EKG parameters
ACCLAIM COPD I Jones et al^Citation39 NCT0363896	Aclidinium 200 μg QD Placebo	627 216	52	Week 12 trough FEV1 change from baseline vs placebo: 61 mL (P<0.001) Week 28 trough FEV1 change from baseline vs placebo: 67 mL (P<0.001)	Aclidinium 200 μg: nasopharyngitis (16.3%); headache (11.3%); cardiac AEs 5.1%; dry mouth 1% Placebo: nasopharyngitis (14.4%); headache (12.5%); cardiac AEs 6.5%; dry mouth 0.9%
ACCLAIM COPD II Jones et al^Citation39 NCT0358436	Aclidinium 200 μg QD Placebo	600 204	52	Week 12 trough FEV1 change from baseline vs placebo: 63 mL (P<0.001) Week 28 trough FEV1 change from baseline vs placebo: 69 mL (P<0.001)	Aclidinium 200 μg: nasopharyngitis (12.7%); headache (14.2%); upper respiratory tract infection (10.8%); cardiac AEs 6.8%; dry mouth 0.3% Placebo: nasopharyngitis (11.3%); headache (12.7%); cardiac AEs 8.3%; dry mouth 1.5%

Abbreviations: ACCLAIM, AClidinium CLinical trial Assessing efficacy and safety In Moderate to severe COPD patients; ACCORD, AClidinium in Chronic Obstructive Respiratory Disease I; ATTAIN, Aclidinium To Treat Airway obstruction In COPD PatieNts; AE, adverse event; AUC, area under curve; AUC_0–12/12h, area under curve from 0–12hrs; BID, twice daily; CI, confidence interval; EKG, electrocardiogram; FEV₁, forced expiratory volume in 1 second; h, hour; N, number of patients; QD, once daily; vs, versus.

Figure 1 Study designs for the two pivotal Phase III studies of aclidinium BID: (A) ACCORD COPD I,³¹ and (B) ATTAIN.³²

Abbreviations: ACCORD, AClidinium in Chronic Obstructive Respiratory Disease I; ATTAIN, Aclidinium To Treat Airway obstruction In COPD PatieNts; BID, twice daily; Wk/wks, week/weeks.

Figure 2 Change from baseline in (A) trough FEV₁ and (B) peak FEV₁ at Week 24 in ACCORD COPD I study.

Notes: *P<0.001 vs placebo; ^†P<0.05, ^‡P<0.01 vs aclidinium 200 μg. From Kerwin EM, D’Urzo AD, Gelb AF, et al. COPD 2012;9(2):90–101. Copyright © 2012, Informa Healthcare. Reproduced with permission of Informa Healthcare.³¹

Abbreviations: ACCORD, AClidinium in Chronic Obstructive Respiratory Disease I; FEV₁, forced expiratory volume in 1 second; LS, least squares; SE, standard error.

Figure 3 Change from baseline in (A) trough FEV₁ and (B) peak FEV₁ at Week 24 in ATTAIN study.

Notes: Data reported as least squares mean (standard error). *P<0.0001 for both treatments vs placebo. There were no statistically significant differences between the two aclidinium arms. Reproduced with permission of the European Respiratory Society: Eur Respir J, October 2012 40:830–836; published ahead of print March 22, 2012, doi:10.1183/09031936.00225511.³²
Abbreviations: ATTAIN, Aclidinium To Treat Airway obstruction In COPD patieNts; BID, twice daily; FEV₁, forced expiratory volume in 1 second.

Figure 4 Least squares mean (standard error) change from baseline in SGRQ total score in patients on continuous aclidinium in 1-year extension study of ACCORD COPD I.

Note: From D’Urzo A, Kerwin E, Rennard S, He T, Garcia Gil E, Caracta C. COPD 2013;10(4):500–510. Copyright © 2013, Informa Healthcare. Reproduced with permission of Informa Healthcare.³⁵
Abbreviations: ACCORD, AClidinium in Chronic Obstructive Respiratory Disease I; SGRQ, St George’s Respiratory Questionnaire.

Figure 5 Percent change from baseline in frequency of night-time COPD symptoms at Week 12 in the ACCORD COPD I study.

Note: ^†P≤0.0023 vs placebo.

Abbreviations: ACCORD, AClidinium in Chronic Obstructive Respiratory Disease I; BID, twice daily.

Figure 6 Percent change from baseline in severity and impact of early morning symptoms at Week 12 in the ACCORD COPD I study.

Notes: ^†P=0.0009, ^‡P=0.0002.

Abbreviations: ACCORD, AClidinium in Chronic Obstructive Respiratory Disease I; BID, twice daily.

Figure 7 Percent change from baseline in daily COPD symptoms as measured by EXACT-RS scores at Week 24 in the ATTAIN study.

Note: ^†P<0.0001 vs placebo.
Abbreviations: ATTAIN, Aclidinium to Treat Airway Obstruction in COPD Patients; BID, twice daily; EXACT-RS, EXAcerbations of Chronic pulmonary disease Tool-Respiratory Systems.

FuhrRMagnussenHSaremKEfficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPDChest2012141374575221903737

 PubMed Web of Science ®Google Scholar

SinghDMagnussenHKirstenAA randomised, placebo- and active-controlled dose-finding study of aclidinium bromide administered twice a day in COPD patientsPulm Pharmacol Ther201225324825322497752

 PubMed Web of Science ®Google Scholar

KerwinEMD’UrzoADGelbAFACCORD I study investigators. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I)COPD2012929010122320148

 PubMedGoogle Scholar

JonesPWSinghDBatemanEDEfficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN studyEur Respir J201240483083622441743

 PubMed Web of Science ®Google Scholar

RennardSIScanlonPDFergusonGTACCORD COPD II: a randomized clinical trial to evaluate the 12-week efficacy and safety of twice-daily aclidinium bromide in chronic obstructive pulmonary disease patientsClin Drug Investig201313312893904

 Google Scholar

D’UrzoAKerwinERennardSHeTGarcia GilECaractaCOne-year extension study of ACCORD COPD I: safety and efficacy of two doses of twice-daily aclidinium bromide in patients with COPDCOPD201310450051023679347

 PubMedGoogle Scholar

GelbAFTashkinDPMakeBJZhongXGarcia GilECaractaCLAS-MD-35 study investigatorsLong-term safety and efficacy of twice-daily aclidinium bromide in patients with COPDRespir Med2013107121957196523916502

 PubMed Web of Science ®Google Scholar

BeierJKirstenAMMrózREfficacy and safety of aclidinium bromide compared with placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled Phase IIIb studyCOPD201310451152223819698

 PubMedGoogle Scholar

ChanezPBurgePSDahlRAclidinium bromide provides long-acting bronchodilation in patients with COPDPulm Pharmacol Ther2010231152119683590

 PubMed Web of Science ®Google Scholar

JoosGFSchelfhoutVJPauwelsRABronchodilatory effects of aclidinium bromide, a long-acting muscarinic antagonist, in COPD patientsRespir Med2010104686587220044242

 PubMed Web of Science ®Google Scholar

JonesPWRennardSIAgustiAEfficacy and safety of once-daily aclidinium in chronic obstructive pulmonary diseaseRespir Res2011125521518460

 PubMed Web of Science ®Google Scholar