Abstract
Background:
No nebulized form of a long-acting dual bronchodilator exists for patients with chronic obstructive pulmonary disease (COPD). With the approval of once-daily, long-acting muscarinic antagonist (LAMA) revefenacin (REV), it may be possible to deliver a LAMA and a long-acting _-agonist via a standard jet nebulizer. These prespecified and post hoc analyses assessed the safety and efficacy of REV 175 µg administered sequentially before or combined with formoterol (FOR) 20 µg via a standard jet nebulizer, in subgroups of patients with COPD defined by certain demographic and clinical characteristics.
Methods:
In Study 0167, a randomized, double-blind, phase 3, 42-day trial (NCT03573817), 122 patients with moderate to very severe COPD were randomized to receive REV (n = 63) or placebo (PBO) (n = 59), then FOR in the morning and evening for 21 days (sequential administration), all via a standard jet nebulizer. Patients continued treatment for an additional 21 days. However, the morning treatments, REV or PBO, and FOR, were given as mixed solutions via a single nebulization (combined administration), and FOR was given alone in the evening. Adverse events (AEs), serious AEs (SAEs), discontinuations, deaths, and trough forced expiratory volume in 1 second (kg/m2) changes vs baseline were assessed in the following subgroups: smoking status, age, current inhaled corticosteroids (ICS) use, reversibility to a short-acting bronchodilator, sex, and Global Obstructive Lung Disease 3 and 4 patients. Approval for this trial was obtained from an Institutional Review Board.
Results:
Patients (mean age 64 y; 57% men; 57% smokers) had an kg/m2 of 55% predicted; 24% were on ICS. The proportion of AEs by subgroups are shown in the Table. Across all subgroups, exacerbation/worsening of COPD, cough, and dizziness were the most common AEs, with more AEs reported in the PBO-treated subgroups. No AEs led to discontinuation in the REV-treated subgroups and there were no SAEs or deaths in any subgroup. Trough kg/m2 vs baseline over each 3-week treatment period by subgroups are shown in the Table. For former smokers and patients who were not reversible to ipratropium, the least squares mean differences were smaller vs the other subgroups.
Conclusions:
Across all subgroups, REV, administered sequentially before or combined with FOR via a standard jet nebulizer, had a tolerability profile similar to FOR alone. Trough kg/m2 response was greater in patients treated with REV + FOR, vs FOR alone.
aAEs were collected from days 1 to 42. b2017 GOLD criteria. cFEV1 was collected in the morning at baseline and on days 21 and 42. n= evaluable n. AE, adverse event; FEV1, forced expiratory volume in 1 second; FOR, formoterol; GOLD, Global Obstructive Lung Disease; ICS, inhaled corticosteroids; LS, least squares; PBO, placebo; REV, revefenacin, SE, standard error. View all access options for this article.AEs and trough FEV1 changes from baseline by subgroup
AEs n (%)
PBO + FORSequential(n=59)
PBO + FOR Combined(n=55)
REV + FOR Sequential(n=63)
REV + FORCombined(n=62)
Current smoker
4 (12.5)(n=32)
1 (3.6)(n=28)
1 (2.7)(n=37)
1 (2.8)(n=36)
Former smoker
3 (11.1)(n=27)
5 (18.5)(n=27)
2 (7.7)(n=26)
4 (15.4)(n=26)
GOLD 3/4
2 (10.0)(n=20)
1 (5.3)(n=19)
2 (8.0)(n=25)
0(n=25)
Aged ≥65 years
4 (14.3)(n=28)
5 (17.9)(n=28)
2 (8.7)(n=23)
4 (17.4)(n=23)
Aged <65 years
3 (9.7)(n=31)
1 (3.7)(n=27)
1 (2.5)(n=40)
1 (2.6)(n=39)
Current ICS use
3 (20.0)(n=15)
2 (14.3)(n=14)
0(n=13)
1 (7.7)(n=13)
No current ICS use
4 (9.1)(n=44)
4 (9.8)(n=41)
3 (6.0)(n=50)
4 (8.2)(n=49)
Reversible to ipratropium
4 (12.1)(n=33)
4 (13.3)(n=30)
2 (6.7)(n=30)
2 (6.9)(n=29)
Not reversible to ipratropium
3 (11.5)(n=26)
2 (8.0)(n=25)
1 (3.0)(n=33)
3 (9.1)(n=33)
Trough FEV1 from baseline, LS change (mL)
Trough FEV1 from baseline, LS change (mL
PBO + FOR Combined(n=59)
REV + FOR Sequential(n=63)
REV + FORCombined(n=63)
Current smoker
30.5 (42.4)(n=27)
−9.5 (42.9)(n=26)
205.3 (41.3)(n=32)
159.1 (41.0)(n=33)
Former smoker
75.6 (41.6)(n=27)
77.6 ( 41.6)(n=27)
98.7 (42.8)(n=25)
63.1 (42.3)(n=26)
GOLDb 3 and 4
75.1 (47.8)(n=19)
65.3 (48.4)(=18)
168.4 (47.9)(n=22)
118.5 (47.2)(n=23)
Aged >65 years
33.4 (43.4)(n=28)
30.5 (43.4)(n=28)
66.0 (47.3)(n=22)
68.6 (46.7)(n=23)
Aged ≤65 years
74.1 (43.0)(n=26)
38.2 (43.5)(n=25)
231.3 (38.7)(n=35)
162.0 (38.5)(n=36)
Current ICS use
-37.3 (57.5)(n=14)
-19.47 (58.6)(n=13)
96.3 (62.3)(n=11)
128.2 (60.7)(n=12)
No current ICS use
116.6 (33.7)(n=40)
86.22 (33.7)(n=40)
207.30 (31.5)(n=46)
147.97 (31.3)(n=47)
Reversible to ipratropium
45.7 (39.3)(n=30)
30.0 (39.3)(n=30)
253.5 (43.4)(n=27)
170.5 (42.8)(n=28)
Not reversible to ipratropium
67.2 (43.9)(n=24)
45.5 (44.6)(n=23)
79.6 (39.1)(n=30)
75.1 (38.7)(n=31)
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