A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy

Figures & data

Figure 1 Patient flow through the study.

Notes: Tiotropium: open-label tiotropium (two puffs 2.5 µg; once daily). Ensifentrine: double-blind study medication (via jet nebulizer with compressor; 0.375 mg, 0.75 mg, 1.5 mg, 3 mg, or placebo; twice daily). Full analysis set: all randomized patients with sufficient data collected after intake of blinded study medication to compute the pharmacodynamic parameters based on FEV1 on at least one occasion (n=413). Safety analysis set: all patients that received at least one dose of study medication (n=413). *One patient was dispensed 3mg drug dosing rather than 0.375 mg.

Abbreviations: FEV1, forced expiratory volume in 1second; n, number of patients.

Table 1 Baseline Demographics and Disease Characteristics in the Full Analysis Set

	Ensifentrine Treatment Arm^† (n)					Total (n=413)
	0.375 mg Arm (n=83)	0.75 mg Arm (n=83)	1.5 mg Arm (n=81)	3 mg Arm (n=82)	Placebo Arm (n=84)
Age
Mean, years (SD)	64.2 (7.86)	65.5 (8.43)	63.8 (7.71)	64.5 (7.92)	63.6 (8.41)	64.3 (8.06)
<65 years, %	53.0	45.8	54.3	50.0	56.0	51.8
Gender, %
Male	38.6	44.6	37.0	45.1	47.6	42.6
Female	61.4	55.4	63.0	54.9	52.4	57.4
Race, %
White	88.0	91.6	88.9	92.7	89.3	90.1
Black or African American	12.0	8.4	11.1	7.3	10.7	9.9
Reversible, %
Yes	45.8	47.0	49.4	50.0	48.8	48.2
No	54.2	53.0	50.6	50.0	51.2	51.8
Baseline FEV1
Mean post-bronchodilator FEV1, L (SD)	1.4 (0.46)	1.4 (0.44)	1.4 (0.38)	1.4 (0.45)	1.4 (0.46)	1.4 (0.44)
Post-bronchodilator FEV1, % predicted normal (SD)	50.4 (10.18)	50.9 (9.67)	49.9 (10.12)	50.4 (10.61)	48.9 (10.93)	50.1 (10.29)
Mean FEV1 reversibility, mL (SD)	189.8 (140.94)	209.3 (147.47)	203.9 (177.91)	214.2 (145.71)	185.5 (143.69)	200.5 (151.28)
% reversibility (SD)	18.2 (13.63)	18.1 (13.34)	21.0 (19.69)	20.2 (14.74)	17.6 (14.19)	19.0 (15.25)
Baseline mean mMRC (SD)	2.7 (0.63)	2.7 (0.59)	2.6 (0.57)	2.6 (0.59)	2.7 (0.62)	2.7 (0.60)
Reported to have chronic bronchitis, %^C
Yes	67.5	62.7	56.8	51.2	56.0	58.8
No	32.5	37.3	43.2	48.8	44.0	41.2
Smoking history^X
Current smoker, %	49.4	59.0	51.9	52.4	63.1	55.2
Ex-smoker, %	50.6	41.0	48.1	47.6	36.9	44.8
Mean smoking exposure, pack years (SD)	52.9 (26.14)	52.5 (26.39)	50.5 (25.54)	51.0 (20.56)	52.5 (27.37)	51.9 (25.22)
Prior COPD medication, %
LAMA	56.6	44.6	34.6	39.0	51.2	45.3
LABA/LAMA	13.3	16.9	25.9	19.5	19.0	18.9
ICS/LABA	10.8	12.0	16.0	6.1	15.5	12.1
ICS	4.8	3.6	2.5	0	2.4	2.7
LABA	1.2	4.8	2.5	0	2.4	2.2
ICS/LABA/LAMA	1.2	0	1.2	3.7	2.4	1.7

Notes: ^CReported chronic bronchitis: patients were asked if they had been diagnosed with chronic bronchitis (yes or no; defined as productive cough and sputum production on most days for 3 months in each of 2 consecutive years; Pauwels et al 2001).¹⁵ †Double-blind study medication (ensifentrine 0.375, 0.75, 1.5 or 3 mg or placebo BID) added to once-daily tiotropium QD. ^XCurrent and former smokers with smoking history of ≥10 pack years. Baseline, post 2 weeks receiving tiotropium.

Abbreviations: BID, twice daily; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LAMA, long-acting muscarinic antagonist; LABA, long-acting beta agonist; mMRC, modified medical research council dyspnea scale; n, number of patients; Pack-years, the number of packs per day multiplied by the number of years smoking; QD, once daily; SD, standard deviation; reversible, ≥12% and ≥200 mL increase in FEV1 post 4 puffs albuterol; non-reversible, <12% or <200 mL increase in FEV1 post 4 puffs albuterol.

Table 2 Baseline Patient-Reported Outcome (PRO) Scores and Rescue Medication Use for Patients with Baseline and Week 4 Values Reported in the Full Analysis Set

	Ensifentrine Treatment Arm^† (n)
	0.375 mg Arm (n=83)	0.75 mg Arm (n=83)	1.5 mg Arm (n=81)	3 mg Arm (n=82)	Placebo Arm (n=84)
SGRQ-C Total Score
n^	75	69	71	73	76
Baseline mean (range)	55.9 (20.6, 96.6)	51.9 (14.4, 85.4)	54.7 (16.0, 96.5)	52.9 (8.1, 91.4)	58.3 (21.2, 99.5)
E-RS™: COPD Total Score
n^	75	69	75	74	77
Baseline mean (range)	12.4 (0.0, 29.8)	12.4 (0.0, 26.3)	12.7 (0.0, 27.6)	12.2 (0.0, 24.2)	14.2 (1.2, 30.3)
Baseline Dyspnea Index
n^	77	74	75	78	80
Baseline mean (range)	5.9 (4.0, 8.0)	5.9 (1.0, 8.0)	5.7 (0.0, 9.0)	6.0 (1.0, 12.0)	5.6 (0.0, 9.0)
Rescue Medication Use, puffs/day
n^	74	68	72	71	76
Baseline mean (range)	2.1 (0.0, 8.0)	2.4 (0.0, 9.7)	2.1 (0.0, 10.6)	2.1 (0.0, 10.6)	2.7 (0.0, 13.6)

Notes: ^† Double-blind study medication (ensifentrine 0.375, 0.75, 1.5 or 3 mg or placebo BID) added to once-daily tiotropium QD. ^Number of patients with valid values at baseline and at Week 4 visits. Baseline, post 2 weeks receiving tiotropium.

Abbreviations: E-RS™: COPD, Evaluating Respiratory Symptoms in COPD; SGRQ-C, St. George’s Respiratory Questionnaire for COPD patients.

Table 3 Change from Baseline to Week 4 in Peak FEV1 (Over 3 Hours), Average FEV1 (0–12 Hours) and Morning Trough FEV1 in the Full Analysis Set

	Ensifentrine Treatment Arm^† (n)
	0.375 mg Arm (n=83)	0.75 mg Arm (n=83)	1.5 mg Arm (n=81)	3 mg Arm (n=82)	Placebo Arm (n=84)
Week 4 Peak FEV1 (0–3h) (change from baseline)
LS mean, mL (95% CI)	196 (144, 248)	210 (157, 263)	226 (174, 278)	243 (191, 295)	119 (68, 170)
Treatment – placebo difference, LS mean, mL (95% CI)	78 (5, 150)	91 (18, 164)	107 (34, 180)	124 (52, 197)
p-value	0.037	0.015	0.004	0.001
Week 4 Average FEV1 (0–12h) (change from baseline)
LS mean, mL (95% CI)	36 (−12, 84)	63 (14, 112)	64 (16, 112)	97 (49, 145)	10 (−38, 57)
Treatment – placebo difference, LS mean, mL (95% CI)	26 (−41, 94)	53 (−15, 121)	54 (−13, 122)	87 (20, 155)
p-value	0.446	0.124	0.115	0.011
Week 4 Morning trough FEV1 (change from baseline)
LS mean, mL (95% CI)	−20 (−65, 25)	−35 (−81, 12)	−14 (−60, 31)	5 (−40, 51)	−22 (−66, 23)
Treatment – placebo difference, LS mean, mL (95% CI)	2 (−62, 65)	−13 (−77, 51)	8 (−56, 71)	27 (−36, 91)
p-value	0.959	0.691	0.812	0.400

Notes: Data are least squares mean treatment – placebo differences, both added on to tiotropium (95% CI); p-value (p<0.05 is significant). ^†Double-blind study medication (ensifentrine 0.375, 0.75, 1.5 or 3 mg or placebo BID) added to once-daily tiotropium QD. Baseline, post 2 weeks receiving tiotropium.

Abbreviations: BID, twice daily; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; LS, least squares; n, number of patients in full analysis set; placebo, ensifentrine placebo added to tiotropium; QD, once daily.

Figure 2 Peak FEV1 between 0 and 3 h post-dose in the full analysis set.

Notes: Mean change from baseline FEV₁ and standard error of mean are shown. Data are least squares means treatment – placebo differences and 95% CI of the least squares mean difference. ^†P<0.05 vs placebo; ^‡P<0.01 vs placebo; ^¥P<0.0001 vs placebo. Least squares mean changes from baseline in the placebo ensifentrine added to tiotropium arm in the full analysis set (placebo, n=84) were 104, 110, 107, and 119 mL at Weeks 1, 2, 3 and 4, respectively. Baseline, post 2 weeks receiving tiotropium.

Abbreviations: CI, confidence interval; FEV1, forced expiratory volume in 1second; p, p-value vs placebo; placebo, placebo ensifentrine added to tiotropium.

Table 4 Change from Baseline to Week 4 in SGRQ-C Total Score, E-RS™: COPD Total Score and TDI Score in the Full Analysis Set

	Ensifentrine Treatment Arm^† (n)
	0.375 mg Arm (n=83)	0.75 mg Arm (n=83)	1.5 mg Arm (n=81)	3 mg Arm (n=82)	Placebo Arm (n=84)
Week 4 SGRQ-C Total Score (change from baseline)
LS mean (95% CI)	−4.4 (−6.96, −1.83)	−2.4 (−5.10, 0.30)	−4.9 (−7.52, −2.22)	−4.2 (−6.81, −1.51)	−0.1 (−2.71, 2.48)
Treatment – placebo difference, LS mean (95% CI)	−4.3 (−7.92, −0.62)	−2.3 (−6.04, 1.47)	−4.8 (−8.46, −1.05)	−4.1 (−7.76, −0.33)
p-value	0.022	0.232	0.012	0.033
Week 4 E-RS™: COPD Total Score (change from baseline)
LS mean (95% CI)	−1.7 (−2.54, −0.84)	−0.6 (−1.46, 0.27)	−1.2 (−2.08, −0.37)	−1.1 (−1.93, −0.21)	−0.2 (−1.08, 0.62)
Treatment – placebo difference, LS mean (95% CI)	−1.5 (−2.67, −0.26)	−0.4 (−1.58, 0.85)	−1.0 (−2.20, 0.21)	−0.8 (−2.05, 0.37)
p-value	0.018	0.555	0.105	0.171
Week 4 Transition Dyspnea Index (TDI) Score (change from baseline)
LS mean (95% CI)	2.1 (1.42, 2.76)	1.5 (0.80, 2.17)	2.1 (1.37, 2.74)	2.1 (1.39, 2.74)	1.8 (1.10, 2.43)
Treatment – placebo difference, LS mean (95% CI)	0.3 (−0.62, 1.27)	−0.3 (−1.24, 0.68)	0.3 (−0.66, 1.24)	0.3 (−0.65, 1.25)
p-value	0.503	0.563	0.551	0.538

Notes: Data are least squares mean treatment – placebo differences, both added on to tiotropium (95% CI); p-value (p<0.05 is significant for the treatment-placebo difference in the Week 4 SGRQ-C total score with the 1.5 and 3 mg arms). ^†Double-blind study medication (ensifentrine 0.375, 0.75, 1.5 or 3 mg or placebo BID) added to once-daily tiotropium QD. Baseline, post 2 weeks receiving tiotropium.

Abbreviations: BID, twice daily; CI, confidence interval; COPD, chronic obstructive pulmonary disease; E-RS™: COPD, Evaluating Respiratory Symptoms in COPD; FEV1, forced expiratory volume in 1 second; LS, least squares; MCID, minimally important clinical difference (4 units for SGRQ-C, 2 units for E-RS™: COPD, and 1 unit for TDI); n, number of patients in full analysis set; placebo, ensifentrine placebo added to tiotropium; QD, once daily; SGRQ-C, St. George’s Respiratory Questionnaire for COPD Patients.

Table 5 Proportion of Treatment Emergent Adverse Events Summary Listed by Prevalence in the Safety Analysis Set

	Ensifentrine Treatment Arm^† (n)
	0.375 mg Arm (n=82)	0.75 mg Arm (n=83)	1.5 mg Arm (n=81)	3 mg Arm (n=83)	Placebo Arm (n=84)
Any TEAE, %	14.6	18.1	17.3	21.7	20.2
Any TEAE leading to drug discontinuation, %	2.4	3.6	0	0	1.2
Any drug-related TEAE, %	1.2	3.6	2.5	2.4	4.8
Any serious TEAE, %	0	1.2	0	2.4	0
Any serious drug related TEAE, %	0	0	0	0	0
Any serious TEAE leading to drug discontinuation, %	0	1.2	0	0	0
Any TEAE leading to death, %	0	0	0	0	0
Most commonly reported TEAEs by preferred term (>1 patient overall), %
COPD^a	3.6^b	2.4^b	0	3.6^c	0
Headache	2.4	1.2	1.2	2.4	1.2
Blood creatinine increased	1.2	2.4	1.2	0	0
Oral candidiasis	0	1.2	0	1.2	2.4
Blood pressure increased	1.2	1.2	1.2	0	0
Dyspnea	0	1.2	0	2.4	0
Nasopharyngitis	0	0	0	1.2	2.4
Osteoarthritis	1.2	0	1.2	1.2	0
Bronchitis	0	1.2	0	0	1.2
Chest discomfort	0	0	0	1.2	1.2
Contusion	1.2	0	1.2	0	0
Cough	0	0	0	1.2	1.2
Diarrhea	0	1.2	0	1.2	0
Edema peripheral	0	0	1.2	0	1.2
Fall	0	1.2	1.2	0	0
Gastroenteritis	0	0	2.5	0	0
Heart rate increased	1.2	0	0	1.2	0
Muscle spasms	0	2.4	0	0	0

Notes: ^†Double-blind study medication (ensifentrine 0.375, 0.75, 1.5 or 3 mg or placebo BID) added to once-daily tiotropium QD. ^aTEAEs of COPD were reported as either worsening of COPD symptoms or COPD exacerbations. COPD exacerbations were reported as moderate TEAEs with PT of COPD that required treatment with systemic steroids for at least 3 days from or after the date of TEAE onset. ^bFive (1.2%) patients had COPD exacerbations (as defined above) reported: 3 (3.6%) in the 0.375 mg and 2 (2.4%) in the 0.75 mg arms. ^cThree (3.6%) patients in the 3 mg arm had events of “worsening of COPD symptoms” (n=2) and “mild COPD exacerbation” (n=1) that were reported as mild TEAEs with PT of COPD.

Abbreviations: BID, twice daily; CI, confidence interval; COPD, chronic obstructive pulmonary disease; n, number of patients in safety analysis set; placebo, ensifentrine placebo added to tiotropium; QD, once daily; TEAE, treatment emergent adverse event.

Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med. 2001;163(5):1256–1276. doi:10.1164/ajrccm.163.5.2101039

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