Trial Outcomes & Findings for Study Evaluating 5 Doses of RPL554 and Placebo in COPD Patients Via a Dry Powder Inhaler (NCT NCT04027439)

Results Overview

RPL554 Plasma pharmacokinetics AUC0-12 (Area under the Curve) after single dose

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

37 participants

Primary outcome timeframe

Day 1

Results posted on

2022-09-26

Participant Flow

37 subjects enrolled for Part A and anticipated to continue into Part B.

Part A: 37 Patients randomized equally to receive a single dose of RPL554 (0.15, 0.5, 1.5, 3, or 6 mg) or matching placebo via dry powder inhaler (DPI). Patients were to continue to Part B after Part A is complete. Part B: 35 Patients continued from Part A and randomly assigned to 1 of 10 treatment sequences in a crossover design (5 x 1-week treatment periods separated by 7-10 day washout). Each sequence included twice daily RPL554 (0.15, 0.5, 1.5, or 3 mg) or matching placebo via DPI.

Participant milestones

Participant milestones
Measure	0.15 mg/Part A Part A: Single dose of RPL554 via DPI (double-blind).	0.50 mg/Part A Part A: Single dose of RPL554 via DPI (double-blind).	1.5 mg/Part A Part A: Single dose of RPL554 via DPI (double-blind).	3 mg/Part A Part A: Single dose of RPL554 via DPI (double-blind).	6 mg/Part A Part A: Single dose of RPL554 via DPI (single-blind). Part B: dose not used.	Placebo/Part A Part A: Single dose via DPI (double-blind).	Seq. 1/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 1 = RPL554 .15 mg/1.5 mg/3.0 mg/.50 mg/Placebo.	Seq. 2/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 2 = RPL554 .15 mg/3.0 mg/Placebo/.50 mg/1.5 mg.	Seq. 3/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 3 = RPL554 .50 mg/3.0 mg/.15 mg/Placebo/1.5 mg.	Seq. 4/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 4 = RPL554 .50 mg/.15 mg/1.5 mg/Placebo/3.0 mg.	Seq. 5/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 5 = RPL554 1.5 mg/.50 mg/Placebo/3.0 mg/.15 mg.	Seq. 6/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 6 = RPL554 1.5 mg/Placebo/.15 mg/3.0 mg/.50 mg.	Seq. 7/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 7 = RPL554 3.0 mg/1.5 mg/.50 mg/.15 mg/Placebo.	Seq. 8/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 8 = RPL554 3.0 mg/Placebo/1.5 mg/.15 mg/.50 mg.	Seq. 9/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 9 = Placebo/.15 mg/.50 mg/1.5 mg/3.0 mg.	Seq. 10/Part B Part B: 7 day, twice daily dose of RPL554 via DPI (double-blind) complete block, cross-over. Seq 10 = Placebo/.50 mg/3.0 mg/1.5 mg/.15 mg.
Part A (R, PC, PG) Single Dose STARTED	6	6	7	6	6	6	0	0	0	0	0	0	0	0	0	0
Part A (R, PC, PG) Single Dose COMPLETED	6	6	7	6	6	6	0	0	0	0	0	0	0	0	0	0
Part A (R, PC, PG) Single Dose NOT COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Part B (R, PC, CO) Twice Daily for 7 Day STARTED	0	0	0	0	0	0	4	3	4	3	4	3	3	4	4	3
Part B (R, PC, CO) Twice Daily for 7 Day COMPLETED	0	0	0	0	0	0	4	1	4	3	4	3	3	4	4	3
Part B (R, PC, CO) Twice Daily for 7 Day NOT COMPLETED	0	0	0	0	0	0	0	2	0	0	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study Evaluating 5 Doses of RPL554 and Placebo in COPD Patients Via a Dry Powder Inhaler

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	0.15 mg n=6 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=7 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=6 Participants Single dose of RPL554 via DPI (single blind)	Placebo n=6 Participants Single dose via DPI (double blind)	Total n=37 Participants Total of all reporting groups
Age, Continuous	61.7 years STANDARD_DEVIATION 10.15 • n=5 Participants	58.3 years STANDARD_DEVIATION 3.56 • n=7 Participants	63.7 years STANDARD_DEVIATION 6.68 • n=5 Participants	52.7 years STANDARD_DEVIATION 3.88 • n=4 Participants	59.3 years STANDARD_DEVIATION 7.81 • n=21 Participants	60.8 years STANDARD_DEVIATION 8.80 • n=8 Participants	59.5 years STANDARD_DEVIATION 7.57 • n=8 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	5 Participants n=7 Participants	3 Participants n=5 Participants	5 Participants n=4 Participants	2 Participants n=21 Participants	4 Participants n=8 Participants	23 Participants n=8 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants	2 Participants n=8 Participants	14 Participants n=8 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	2 Participants n=8 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	6 Participants n=4 Participants	6 Participants n=21 Participants	6 Participants n=8 Participants	35 Participants n=8 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants
Region of Enrollment United States	6 participants n=5 Participants	6 participants n=7 Participants	7 participants n=5 Participants	6 participants n=4 Participants	6 participants n=21 Participants	6 participants n=8 Participants	37 participants n=8 Participants

PRIMARY outcome

Timeframe: Day 1

Population: Pharmacokinetic (PK) Analysis Set in Part A: all randomized patients who had blood sampling performed after the single dose of RPL554 and had evaluable PK parameter data. The PK Analysis Set included the 31 patients who received RPL554 in Part A but not the 6 patients in the placebo group.

RPL554 Plasma pharmacokinetics AUC0-12 (Area under the Curve) after single dose

Outcome measures

Outcome measures
Measure	0.15 mg n=6 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=7 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=6 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part A: RPL554 Plasma Pharmacokinetic Parameter (AUC0-12)	260 h*pg/mL Geometric Coefficient of Variation 53.5	472 h*pg/mL Geometric Coefficient of Variation 106.7	2210 h*pg/mL Geometric Coefficient of Variation 62.3	4160 h*pg/mL Geometric Coefficient of Variation 47.2	9730 h*pg/mL Geometric Coefficient of Variation 62.3	—

PRIMARY outcome

Timeframe: Day 1

Population: Pharmacokinetic (PK) Analysis Set in Part A: all randomized patients who had blood sampling performed after the single dose of RPL554 and had evaluable PK parameter data. The PK Analysis Set included the 31 patients who received RPL554 in Part A but not the 6 patients in the placebo group.

RPL554 Area under the curve at maximum concentration after a single dose

Outcome measures

Outcome measures
Measure	0.15 mg n=6 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=7 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=6 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part A: RPL554 Plasma Pharmacokinetic Parameter (AUC 0-t)	222 h*pg/mL Geometric Coefficient of Variation 55.5	495 h*pg/mL Geometric Coefficient of Variation 128.2	2680 h*pg/mL Geometric Coefficient of Variation 56.5	4920 h*pg/mL Geometric Coefficient of Variation 44.5	11600 h*pg/mL Geometric Coefficient of Variation 68.3	—

PRIMARY outcome

Timeframe: Day 1

Population: Pharmacokinetic (PK) Analysis Set in Part A: all randomized patients who had blood sampling performed after the single dose of RPL554 and had evaluable PK parameter data. The PK Analysis Set included the 31 patients who received RPL554 in Part A but not the 6 patients in the placebo group.

RPL554 Plasma pharmacokinetics Half-life concentration after a single dose

Outcome measures

Outcome measures
Measure	0.15 mg n=1 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=5 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=7 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=6 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life)	3.59 h	5.39 h Geometric Coefficient of Variation 28.7	7.48 h Geometric Coefficient of Variation 43.3	6.65 h Geometric Coefficient of Variation 33.6	6.66 h Geometric Coefficient of Variation 25.4	—

PRIMARY outcome

Timeframe: Day 7

Population: All efficacy analyses were carried out using the Full Analysis Set (FAS) in Part B: all randomized patients with sufficient data (pre-dose and at least 1 post-dose assessment of spirometry) collected after intake of study medication to compute the PD parameters (FEV1, FRC measurements) on at least 2 treatment periods in Part B. The FAS comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

Change from Baseline FEV1 to Peak FEV1 (over 4 hours) on Day 7

Outcome measures

Outcome measures
Measure	0.15 mg n=34 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=31 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=32 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: Change From Baseline in Peak FEV1 (Over 4 Hours)	0.220 L Standard Deviation 0.1593	0.293 L Standard Deviation 0.2411	0.298 L Standard Deviation 0.2355	0.378 L Standard Deviation 0.2182	0.118 L Standard Deviation 0.1437	—

SECONDARY outcome

Timeframe: Day 1

Population: Full Analysis Set (FAS) in Part A: all randomized patients with sufficient data collected after intake of study medication to compute the PD parameters (FEV1 measurements pre dose and at least 1 post-baseline). All 37 patients randomized into Part A were included in the FAS.

Change from Baseline FEV1 to Average FEV1 (over 4 hours) After Single Dose

Outcome measures

Outcome measures
Measure	0.15 mg n=6 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=7 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=6 Participants Single dose of RPL554 via DPI (single blind)	Placebo n=6 Participants Single dose via DPI (double blind)
Part A: Change From Baseline in Average FEV1 (Over 4 Hours)	0.109 L Standard Deviation 0.0380	0.213 L Standard Deviation 0.1226	0.326 L Standard Deviation 0.249	0.337 L Standard Deviation 0.1831	0.334 L Standard Deviation 0.1170	0.040 L Standard Deviation 0.0517

SECONDARY outcome

Timeframe: Day 1

Population: Full Analysis Set (FAS) in Part A: all randomized patients with sufficient data collected after intake of study medication to compute the PD parameters (FEV1 measurements pre dose and at least 1 post-baseline). All 37 patients randomized into Part A were included in the FAS.

Change from Baseline FEV1 to Average FEV1 (over 12 hours) After Single Dose

Outcome measures

Outcome measures
Measure	0.15 mg n=6 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=7 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=6 Participants Single dose of RPL554 via DPI (single blind)	Placebo n=6 Participants Single dose via DPI (double blind)
Part A: Change From Baseline in Average FEV1 (Over 12 Hours)	0.045 L Standard Deviation 0.0384	0.113 L Standard Deviation 0.1703	0.214 L Standard Deviation 0.2172	0.243 L Standard Deviation 0.2715	0.176 L Standard Deviation 0.0481	-0.011 L Standard Deviation 0.0749

SECONDARY outcome

Timeframe: Day 1

Population: Full Analysis Set (FAS) in Part A: all randomized patients with sufficient data collected after intake of study medication to compute the PD parameters (FEV1 measurements pre dose and at least 1 post-baseline). All 37 patients randomized into Part A were included in the FAS.

Change from Baseline FEV1 to Peak FEV1 (over 4 hours) After Single Dose

Outcome measures

Outcome measures
Measure	0.15 mg n=6 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=7 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=6 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=6 Participants Single dose of RPL554 via DPI (single blind)	Placebo n=6 Participants Single dose via DPI (double blind)
Part A: Change From Baseline in Peak FEV1 (Over 4 Hours)	0.203 L Standard Deviation 0.0646	0.298 L Standard Deviation 0.1280	0.429 L Standard Deviation 0.2504	0.468 L Standard Deviation 0.2135	0.452 L Standard Deviation 0.1382	0.135 L Standard Deviation 0.0922

SECONDARY outcome

Timeframe: Day 1

number of patients with treatment-emergent hematology abnormal laboratory assessments

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1

number of patients with treatment-emergent blood chemistry abnormal laboratory assessments

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1

number of patients with treatment-emergent urinalysis abnormal laboratory assessments

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1

Change from Baseline Pulse Rate to Peak Pulse Rate (over 4 hours) After Single Dose

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1

number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg) (An increase from baseline of \>=20 in systolic bp)

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1

number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1

number of patients with treatment-emergent clinically significant abnormal ECG parameters, heart rate in bpm

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 7

Population: All efficacy analyses were carried out using the Full Analysis Set (FAS) in Part B: all randomized patients with sufficient data (pre-dose and at least 1 post-dose assessment of spirometry) collected after intake of study medication to compute the PD parameters (FEV1, FRC measurements) on at least 2 treatment periods in Part B. The FAS comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

Change from baseline in average FEV1 (over 4 hours) on Day 7

Outcome measures

Outcome measures
Measure	0.15 mg n=34 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=31 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=32 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: Change From Baseline in Average FEV1 (Over 4 Hrs)	0.100 L Standard Deviation 0.1430	0.176 L Standard Deviation 0.2253	0.184 L Standard Deviation 0.2176	0.244 L Standard Deviation 0.1953	0.017 L Standard Deviation 0.1526	—

SECONDARY outcome

Timeframe: Day 7

Population: All efficacy analyses were carried out using the Full Analysis Set (FAS) in Part B: all randomized patients with sufficient data (pre-dose and at least 1 post-dose assessment of spirometry) collected after intake of study medication to compute the PD parameters (FEV1, FRC measurements) on at least 2 treatment periods in Part B. The FAS comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 7

Outcome measures

Outcome measures
Measure	0.15 mg n=34 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=31 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=32 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: Change From Baseline in Average FEV1 (Over 12 Hours)	0.052 L Standard Deviation 0.1759	0.106 L Standard Deviation 0.2125	0.096 L Standard Deviation 0.1796	0.163 L Standard Deviation 0.1679	0.016 L Standard Deviation 0.1455	—

SECONDARY outcome

Timeframe: Day 7

Population: All efficacy analyses were carried out using the Full Analysis Set (FAS) in Part B: all randomized patients with sufficient data (pre-dose and at least 1 post-dose assessment of spirometry) collected after intake of study medication to compute the PD parameters (FEV1, FRC measurements) on at least 2 treatment periods in Part B. The FAS comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

Change from Baseline FEV1 to Morning Trough FEV1 on Day 7

Outcome measures

Outcome measures
Measure	0.15 mg n=34 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=31 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=32 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: Change From Baseline in Trough FEV1	-0.036 L Standard Deviation 0.1332	0.031 L Standard Deviation 0.1821	0.020 L Standard Deviation 0.1838	0.030 L Standard Deviation 0.1539	-0.067 L Standard Deviation 0.1577	—

SECONDARY outcome

Timeframe: Day 1

Population: All efficacy analyses were carried out using the Full Analysis Set (FAS) in Part B: all randomized patients with sufficient data (pre-dose and at least 1 post-dose assessment of spirometry) collected after intake of study medication to compute the PD parameters (FEV1, FRC measurements) on at least 2 treatment periods in Part B. The FAS comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

Change from baseline FEV1 in peak FEV1 (over 4 hours) after first dose

Outcome measures

Outcome measures
Measure	0.15 mg n=34 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=33 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=33 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=32 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: Change From Baseline in Peak FEV1 (Over 4 Hours)	0.310 L Standard Deviation 0.1382	0.332 L Standard Deviation 0.2181	0.401 L Standard Deviation 0.1705	0.404 L Standard Deviation 0.1867	0.188 L Standard Deviation 0.1267	—

SECONDARY outcome

Timeframe: Day 1

Population: All efficacy analyses were carried out using the Full Analysis Set (FAS) in Part B: all randomized patients with sufficient data (pre-dose and at least 1 post-dose assessment of spirometry) collected after intake of study medication to compute the PD parameters (FEV1, FRC measurements) on at least 2 treatment periods in Part B. The FAS comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

Change from baseline FEV1 in average FEV1 (over 4 hours) on Day 1

Outcome measures

Outcome measures
Measure	0.15 mg n=34 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=33 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=33 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=32 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: Change From Baseline in Average FEV1 (Over 4 Hours)	0.201 L Standard Deviation 0.1180	0.227 L Standard Deviation 0.2026	0.268 L Standard Deviation 0.1518	0.285 L Standard Deviation 0.1597	0.079 L Standard Deviation 0.1081	—

SECONDARY outcome

Timeframe: Day 1

Population: All efficacy analyses were carried out using the Full Analysis Set (FAS) in Part B: all randomized patients with sufficient data (pre-dose and at least 1 post-dose assessment of spirometry) collected after intake of study medication to compute the PD parameters (FEV1, FRC measurements) on at least 2 treatment periods in Part B. The FAS comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 1

Outcome measures

Outcome measures
Measure	0.15 mg n=34 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=33 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=32 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=33 Participants Single dose of RPL554 via DPI (double blind)	6 mg n=32 Participants Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: Change From Baseline in Average FEV1 (Over 12 Hours)	0.101 L Standard Deviation 0.1314	0.139 L Standard Deviation 0.1921	0.135 L Standard Deviation 0.1655	0.182 L Standard Deviation 0.1536	0.044 L Standard Deviation 0.1073	—

SECONDARY outcome

Timeframe: Day 1

Population: Pharmacokinetic (PK) Analysis Set in Part B: all randomized patients who had blood sampling performed after at least 1 dose of RPL554 in Part B and with data sufficient to calculate PK parameters. The PK analysis set comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

Determination of onset of action (\>10% increase in FEV1 from pre- to post-first dose, censored at 120 minutes) on Day 1

Outcome measures

Outcome measures
Measure	0.15 mg n=29 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=27 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=30 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=31 Participants Single dose of RPL554 via DPI (double blind)	6 mg Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: RPL554 Plasma Pharmacokinetic Parameter (Onset of Action)	13.0 mins Interval 3.0 to 120.0	15 mins Interval 3.0 to 120.0	15 mins Interval 4.0 to 125.0	13 mins Interval 4.0 to 120.0	—	—

SECONDARY outcome

Timeframe: Day 7

number of patients with treatment-emergent hematology abnormal laboratory assessments (changes from normal at baseline to low or high on Day 7 or at the end of study in \>3 patients in each treatment group).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 7

number of patients with treatment-emergent blood chemistry abnormal laboratory assessments (changes from normal at baseline to low or high on Day 7 in each treatment group).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 7

number of patients with treatment-emergent urinalysis abnormal laboratory assessments

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 7

number of patients with treatment-emergent clinically significant abnormal ECG parameters, QTcF in msec

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 7

number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 7

number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm) An increase from baseline of \>=20

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 7

number of patients with treatment-emergent abnormal vital signs (systolic blood pressure in mm Hg) (An increase from baseline of \>=20)

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1

Change from baseline in peak pulse after first dose on Day 1

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 7

Change from baseline in peak pulse after morning dosing on Day 7

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 7

Population: Pharmacokinetic (PK) Analysis Set in Part B: all randomized patients who had blood sampling performed after at least 1 dose of RPL554 in Part B and with data sufficient to calculate PK parameters. The PK analysis set comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

RPL554 steady-state PK (tmax) after morning dose on Day 7

Outcome measures

Outcome measures
Measure	0.15 mg n=33 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=31 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=30 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=31 Participants Single dose of RPL554 via DPI (double blind)	6 mg Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: RPL554 Plasma Pharmacokinetic Parameter (Tmax)	1.000 h Interval 0.417 to 2.0	1.000 h Interval 0.0 to 3.917	1.000 h Interval 0.0 to 2.0	1.000 h Interval 0.0 to 2.0	—	—

SECONDARY outcome

Timeframe: Day 7

Population: Pharmacokinetic (PK) Analysis Set in Part B: all randomized patients who had blood sampling performed after at least 1 dose of RPL554 in Part B and with data sufficient to calculate PK parameters. The PK analysis set comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

RPL554 steady-state PK (Cmax and accumulation ratio) after morning dose on Day 7

Outcome measures

Outcome measures
Measure	0.15 mg n=33 Participants Single dose of RPL554 via DPI (double-blind)	0.50 mg n=31 Participants Single dose of RPL554 via DPI (double blind)	1.5 mg n=30 Participants Single dose of RPL554 via DPI (double blind)	3 mg n=31 Participants Single dose of RPL554 via DPI (double blind)	6 mg Single dose of RPL554 via DPI (single blind)	Placebo Single dose via DPI (double blind)
Part B: RPL554 Plasma Pharmacokinetic Parameter (Cmax)	68.7 pg/mL Geometric Coefficient of Variation 41.6	237 pg/mL Geometric Coefficient of Variation 47.4	591 pg/mL Geometric Coefficient of Variation 71.1	1240 pg/mL Geometric Coefficient of Variation 41.4	—	—

SECONDARY outcome

Timeframe: Day 7

Population: Pharmacokinetic (PK) Analysis Set in Part B: all randomized patients who had blood sampling performed after at least 1 dose of RPL554 in Part B and with data sufficient to calculate PK parameters. The PK analysis set comprised: RPL554 0.15 mg (N=34); RPL554 0.5 mg (N=33); RPL554 1.5 mg (N=32); RPL554 3 mg (N=33); Placebo (N=32).

RPL554 steady-state PK (AUC0-12h and accumulation ratio) after morning dose on Day 7