Trial Outcomes & Findings for Study Investigating the Effect of 4 Doses of RPL554 Given in Addition to Tiotropium to Patients With COPD (NCT NCT03937479)

NCT ID: NCT03937479

Last Updated: 2020-11-20

Results Overview

Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 416 participants
• Primary outcome timeframe: Baseline and Week 4
• Results posted on: 2020-11-20

Participant Flow

The study was conducted at 49 study centers in the United States of America between 01 May 2019 and 15 November 2019. Overall, 416 adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) on a stable background therapy of open-label tiotropium were randomized and 413 patients received double-blind study treatment.

Following Screening on Visit 1, eligible patients entered a 14-day run-in period, where they received tiotropium once daily. At Visit 2, patients were re-assessed for eligibility according to randomization criteria. Patients were randomized equally across 5 double-blind treatment groups (4 doses of RPL554 or placebo).

Participant milestones

Measure	RPL554 0.375 mg Patients were administered 0.375 milligram (mg) RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
Overall Study STARTED	83	85	82	82	84
Overall Study Received Treatment	83	83	81	82	84
Overall Study COMPLETED	73	70	75	76	79
Overall Study NOT COMPLETED	10	15	7	6	5

Reasons for withdrawal

Measure	RPL554 0.375 mg Patients were administered 0.375 milligram (mg) RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
Overall Study Adverse Event	2	3	0	0	1
Overall Study Withdrawal by Subject	3	5	2	2	1
Overall Study Protocol Violation	5	6	4	3	2
Overall Study Lost to Follow-up	0	1	0	1	0
Overall Study Physician Decision	0	0	1	0	1

Baseline Characteristics

Study Investigating the Effect of 4 Doses of RPL554 Given in Addition to Tiotropium to Patients With COPD

Baseline characteristics by cohort

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=85 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=82 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Total n=416 Participants Total of all reporting groups
Age, Categorical <=18 years	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=10 Participants
Age, Categorical Between 18 and 65 years	44 Participants n=5 Participants	40 Participants n=7 Participants	45 Participants n=5 Participants	41 Participants n=4 Participants	47 Participants n=21 Participants	217 Participants n=10 Participants
Age, Categorical >=65 years	39 Participants n=5 Participants	45 Participants n=7 Participants	37 Participants n=5 Participants	41 Participants n=4 Participants	37 Participants n=21 Participants	199 Participants n=10 Participants
Age, Continuous	64.2 years STANDARD_DEVIATION 7.86 • n=5 Participants	65.5 years STANDARD_DEVIATION 8.33 • n=7 Participants	63.8 years STANDARD_DEVIATION 7.67 • n=5 Participants	64.5 years STANDARD_DEVIATION 7.92 • n=4 Participants	63.6 years STANDARD_DEVIATION 8.41 • n=21 Participants	64.3 years STANDARD_DEVIATION 8.03 • n=10 Participants
Sex: Female, Male Female	51 Participants n=5 Participants	48 Participants n=7 Participants	51 Participants n=5 Participants	45 Participants n=4 Participants	44 Participants n=21 Participants	239 Participants n=10 Participants
Sex: Female, Male Male	32 Participants n=5 Participants	37 Participants n=7 Participants	31 Participants n=5 Participants	37 Participants n=4 Participants	40 Participants n=21 Participants	177 Participants n=10 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	3 Participants n=21 Participants	8 Participants n=10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	82 Participants n=5 Participants	84 Participants n=7 Participants	81 Participants n=5 Participants	80 Participants n=4 Participants	81 Participants n=21 Participants	408 Participants n=10 Participants
Ethnicity (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=10 Participants
Race/Ethnicity, Customized 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=10 Participants
Race/Ethnicity, Customized 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=10 Participants
Race/Ethnicity, Customized Black or African American	10 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants	6 Participants n=4 Participants	9 Participants n=21 Participants	41 Participants n=10 Participants
Race/Ethnicity, Customized 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=10 Participants
Race/Ethnicity, Customized White	73 Participants n=5 Participants	78 Participants n=7 Participants	73 Participants n=5 Participants	76 Participants n=4 Participants	75 Participants n=21 Participants	375 Participants n=10 Participants
Race/Ethnicity, Customized Other	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=10 Participants

PRIMARY outcome

Timeframe: Baseline and Week 4

Population: The Full Analysis Set (FAS) included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Only patients with valid values at baseline and Week 4 are included in the analysis.

Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines.

Outcome measures

Measure	RPL554 0.375 mg n=73 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=70 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=75 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=76 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=79 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4	0.1963 liters Standard Error 0.02639	0.2100 liters Standard Error 0.02676	0.2260 liters Standard Error 0.02647	0.2431 liters Standard Error 0.02631	0.1188 liters Standard Error 0.02589

SECONDARY outcome

Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-3h FEV1 was defined as area under the curve over 3 hours of the FEV1, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 Day 1	0.1533 liters Standard Error 0.01600	0.1614 liters Standard Error 0.01602	0.1810 liters Standard Error 0.01620	0.2017 liters Standard Error 0.01609	0.0654 liters Standard Error 0.01590
LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 Week 1	0.1118 liters Standard Error 0.02129	0.1301 liters Standard Error 0.02144	0.1308 liters Standard Error 0.02143	0.1526 liters Standard Error 0.02149	0.0246 liters Standard Error 0.02107
LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 Week 2	0.1154 liters Standard Error 0.02308	0.1309 liters Standard Error 0.02338	0.1433 liters Standard Error 0.02334	0.1651 liters Standard Error 0.02321	0.0304 liters Standard Error 0.02285
LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 Week 3	0.1156 liters Standard Error 0.02323	0.1243 liters Standard Error 0.02364	0.1444 liters Standard Error 0.02343	0.1385 liters Standard Error 0.02324	0.0294 liters Standard Error 0.02297
LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 Week 4	0.1095 liters Standard Error 0.02538	0.1305 liters Standard Error 0.02574	0.1394 liters Standard Error 0.02544	0.1626 liters Standard Error 0.02530	0.0369 liters Standard Error 0.02488

SECONDARY outcome

Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-12h FEV1 was defined as area under the curve over 12 hours of the FEV1, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 Day 1	0.0795 liters Standard Error 0.01767	0.0909 liters Standard Error 0.01770	0.1020 liters Standard Error 0.01790	0.1374 liters Standard Error 0.01777	0.0282 liters Standard Error 0.01756
LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 Week 4	0.0359 liters Standard Error 0.02455	0.0630 liters Standard Error 0.02486	0.0640 liters Standard Error 0.02451	0.0969 liters Standard Error 0.02426	0.0096 liters Standard Error 0.02413

SECONDARY outcome

Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2 and 3

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 Day 1	0.2353 liters Standard Error 0.01926	0.2426 liters Standard Error 0.01930	0.2610 liters Standard Error 0.01951	0.2852 liters Standard Error 0.01938	0.1469 liters Standard Error 0.01914
LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 Week 1	0.1860 liters Standard Error 0.02305	0.2026 liters Standard Error 0.02322	0.2116 liters Standard Error 0.02321	0.2353 liters Standard Error 0.02326	0.1041 liters Standard Error 0.02277
LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 Week 2	0.1963 liters Standard Error 0.02453	0.2121 liters Standard Error 0.02483	0.2191 liters Standard Error 0.02481	0.2421 liters Standard Error 0.02466	0.1098 liters Standard Error 0.02429
LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 Week 3	0.1987 liters Standard Error 0.02503	0.2006 liters Standard Error 0.02544	0.2277 liters Standard Error 0.02526	0.2197 liters Standard Error 0.02505	0.1072 liters Standard Error 0.02476

SECONDARY outcome

Timeframe: Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and morning trough FEV1 was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 Week 1	-0.0088 liters Standard Error 0.02038	-0.0354 liters Standard Error 0.02058	-0.0451 liters Standard Error 0.02056	-0.0216 liters Standard Error 0.02081	-0.0520 liters Standard Error 0.02024
LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 Week 2	-0.0278 liters Standard Error 0.02183	-0.0696 liters Standard Error 0.02243	-0.0070 liters Standard Error 0.02212	0.0136 liters Standard Error 0.02220	-0.0377 liters Standard Error 0.02169
LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 Week 3	-0.0385 liters Standard Error 0.02185	-0.0630 liters Standard Error 0.02254	-0.0413 liters Standard Error 0.02222	-0.0232 liters Standard Error 0.02205	-0.0533 liters Standard Error 0.02162
LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 Week 4	-0.0201 liters Standard Error 0.02296	-0.0348 liters Standard Error 0.02356	-0.0141 liters Standard Error 0.02311	0.0054 liters Standard Error 0.02306	-0.0218 liters Standard Error 0.02256

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS:COPD scale has a scoring range of 0 to 40. Higher scores indicates severe respiratory symptoms. Baseline was the mean over the 7 days prior to first intake of study treatment. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS:COPD was measured by daily electronic diary (e-diary).

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 Week 1	-0.978 units on a scale Standard Error 0.3375	-0.669 units on a scale Standard Error 0.3375	-0.617 units on a scale Standard Error 0.3403	-1.142 units on a scale Standard Error 0.3405	-0.319 units on a scale Standard Error 0.3397
LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 Week 2	-0.873 units on a scale Standard Error 0.3916	-0.471 units on a scale Standard Error 0.3932	-0.597 units on a scale Standard Error 0.3921	-0.598 units on a scale Standard Error 0.3952	-0.102 units on a scale Standard Error 0.3908
LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 Week 3	-0.950 units on a scale Standard Error 0.3830	-0.338 units on a scale Standard Error 0.3865	-1.091 units on a scale Standard Error 0.3843	-1.097 units on a scale Standard Error 0.3827	-0.287 units on a scale Standard Error 0.3832
LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 Week 4	-1.690 units on a scale Standard Error 0.4337	-0.593 units on a scale Standard Error 0.4412	-1.226 units on a scale Standard Error 0.4346	-1.071 units on a scale Standard Error 0.4357	-0.228 units on a scale Standard Error 0.4320

SECONDARY outcome

Timeframe: Baseline, Weeks 2 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Patients completed the SGRQ-C consisting of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome. The SGRQ-C was measured at Week 2 and 4 visits.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 Week 4	-4.387 units on a scale Standard Error 1.3087	-2.400 units on a scale Standard Error 1.3732	-4.870 units on a scale Standard Error 1.3480	-4.163 units on a scale Standard Error 1.3479	-0.116 units on a scale Standard Error 1.3195
LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 Week 2	-1.808 units on a scale Standard Error 1.1960	-1.132 units on a scale Standard Error 1.2583	-3.465 units on a scale Standard Error 1.2311	-3.618 units on a scale Standard Error 1.2491	-0.249 units on a scale Standard Error 1.2277

SECONDARY outcome

Timeframe: Weeks 2 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

The TDI is a questionnaire that focussed on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 Week 2	1.682 units on a scale Standard Error 0.3183	1.285 units on a scale Standard Error 0.3263	1.582 units on a scale Standard Error 0.3229	1.589 units on a scale Standard Error 0.3255	1.421 units on a scale Standard Error 0.3202
LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 Week 4	2.089 units on a scale Standard Error 0.3423	1.484 units on a scale Standard Error 0.3496	2.055 units on a scale Standard Error 0.3475	2.063 units on a scale Standard Error 0.3437	1.766 units on a scale Standard Error 0.3381

SECONDARY outcome

Timeframe: Weeks 2 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

The PGAC is a single question assessment to determine whether patients noticed a change in their breathing since the start of the study. Patients were asked to respond to a PGAC question asking, "Compared with prior to the study start, how do you feel your breathing is?" on a scale of '1=much worse' to '5=much better', with '3=no change'. Higher scores indicate better outcome.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 Week 2	3.512 units on a scale Standard Error 0.0867	3.522 units on a scale Standard Error 0.0895	3.456 units on a scale Standard Error 0.0876	3.523 units on a scale Standard Error 0.0889	3.427 units on a scale Standard Error 0.0876
LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 Week 4	3.553 units on a scale Standard Error 0.0922	3.543 units on a scale Standard Error 0.0944	3.536 units on a scale Standard Error 0.0932	3.577 units on a scale Standard Error 0.0922	3.506 units on a scale Standard Error 0.0909

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Use of rescue medication (albuterol) per visit was calculated as the LS mean use daily over total number of days between previous visit (inclusive) and the following visit. Baseline use was the mean over the last 7 days of the run-in phase (calculated as the sum of puffs taken, divided by number of days data has been recorded).

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication Week 1	-0.510 number of rescue medication puffs Standard Error 0.1384	-0.580 number of rescue medication puffs Standard Error 0.1407	-0.539 number of rescue medication puffs Standard Error 0.1395	-0.629 number of rescue medication puffs Standard Error 0.1412	-0.556 number of rescue medication puffs Standard Error 0.1386
LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication Week 2	-0.325 number of rescue medication puffs Standard Error 0.1822	-0.360 number of rescue medication puffs Standard Error 0.1847	-0.388 number of rescue medication puffs Standard Error 0.1828	-0.379 number of rescue medication puffs Standard Error 0.1850	-0.544 number of rescue medication puffs Standard Error 0.1812
LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication Week 3	-0.302 number of rescue medication puffs Standard Error 0.1726	-0.139 number of rescue medication puffs Standard Error 0.1765	-0.647 number of rescue medication puffs Standard Error 0.1736	-0.558 number of rescue medication puffs Standard Error 0.1742	-0.504 number of rescue medication puffs Standard Error 0.1724
LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication Week 4	-0.412 number of rescue medication puffs Standard Error 0.1753	-0.510 number of rescue medication puffs Standard Error 0.1799	-0.784 number of rescue medication puffs Standard Error 0.1766	-0.506 number of rescue medication puffs Standard Error 0.1777	-0.671 number of rescue medication puffs Standard Error 0.1741

SECONDARY outcome

Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2, 3 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and peak FVC was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 Day 1	0.3463 liters Standard Error 0.02857	0.3775 liters Standard Error 0.02858	0.3852 liters Standard Error 0.02892	0.4035 liters Standard Error 0.02874	0.2241 liters Standard Error 0.02840
LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 Week 1	0.2839 liters Standard Error 0.03281	0.3199 liters Standard Error 0.03302	0.3065 liters Standard Error 0.03302	0.3545 liters Standard Error 0.03311	0.1717 liters Standard Error 0.03242
LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 Week 2	0.2597 liters Standard Error 0.03401	0.3282 liters Standard Error 0.03446	0.3070 liters Standard Error 0.03440	0.3343 liters Standard Error 0.03417	0.1524 liters Standard Error 0.03368
LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 Week 3	0.2744 liters Standard Error 0.03512	0.3177 liters Standard Error 0.03570	0.3176 liters Standard Error 0.03544	0.3008 liters Standard Error 0.03513	0.1626 liters Standard Error 0.03475
LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 Week 4	0.2706 liters Standard Error 0.03724	0.3198 liters Standard Error 0.03775	0.2951 liters Standard Error 0.03729	0.3414 liters Standard Error 0.03707	0.1736 liters Standard Error 0.03647

SECONDARY outcome

Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-3h FVC was defined as area under the curve over 3 hours of the FVC, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 Day 1	0.2165 liters Standard Error 0.02390	0.2397 liters Standard Error 0.02390	0.2519 liters Standard Error 0.02419	0.2715 liters Standard Error 0.02404	0.0864 liters Standard Error 0.02375
LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 Week 1	0.1460 liters Standard Error 0.03045	0.1890 liters Standard Error 0.03065	0.1691 liters Standard Error 0.03064	0.2039 liters Standard Error 0.03074	0.0323 liters Standard Error 0.03014
LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 Week 2	0.1362 liters Standard Error 0.03261	0.2010 liters Standard Error 0.03302	0.1783 liters Standard Error 0.03296	0.2104 liters Standard Error 0.03279	0.0217 liters Standard Error 0.03228
LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 Week 3	0.1431 liters Standard Error 0.03318	0.1860 liters Standard Error 0.03372	0.1798 liters Standard Error 0.03346	0.1739 liters Standard Error 0.03321	0.0252 liters Standard Error 0.03281
LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 Week 4	0.1350 liters Standard Error 0.03606	0.1928 liters Standard Error 0.03654	0.1623 liters Standard Error 0.03610	0.2134 liters Standard Error 0.03594	0.0382 liters Standard Error 0.03533

SECONDARY outcome

Timeframe: Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-12h FVC was defined as area under the curve over 12 hours of the FVC, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 Day 1	0.0838 liters Standard Error 0.02543	0.1294 liters Standard Error 0.02543	0.1187 liters Standard Error 0.02574	0.1514 liters Standard Error 0.02558	0.0344 liters Standard Error 0.02527
LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 Week 4	0.0152 liters Standard Error 0.03486	0.0838 liters Standard Error 0.03529	0.0438 liters Standard Error 0.03478	0.0982 liters Standard Error 0.03443	-0.0030 liters Standard Error 0.03425

SECONDARY outcome

Timeframe: Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4

Population: The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed.

Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and morning trough FVC was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines.

Outcome measures

Measure	RPL554 0.375 mg n=83 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=82 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 Week 1	-0.0159 liters Standard Error 0.03028	-0.0650 liters Standard Error 0.03053	-0.0887 liters Standard Error 0.03053	-0.0624 liters Standard Error 0.03092	-0.0617 liters Standard Error 0.03008
LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 Week 2	-0.0647 liters Standard Error 0.03190	-0.0744 liters Standard Error 0.03275	-0.0458 liters Standard Error 0.03231	-0.0045 liters Standard Error 0.03245	-0.0614 liters Standard Error 0.03170
LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 Week 3	-0.0966 liters Standard Error 0.03354	-0.0936 liters Standard Error 0.03456	-0.0857 liters Standard Error 0.03410	-0.0690 liters Standard Error 0.03383	-0.0969 liters Standard Error 0.03318
LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 Week 4	-0.0390 liters Standard Error 0.03323	-0.0347 liters Standard Error 0.03408	-0.0570 liters Standard Error 0.03344	-0.0217 liters Standard Error 0.03336	-0.0198 liters Standard Error 0.03264

SECONDARY outcome

Timeframe: Pre-dose on Day 1 and Week 2

Population: The Pharmacokinetic (PK) analysis set included all randomized patients who had blood sampling performed and quantitative values of study treatment concentrations determined. Patients were classified according to actual treatment received for PK analysis set. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Number of patients with values available at the specific visit were analyzed.

Blood samples were taken to determine steady-state plasma concentrations of tiotropium prior to and following 14 days of treatment with RPL554.

Outcome measures

Measure	RPL554 0.375 mg n=82 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=82 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=83 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 Day 1	2.8 picogram per milliliter (pg/mL) Standard Deviation 1.18	2.1 picogram per milliliter (pg/mL) Standard Deviation 2.98	1.9 picogram per milliliter (pg/mL) Standard Deviation 1.4	2.4 picogram per milliliter (pg/mL) Standard Deviation 3.56	2.4 picogram per milliliter (pg/mL) Standard Deviation 3.06
Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 Week 2	2.2 picogram per milliliter (pg/mL) Standard Deviation 3.85	2.3 picogram per milliliter (pg/mL) Standard Deviation 3.56	1.9 picogram per milliliter (pg/mL) Standard Deviation 1.58	2.0 picogram per milliliter (pg/mL) Standard Deviation 2.22	2.2 picogram per milliliter (pg/mL) Standard Deviation 2.13

SECONDARY outcome

Timeframe: Pre-dose at Week 2

Population: The PK analysis set included all randomized patients who had blood sampling performed and quantitative values of study treatment concentrations determined. Patients were classified according to actual treatment received for PK analysis set. Number of patients with values available at the specific visit were analyzed.

Blood samples were taken to determine steady-state plasma concentrations of RPL554 following 14 days of treatment with RPL554.

Outcome measures

Measure	RPL554 0.375 mg n=59 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=57 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=63 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=70 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=80 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
Steady-State Plasma Concentrations of RPL554 at Week 2	37.3 pg/mL Standard Deviation 58.84	53.7 pg/mL Standard Deviation 51.71	107.9 pg/mL Standard Deviation 92.98	170.6 pg/mL Standard Deviation 154.3	NA pg/mL Standard Deviation NA

SECONDARY outcome

Timeframe: TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks.

Population: The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.

An adverse event (AE) was defined as any undesirable experience occurring to a patient, or worsening in a patient, whether considered related to the study medication or not. All AEs which started after the first dose of study treatment or started prior to first dose of study treatment and worsened, based on the Investigator's assessment of severity, on or after first dose of study treatment were considered to be treatment-emergent. A serious adverse event is any adverse experience that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events.

Outcome measures

Measure	RPL554 0.375 mg n=82 Participants Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 0.75 mg n=83 Participants Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 1.5 mg n=81 Participants Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	RPL554 3.0 mg n=83 Participants Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.	Placebo n=84 Participants Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
Number of Patients With Treatment Emergent Adverse Events (TEAEs) Any serious TEAE	0 Participants	1 Participants	0 Participants	2 Participants	0 Participants
Number of Patients With Treatment Emergent Adverse Events (TEAEs) Any serious drug-related TEAE	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Patients With Treatment Emergent Adverse Events (TEAEs) Any TEAE	12 Participants	15 Participants	14 Participants	18 Participants	17 Participants
Number of Patients With Treatment Emergent Adverse Events (TEAEs) Any TEAE leading to drug discontinuation	2 Participants	3 Participants	0 Participants	0 Participants	1 Participants
Number of Patients With Treatment Emergent Adverse Events (TEAEs) Any drug-related TEAE	1 Participants	3 Participants	2 Participants	2 Participants	4 Participants
Number of Patients With Treatment Emergent Adverse Events (TEAEs) Any serious TEAE leading drug discontinuation	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Number of Patients With Treatment Emergent Adverse Events (TEAEs) Any TEAE leading to death	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

Adverse Events

RPL554 0.375 mg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

RPL554 0.75 mg

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

RPL554 1.5 mg

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

RPL554 3.0 mg

Serious events: 2 serious events

Other events: 8 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Measure	RPL554 0.375 mg n=82 participants at risk Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.	RPL554 0.75 mg n=83 participants at risk Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.	RPL554 1.5 mg n=81 participants at risk Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.	RPL554 3.0 mg n=83 participants at risk Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.	Placebo n=84 participants at risk Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.
Injury, poisoning and procedural complications Jaw fracture	0.00% 0/82 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/83 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/81 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/83 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/84 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Nervous system disorders Syncope	0.00% 0/82 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/83 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/81 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/83 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/84 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Psychiatric disorders Alcohol abuse	0.00% 0/82 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/83 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/81 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/83 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/84 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Renal and urinary disorders Chronic kidney disease	0.00% 0/82 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/83 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/81 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/83 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/84 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.

Other adverse events

Measure	RPL554 0.375 mg n=82 participants at risk Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.	RPL554 0.75 mg n=83 participants at risk Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.	RPL554 1.5 mg n=81 participants at risk Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.	RPL554 3.0 mg n=83 participants at risk Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.	Placebo n=84 participants at risk Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set.
Infections and infestations Oral candidiasis	0.00% 0/82 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/83 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/81 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/83 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	2.4% 2/84 • Number of events 2 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Infections and infestations Nasopharyngitis	0.00% 0/82 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/83 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/81 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/83 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	2.4% 2/84 • Number of events 2 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Infections and infestations Gastroenteritis	0.00% 0/82 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/83 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	2.5% 2/81 • Number of events 2 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/83 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/84 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	3.7% 3/82 • Number of events 3 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	2.4% 2/83 • Number of events 2 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/81 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	3.6% 3/83 • Number of events 3 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/84 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/82 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/83 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/81 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	2.4% 2/83 • Number of events 2 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/84 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Nervous system disorders Headache	2.4% 2/82 • Number of events 2 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/83 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/81 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	2.4% 2/83 • Number of events 2 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/84 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Investigations Blood creatinine increased	1.2% 1/82 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	2.4% 2/83 • Number of events 2 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	1.2% 1/81 • Number of events 1 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/83 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/84 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/82 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	2.4% 2/83 • Number of events 2 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/81 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/83 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.	0.00% 0/84 • TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.

Additional Information

Nancy Herje

Verona Pharma Plc

Phone: +1 646-951-0961

Email: nancy.herje@veronapharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place