Bronchodilator Effect of RPL554 Administered in Addition to Tiotropium/Olodaterol in Patients With COPD

• Sponsor: Verona Pharma plc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03673670
• Collaborator: (none)
• Enrollment: 79
• Locations: 4
• Arms: 3
• Actual Duration (Months): 3.9
• Patients Per Site: 19.8
• Patients Per Site Per Month: 5

Study Details

Study Description

Brief Summary

The study investigates the effect of 3 days of twice daily treatment of two different doses of RPL554 (a phosphodiesterase [PDE]3/4 inhibitor) or placebo, each administered in addition to once daily tiotropium/olodaterol (Respimat) in patients with moderate to severe chronic obstructive pulmonary disease (COPD). Patients will receive each of the three treatment combinations in a randomized sequence using a crossover design

Condition or Disease	Intervention/Treatment	Phase
COPD	Drug: RPL554 Suspension; Drug: Placebo; Drug: Tiotropium/olodaterol (Respimat)	Phase 2

Detailed Description

RPL554 is a dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) which are known to have a role in modulating the inflammatory airway response in respiratory diseases, including COPD. PDE3 inhibitors act as bronchodilators whilst PDE4 inhibitors have anti-inflammatory properties and there is also evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive or synergistic anti-inflammatory and bronchodilator. The two doses of RPL554 (1.5 mg and 6 mg)have been selected based on the results from prior studies investigating single and multiple ascending doses in healthy subjects, single doses in asthmatics, single/multiple ascending doses in COPD patients, and 3 days of dosing in COPD patients. These doses were demonstrated to be both effective as a bronchodilator and well tolerated.

The purpose of the study is to investigate if RPL554 has an additive bronchodilator effect when administered in combination with a commonly used anticholinergic/β-agonist combination medication, tiotropium/olodaterol (Respimat), in this patient population measured by the peak forced expiratory volume in one second (FEV1), and forced vital capacity (FVC).

Study Design

• Study Type: Interventional
• Actual Enrollment: 79 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Masking Description: The nebulizer cup will be obscured so the contents are not visible to the subject and the blinded study staff.
• Primary Purpose: Treatment
• Official Title: A Phase II, Randomized, Double Blind, Placebo Controlled, Three-way Crossover Study to Assess the Bronchodilator Effect of RPL554 Administered in Addition to Open Label Tiotropium/Olodaterol in Patients With COPD
• Actual Study Start Date: Jul 16, 2018
• Actual Primary Completion Date: Nov 13, 2018
• Actual Study Completion Date: Nov 13, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1.5 mg RPL554 and tiotropium/olodaterol 1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily	Drug: RPL554 Suspension; A PDE3/4 inhibitor; Drug: Tiotropium/olodaterol (Respimat); An anticholinergic/β-agonist combination medication
Experimental: 6 mg RPL554 and tiotropium/olodaterol 6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily	Drug: RPL554 Suspension; A PDE3/4 inhibitor; Drug: Tiotropium/olodaterol (Respimat); An anticholinergic/β-agonist combination medication
Experimental: Placebo and tiotropium/olodaterol Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily	Drug: Placebo; A placebo solution; Drug: Tiotropium/olodaterol (Respimat); An anticholinergic/β-agonist combination medication

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Peak FEV1 on Day 3 [Change from pre-dose at 5, 15 and 30 minutes and 1, 1.5, 2 & 4 hours on Day 3]

   Change from baseline FEV1 to peak FEV1 (measured as the greatest value in the 4 hours post-dose after the morning dose) on Day 3

Secondary Outcome Measures

1. Change From Baseline to Trough FEV1 on Day 4 [Change from pre-dose on Day 1 to pre-dose on Day 4]

   Change from baseline to morning trough FEV1 on Day 4

2. Change From Baseline in AUC0-4h FEV1 on Day 3 [Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the morning dose)]

   Change from baseline FEV1 to AUC FEV1 over 4 hours post-dose after the morning dose on Day 3. The endpoint is measured as AUC/interval length (average) and measured in liters. (Note: Endpoint is AUC/interval length (average) so the units are in liters.)

3. Change From Baseline in AUC0-12h FEV1 on Day 3 [Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 3 (after the morning dose)]

   Change from baseline in AUC over 12 hours post-dose after the morning dose on Day 3. The endpoint is measured as AUC/interval length (average) and measured in liters (Note: Endpoint is AUC/interval length (average) so the units are in liters.)

4. Change From Baseline in Peak FEV1 on Day 1 [Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 1 (after the morning dose), with the maximum change reported]

   Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the morning dose on Day 1

5. Change From Baseline in Peak FEV1 After Evening Dose on Day 3 [Change from pre-dose to each of the ollowing timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the evening dose), with the maximum change reported]

   Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the evening dose on Day 3

6. Change From Baseline in AUC0-12h FEV1 on Day 1 [Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 1 (after the morning dose)]

   Change from baseline FEV1 to AUC FEV1 over 12 hours post-dose after the morning dose on Day 1. The endpoint is measured as AUC/interval length (average) and measured in liters (Note: Endpoint is AUC/interval length (average) so the units are in liters.)

7. Determination of Onset of Action on Day 1 [Change from pre-dose to the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2 hours on Day 1 (after the morning dose)]

   Time to >10% increase in FEV1 from pre-first dose, censored at 2 hours

8. Residual Volume on Day 1 [Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)]

   Change in residual volume during treatment

9. Residual Volume on Day 3 [Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)]

   Change in residual volume during treatment

10. Functional Residual Capacity on Day 1 [Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)]

    Change in functional residual capacity during treatment

11. Functional Residual Capacity on Day 3 [Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)]

    Change in functional residual capacity during treatment

12. Specific Airway Conductance on Day 1 [Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)]

    Change in specific airway conductance during treatment

13. Specific Airway Conductance on Day 3 [Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)]

    Change in specific airway conductance during treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Written informed consent

2. Male or female aged 40 and 80 years

3. For males, not to donate sperm and either be sexually abstinent or use contraception as specified by the protocol. For females, be of non-childbearing potential or use a highly effective form of contraception

4. 12-lead ECG with heart rate between 45 and 90 beats per minute, QTcF ≤450 msec for males, and ≤ 470 msec for females, QRS interval ≤120 msec and no clinically significant abnormality including morphology

5. Screening Holter report with a minimum of 18 hours recording that is able to be evaluated for rhythm analysis showing no abnormality which indicates a significant impairment of patient safety or which may significantly impair interpretation

6. Capable of complying with all study restrictions and procedures including ability to use the study nebulizer and Respimat® correctly.

7. Body mass index (BMI) between 18 and 36 kg/m2 and minimum weight of 45 kg.

8. COPD diagnosis for at least 1 year and clinically stable COPD for 4 week

9. Post-bronchodilator (two puffs of salbutamol/albuterol followed by two puffs of ipratropium) spirometry at Screening:

• Post-bronchodilator FEV1/forced vital capacity (FVC) ratio of ≤0.70

• Post-bronchodilator FEV1 ≥30 % and ≤70% of predicted normal

• Demonstrates ≥150 mL increase from pre-bronchodilator FEV1

1. A chest X-ray showing no abnormalities, which are both clinically significant and unrelated to COPD.

2. Meet the concomitant medication restrictions and be expected to do so for the rest of the study.

3. Current and former smokers with smoking history of ≥10 pack years. 14. Capable of withdrawing from long acting bronchodilators for the duration of the study, and short acting bronchodilators for 8 hours prior to dosing.

Exclusion Criteria:

1. A history of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation.

2. COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract infection requiring antibiotics, in the last 3 months

3. A history of one or more hospitalizations for COPD in the last 12 months

4. Intolerance or hypersensitivity to tiotropium, olodaterol, atropine, ipratropium, or RPL554.

5. Evidence of cor pulmonale or clinically significant pulmonary hypertension.

6. Other respiratory disorders

7. Previous lung resection or lung reduction surgery.

8. Use of oral COPD medications, except mucolytics, in the last 3 months

9. Pulmonary rehabilitation, unless such treatment has been stable in the last 4 weeks

10. History of, or reason to believe a patient has, drug or alcohol abuse within the past 5 years.

11. Inability to perform acceptable spirometry or whole body plethysmography

12. Received an experimental drug within 30 days or five half lives, whichever is longer.

13. Patients with uncontrolled disease that the Investigator believes are clinically significant. This includes any hepatic disease, or an alanine aminotransferase or aspartate aminotransferase>2 x upper limit of normal (ULN).

14. Documented cardiovascular disease: arrhythmias, angina, recent (<1 year) or suspected myocardial infarction, congestive heart failure, unstable or uncontrolled hypertension, or diagnosis of hypertension in the last 3 months

15. Use of non-selective oral β-blockers.

16. Major surgery (requiring general anesthesia) in the last 6 weeks or will not have fully recovered from surgery, or planned surgery through the end of the study.

17. A disclosed history or one known to the Investigator, of significant non compliance in previous investigational studies or with prescribed medications.

18. Required use of oxygen therapy, even on an occasional basis.

19. Symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma.

20. History of malignancy of any organ system within 5 years, with the exception of localized skin cancers (basal or squamous cell).

21. Clinically significant abnormal values for safety laboratory tests (hematology, biochemistry, virology or urinalysis) as determined by the Investigator

22. Any other reason that the Investigator considers makes the patient unsuitable to participate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Site Partners, LLC	Winter Park	Florida	United States	32789
2	Allied Biomedical Research Holdings, d/b/a Vitalink Research	Greenville	South Carolina	United States	29615
3	Respiratory Clinical Trials LTD,	London		United Kingdom	W1G8HU
4	Medicines Evaluation Unit	Manchester		United Kingdom	M23 9QZ

Sponsors and Collaborators

• Verona Pharma plc

Investigators

• Principal Investigator: Dave Singh, Medicines Evaluation Unit

Study Documents (Full-Text)

• Study Protocol - May 28, 2018
• Statistical Analysis Plan - Oct 18, 2018

More Information

Publications

None provided.

• Responsible Party: Verona Pharma plc
• ClinicalTrials.gov Identifier: NCT03673670
• Other Study ID Numbers: RPL554-CO-204
• First Posted: Sep 17, 2018
• Last Update Posted: Oct 10, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Verona Pharma plc: COPD; Bronchodilation; FEV1
• Additional relevant MeSH terms: Tiotropium Bromide; Olodaterol

Study Results

Participant Flow

Arm/Group Title	Low Dose RPL554 Then High Dose RPL554 Then Placebo	Low Dose RPL554 Then Placebo Then High Dose RPL554	High Dose RPL554 Then Low Dose RPL554 Then Placebo	High Dose RPL554 Then Placebo Then Low Dose RPL554	Placebo Then Low Dose RPL554 Then High Dose RPL554	Placebo Then High Dose RPL554 Then Low Dose RPL554
Arm/Group Description	1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	Placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	Placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods
Period Title: Treatment Period 1 (3 Days)
STARTED	14	14	13	12	13	13
COMPLETED	13	14	12	12	13	11
NOT COMPLETED	1	0	1	0	0	2
Period Title: Treatment Period 1 (3 Days)
STARTED	13	14	12	12	13	11
COMPLETED	13	14	12	12	13	11
NOT COMPLETED	0	0	0	0	0	0
Period Title: Treatment Period 1 (3 Days)
STARTED	13	14	12	12	13	11
COMPLETED	13	14	11	12	12	11
NOT COMPLETED	0	0	1	0	1	0
Period Title: Treatment Period 1 (3 Days)
STARTED	13	14	11	12	12	11
COMPLETED	13	14	11	12	11	11
NOT COMPLETED	0	0	0	0	1	0
Period Title: Treatment Period 1 (3 Days)
STARTED	13	14	11	12	11	11
COMPLETED	13	14	11	12	10	11
NOT COMPLETED	0	0	0	0	1	0

Baseline Characteristics

Arm/Group Title	Low Dose RPL554 Then High Dose RPL554 Then Placebo	Low Dose RPL554 Then Placebo Then High Dose RPL554	High Dose RPL554 Then Low Dose RPL554 Then Placebo	High Dose RPL554 Then Placebo Then Low Dose RPL554	Placebo Then Low Dose RPL554 Then High Dose RPL554	Placebo Then High Dose RPL554 Then Low Dose RPL554	Total
Arm/Group Description	1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	Placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	Placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days with a 7-14 day washout between treatment periods	Total of all reporting groups
Overall Participants	14	14	13	12	13	13	79
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65.5	64.5	63.0	63.0	67.0	61.0	64.0
Sex: Female, Male (Count of Participants)
Female	9 64.3%	9 64.3%	8 61.5%	7 58.3%	8 61.5%	8 61.5%	49 62%
Male	5 35.7%	5 35.7%	5 38.5%	5 41.7%	5 38.5%	5 38.5%	30 38%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%	1 1.3%
Black or African American	1 7.1%	1 7.1%	1 7.7%	2 16.7%	0 0%	1 7.7%	6 7.6%
White	13 92.9%	13 92.9%	12 92.3%	10 83.3%	13 100%	11 84.6%	72 91.1%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Peak FEV1 on Day 3
Description	Change from baseline FEV1 to peak FEV1 (measured as the greatest value in the 4 hours post-dose after the morning dose) on Day 3
Time Frame	Change from pre-dose at 5, 15 and 30 minutes and 1, 1.5, 2 & 4 hours on Day 3

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol	6 mg RPL554 and Tiotropium/Olodaterol	Placebo and Tiotropium/Olodaterol
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Mean (Standard Deviation) [Liters]	0.565 (0.2783)	0.506 (0.2506)	0.519 (0.2809)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1.5 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.168
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.021
	Confidence Interval	(2-Sided) 95%; 0.991 to 1.052
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.731
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	0.995
	Confidence Interval	(2-Sided) 95%; 0.966 to 1.025
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Trough FEV1 on Day 4
Description	Change from baseline to morning trough FEV1 on Day 4
Time Frame	Change from pre-dose on Day 1 to pre-dose on Day 4

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol	6 mg RPL554 and Tiotropium/Olodaterol	Placebo and Tiotropium/Olodaterol
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Mean (Standard Deviation) [Liters]	0.186 (0.2496)	0.178 (0.2123)	0.150 (0.2218)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1.5 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.115
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.024
	Confidence Interval	(2-Sided) 95%; 0.994 to 1.055
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.111
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.024
	Confidence Interval	(2-Sided) 95%; 0.994 to 1.055
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in AUC0-4h FEV1 on Day 3
Description	Change from baseline FEV1 to AUC FEV1 over 4 hours post-dose after the morning dose on Day 3. The endpoint is measured as AUC/interval length (average) and measured in liters. (Note: Endpoint is AUC/interval length (average) so the units are in liters.)
Time Frame	Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol	6 mg RPL554 and Tiotropium/Olodaterol	Placebo and Tiotropium/Olodaterol
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Mean (Standard Deviation) [Liters]	0.429 (0.2518)	0.390 (0.2246)	0.377 (0.2485)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	6 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.303
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.014
	Confidence Interval	(2-Sided) 95%; 0.987 to 1.043
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in AUC0-12h FEV1 on Day 3
Description	Change from baseline in AUC over 12 hours post-dose after the morning dose on Day 3. The endpoint is measured as AUC/interval length (average) and measured in liters (Note: Endpoint is AUC/interval length (average) so the units are in liters.)
Time Frame	Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 3 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol	6 mg RPL554 and Tiotropium/Olodaterol	Placebo and Tiotropium/Olodaterol
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Mean (Standard Deviation) [Liters]	0.390 (0.2426)	0.347 (0.2219)	0.337 (0.2447)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1.5 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.067
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.027
	Confidence Interval	(2-Sided) 95%; 0.998 to 1.057
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.395
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.012
	Confidence Interval	(2-Sided) 95%; 0.984 to 1.042
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Peak FEV1 on Day 1
Description	Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the morning dose on Day 1
Time Frame	Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 1 (after the morning dose), with the maximum change reported

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol	6 mg RPL554 and Tiotropium/Olodaterol	Placebo and Tiotropium/Olodaterol
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Mean (Standard Deviation) [Liters]	0.490 (0.2219)	0.467 (0.2393)	0.445 (0.2306)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	6 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.404
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.012
	Confidence Interval	(2-Sided) 95%; 0.984 to 1.039
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Peak FEV1 After Evening Dose on Day 3
Description	Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the evening dose on Day 3
Time Frame	Change from pre-dose to each of the ollowing timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the evening dose), with the maximum change reported

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol	6 mg RPL554 and Tiotropium/Olodaterol	Placebo and Tiotropium/Olodaterol
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Mean (Standard Deviation) [Liters]	0.453 (0.2625)	0.405 (0.2581)	0.324 (0.2211)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1.5 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.082
	Confidence Interval	(2-Sided) 95%; 1.043 to 1.123
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.061
	Confidence Interval	(2-Sided) 95%; 1.023 to 1.101
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in AUC0-12h FEV1 on Day 1
Description	Change from baseline FEV1 to AUC FEV1 over 12 hours post-dose after the morning dose on Day 1. The endpoint is measured as AUC/interval length (average) and measured in liters (Note: Endpoint is AUC/interval length (average) so the units are in liters.)
Time Frame	Change from pre-dose to each of the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 1 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol	6 mg RPL554 and Tiotropium/Olodaterol	Placebo and Tiotropium/Olodaterol
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Mean (Standard Deviation) [Liters]	0.333 (0.1815)	0.308 (0.1854)	0.303 (0.1920)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1.5 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.096
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.020
	Confidence Interval	(2-Sided) 95%; 0.997 to 1.043
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments	A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
Statistical Test of Hypothesis	p-Value	0.862
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	GeoMean Ratio
	Estimated Value	1.002
	Confidence Interval	(2-Sided) 95%; 0.979 to 1.025
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Determination of Onset of Action on Day 1
Description	Time to >10% increase in FEV1 from pre-first dose, censored at 2 hours
Time Frame	Change from pre-dose to the following timepoints: 5, 15 and 30 minutes and 1, 1.5, 2 hours on Day 1 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol	6 mg RPL554 and Tiotropium/Olodaterol	Placebo and Tiotropium/Olodaterol
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Median (Full Range) [minutes]	10.0	6.0	11.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1.5 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.945
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	6 mg RPL554 and Tiotropium/Olodaterol, Placebo and Tiotropium/Olodaterol
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.501
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.0
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Residual Volume on Day 1
Description	Change in residual volume during treatment
Time Frame	Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1	6 mg RPL554 and Tiotropium/Olodaterol on Day 1	Placebo and Tiotropium/Olodaterol on Day 1
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	74
Mean (Standard Deviation) [Liters]	-0.469 (0.5521)	-0.408 (0.4803)	-0.377 (0.4810)

10. Secondary Outcome

Title	Residual Volume on Day 3
Description	Change in residual volume during treatment
Time Frame	Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 3	6 mg RPL554 and Tiotropium/Olodaterol on Day 3	Placebo and Tiotropium/Olodaterol on Day 3
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Pre-dose Day 3	-0.323 (0.4548)	-0.313 (0.8946)	-0.184 (0.6274)
1.25 hours	-0.648 (0.5173)	-0.510 (0.6304)	-0.510 (0.6257)
8.25 hours	-0.526 (0.5594)	-0.481 (0.4994)	-0.471 (0.6186)
12.25 hours	-0.353 (0.4561)	-0.236 (0.7566)	-0.094 (0.7118)

11. Secondary Outcome

Title	Functional Residual Capacity on Day 1
Description	Change in functional residual capacity during treatment
Time Frame	Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1	6 mg RPL554 and Tiotropium/Olodaterol on Day 1	Placebo and Tiotropium/Olodaterol on Day 1
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Mean (Standard Deviation) [Liters]	-0.344 (0.5097)	-0.294 (0.4524)	-0.277 (0.4279)

12. Secondary Outcome

Title	Functional Residual Capacity on Day 3
Description	Change in functional residual capacity during treatment
Time Frame	Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Oldaterol on Day 3	6 mg RPL554 and Tiotropium/Oldaterol on Day 3	Placebo and Tiotropium/Oldaterol on Day 3
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
1.25 hours	-0.490 (0.4654)	-0.408 (0.6102)	-0.382 (0.5610)
8.25 hours	-0.420 (0.5003)	-0.405 (0.6111)	-0.355 (0.6004)
12.25 hours	-0.255 (0.4003)	-0.155 (0.7788)	-0.075 (0.5881)
Pre-dose on Day 3	-0.278 (0.4340)	-0.206 (0.5925)	-0.163 (0.5742)

13. Secondary Outcome

Title	Specific Airway Conductance on Day 1
Description	Change in specific airway conductance during treatment
Time Frame	Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1	6 mg RPL554 and Tiotropium/Olodaterol on Day 1	Placebo and Tiotropium/Olodaterol on Day 1
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Mean (Standard Deviation) [1/kPa*sec]	0.064 (0.1148)	0.042 (0.0483)	0.043 (0.1072)

14. Secondary Outcome

Title	Specific Airway Conductance on Day 3
Description	Change in specific airway conductance during treatment
Time Frame	Change from pre-dose on Day 1 to the following timepoints: pre-dose, 1.25, 8.25 and 12.25 hours on Day 3 (after the morning dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 3	6 mg RPL554 and Tiotropium/Olodaterol on Day 3	Placebo and Tiotropium/Olodaterol on Day 3
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
Measure Participants	74	73	73
Pre-dose Day 3	0.021 (0.608)	0.046 (0.1060)	0.016 (0.0890)
1.25 hours	0.064 (0.0824)	0.050 (0.0682)	0.049 (0.1193)
8.25 hours	0.059 (0.1312)	0.048 (0.0733)	0.037 (0.1125)
12.25 hours	0.029 (0.0774)	0.032 (0.0629)	0.021 (0.1071)

Adverse Events

Time Frame	From informed consent until the end of the study, approximately 2 months for each patient
Adverse Event Reporting Description	As this is a cross over study, the number of patients at risk for each event was specified as the total number of patients who received the specified treatment in either Treatment Period 1, 2 or 3.
Arm/Group Title	1.5 mg RPL554 and Tiotropium/Olodaterol		6 mg RPL554 and Tiotropium/Olodaterol		Placebo and Tiotropium/Olodaterol
Arm/Group Description	1.5 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication		6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication		Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily Placebo: A placebo solution Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
All Cause Mortality
	1.5 mg RPL554 and Tiotropium/Olodaterol		6 mg RPL554 and Tiotropium/Olodaterol		Placebo and Tiotropium/Olodaterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/74 (0%)		0/76 (0%)
Serious Adverse Events
	1.5 mg RPL554 and Tiotropium/Olodaterol		6 mg RPL554 and Tiotropium/Olodaterol		Placebo and Tiotropium/Olodaterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		1/74 (1.4%)		0/76 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/75 (0%)	0	1/74 (1.4%)	1	0/76 (0%)	0
Other (Not Including Serious) Adverse Events
	1.5 mg RPL554 and Tiotropium/Olodaterol		6 mg RPL554 and Tiotropium/Olodaterol		Placebo and Tiotropium/Olodaterol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/75 (20%)		15/74 (20.3%)		8/76 (10.5%)
Cardiac disorders
Ventricular extrasystoles	2/75 (2.7%)		3/74 (4.1%)		0/76 (0%)
Accelerated idioventricular rhythm	1/75 (1.3%)		0/74 (0%)		0/76 (0%)
Atrioventricular block second degree	1/75 (1.3%)		0/74 (0%)		1/76 (1.3%)
Tachycardia	1/75 (1.3%)		0/74 (0%)		0/76 (0%)
Ventricular tachycardia	1/75 (1.3%)		0/74 (0%)		0/76 (0%)
Gastrointestinal disorders
Constipation	0/75 (0%)		1/74 (1.4%)		0/76 (0%)
Nausea	1/75 (1.3%)		0/74 (0%)		0/76 (0%)
General disorders
Medical device site rash	1/75 (1.3%)		0/74 (0%)		0/76 (0%)
Infections and infestations
Oral candidiasis	1/75 (1.3%)		0/74 (0%)		1/76 (1.3%)
Bronchitis	1/75 (1.3%)		0/74 (0%)		0/76 (0%)
Injury, poisoning and procedural complications
Upper limb fracture	0/75 (0%)		1/74 (1.4%)		0/76 (0%)
Investigations
Blood glucose increased	0/75 (0%)		1/74 (1.4%)		0/76 (0%)
Electrocardiogram QT prolonged	1/75 (1.3%)		1/74 (1.4%)		0/76 (0%)
Musculoskeletal and connective tissue disorders
Muscle spasms	1/75 (1.3%)		1/74 (1.4%)		1/76 (1.3%)
Nervous system disorders
Headache	5/75 (6.7%)		5/74 (6.8%)		1/76 (1.3%)
syncope	0/75 (0%)		0/74 (0%)		1/76 (1.3%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/75 (1.3%)		2/74 (2.7%)		1/76 (1.3%)
Bronchospasm	0/75 (0%)		1/74 (1.4%)		1/76 (1.3%)
Dyspnoea	0/75 (0%)		0/74 (0%)		1/76 (1.3%)
Vascular disorders
Hypertension	0/75 (0%)		2/74 (2.7%)		1/76 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The PI shall not be permitted to present at symposia, national or regional professional meetings, and to publish in journals, theses or dissertations, or otherwise of their own choosing, methods and results of the Clinical Trial subject to the publication policy described in the Protocol without prior written approval of the Sponsor.