Bronchodilator Effect of RPL554 Administered in Addition... | NCT03673670

Status Module

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
1.5 mg RPL554 and tiotropium/olodaterol	Experimental	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 Drug: Tiotropium/olodaterol (Respimat)
6 mg RPL554 and tiotropium/olodaterol	Experimental	6 mg RPL554 suspension administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily	Drug: RPL554 Suspension Drug: Tiotropium/olodaterol (Respimat)
Placebo and tiotropium/olodaterol	Experimental	Placebo administered using a nebulizer twice daily plus 5 mcg/5 mcg tiotropium/olodaterol (Respimat) administered once daily	Drug: Placebo Drug: Tiotropium/olodaterol (Respimat)

Name	Type	Description	Arm Group Labels	Other Names
RPL554 Suspension	Drug	A PDE3/4 inhibitor	1.5 mg RPL554 and tiotropium/olodaterol 6 mg RPL554 and tiotropium/olodaterol

Measure	Description	Time Frame
Change From Baseline in Peak FEV1 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	Change from pre-dose at 5, 15 and 30 minutes and 1, 1.5, 2 & 4 hours on Day 3

Measure	Description	Time Frame
Change From Baseline to Trough FEV1 on Day 4	Change from baseline to morning trough FEV1 on Day 4	Change from pre-dose on Day 1 to pre-dose on Day 4
Change From Baseline in AUC0-4h FEV1 on Day 3

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Written informed consent
Male or female aged 40 and 80 years
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
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
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
Capable of complying with all study restrictions and procedures including ability to use the study nebulizer and Respimat® correctly.
Body mass index (BMI) between 18 and 36 kg/m2 and minimum weight of 45 kg.
COPD diagnosis for at least 1 year and clinically stable COPD for 4 week
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
A chest X-ray showing no abnormalities, which are both clinically significant and unrelated to COPD.

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

13. 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:

A history of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation.
COPD exacerbation requiring oral or parenteral steroids, or lower respiratory tract infection requiring antibiotics, in the last 3 months
A history of one or more hospitalizations for COPD in the last 12 months
Intolerance or hypersensitivity to tiotropium, olodaterol, atropine, ipratropium, or RPL554.
Evidence of cor pulmonale or clinically significant pulmonary hypertension.
Other respiratory disorders
Previous lung resection or lung reduction surgery.
Use of oral COPD medications, except mucolytics, in the last 3 months
Pulmonary rehabilitation, unless such treatment has been stable in the last 4 weeks
History of, or reason to believe a patient has, drug or alcohol abuse within the past 5 years.
Inability to perform acceptable spirometry or whole body plethysmography
Received an experimental drug within 30 days or five half lives, whichever is longer.
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).
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
Use of non-selective oral β-blockers.
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.
A disclosed history or one known to the Investigator, of significant non compliance in previous investigational studies or with prescribed medications.
Required use of oxygen therapy, even on an occasional basis.
Symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma.
History of malignancy of any organ system within 5 years, with the exception of localized skin cancers (basal or squamous cell).
Clinically significant abnormal values for safety laboratory tests (hematology, biochemistry, virology or urinalysis) as determined by the Investigator
Any other reason that the Investigator considers makes the patient unsuitable to participate.

Name	Affiliation	Role
Dave Singh	Medicines Evaluation Unit	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Clinical Site Partners, LLC		Winter Park	Florida	32789	United States
Allied Biomedical Research Holdings, d/b/a Vitalink Research

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Low Dose RPL554 Then High Dose RPL554 Then Placebo	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
FG001

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	May 28, 2018	Jun 5, 2019

Arm/Group Information

ID	Title	Description
BG000	Low Dose RPL554 Then High Dose RPL554 Then Placebo	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
BG001	Low Dose RPL554 Then Placebo Then High Dose RPL554	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
BG002	High Dose RPL554 Then Low Dose RPL554 Then Placebo	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
BG003	High Dose RPL554 Then Placebo Then Low Dose RPL554	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
BG004	Placebo Then Low Dose RPL554 Then High Dose RPL554	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
BG005	Placebo Then High Dose RPL554 Then Low Dose RPL554	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
BG006	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Peak FEV1 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

Full analysis set

Posted

Mean

Standard Deviation

Liters

Change from pre-dose at 5, 15 and 30 minutes and 1, 1.5, 2 & 4 hours on Day 3

ID	Title	Description
OG000	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG001	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG002	Placebo and Tiotropium/Olodaterol	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

Units	Counts
Participants	OG00074 OG00173 OG00273

Title

Denominators

Categories

Title	Measurements
	OG0000.565± 0.2783 OG0010.506± 0.2506 OG0020.519± 0.2809

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		ANCOVA		0.168		GeoMean Ratio	1.021			2-Sided	95	0.991	1.052					Other	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.

Secondary

Change From Baseline to Trough FEV1 on Day 4

Change from baseline to morning trough FEV1 on Day 4

Full analysis set

Posted

Mean

Standard Deviation

Liters

Change from pre-dose on Day 1 to pre-dose on Day 4

ID	Title	Description
OG000	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG001	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG002	Placebo and Tiotropium/Olodaterol	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

Secondary

Change From Baseline in AUC0-4h FEV1 on Day 3

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.)

Full analysis set

Posted

Mean

Standard Deviation

Liters

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)

ID	Title	Description
OG000	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG001	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG002	Placebo and Tiotropium/Olodaterol	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

Secondary

Change From Baseline in AUC0-12h FEV1 on Day 3

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.)

Full analysis set

Posted

Mean

Standard Deviation

Liters

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)

ID	Title	Description
OG000	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG001	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG002	Placebo and Tiotropium/Olodaterol	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

Secondary

Change From Baseline in Peak FEV1 on Day 1

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

Full analysis set

Posted

Mean

Standard Deviation

Liters

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

ID	Title	Description
OG000	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG001	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG002	Placebo and Tiotropium/Olodaterol	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

Secondary

Change From Baseline in Peak FEV1 After Evening Dose on Day 3

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

Full analysis set

Posted

Mean

Standard Deviation

Liters

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

ID	Title	Description
OG000	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG001	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG002	Placebo and Tiotropium/Olodaterol	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

Secondary

Change From Baseline in AUC0-12h FEV1 on Day 1

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.)

Full analysis set

Posted

Mean

Standard Deviation

Liters

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)

ID	Title	Description
OG000	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG001	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG002	Placebo and Tiotropium/Olodaterol

Secondary

Determination of Onset of Action on Day 1

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

Full analysis set

Posted

Median

Full Range

minutes

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)

ID	Title	Description
OG000	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG001	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication
OG002	Placebo and Tiotropium/Olodaterol	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

Secondary

Residual Volume on Day 1

Change in residual volume during treatment

Full analysis set

Posted

Mean

Standard Deviation

Liters

Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)

ID	Title	Description
OG000	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1	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
OG001	6 mg RPL554 and Tiotropium/Olodaterol on Day 1	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
OG002	Placebo and Tiotropium/Olodaterol on Day 1	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

Secondary

Residual Volume on Day 3

Change in residual volume during treatment

Full analysis set

Posted

Mean

Standard Deviation

Liters

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)

ID	Title	Description
OG000	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 3	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
OG001	6 mg RPL554 and Tiotropium/Olodaterol on Day 3	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
OG002	Placebo and Tiotropium/Olodaterol on Day 3	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

Secondary

Functional Residual Capacity on Day 1

Change in functional residual capacity during treatment

Full analysis set

Posted

Mean

Standard Deviation

Liters

Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)

ID	Title	Description
OG000	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1	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
OG001	6 mg RPL554 and Tiotropium/Olodaterol on Day 1	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
OG002	Placebo and Tiotropium/Olodaterol on Day 1	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

Secondary

Functional Residual Capacity on Day 3

Change in functional residual capacity during treatment

Full analysis set

Posted

Mean

Standard Deviation

Liters

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)

ID	Title	Description
OG000	1.5 mg RPL554 and Tiotropium/Oldaterol on Day 3	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
OG001	6 mg RPL554 and Tiotropium/Oldaterol on Day 3	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
OG002	Placebo and Tiotropium/Oldaterol on Day 3	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

Secondary

Specific Airway Conductance on Day 1

Change in specific airway conductance during treatment

Full analysis set

Posted

Mean

Standard Deviation

1/kPa*sec

Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)

ID	Title	Description
OG000	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 1	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
OG001	6 mg RPL554 and Tiotropium/Olodaterol on Day 1	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
OG002	Placebo and Tiotropium/Olodaterol on Day 1	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

Secondary

Specific Airway Conductance on Day 3

Change in specific airway conductance during treatment

Full analysis set

Posted

Mean

Standard Deviation

1/kPa*sec

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)

ID	Title	Description
OG000	1.5 mg RPL554 and Tiotropium/Olodaterol on Day 3	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
OG001	6 mg RPL554 and Tiotropium/Olodaterol on Day 3	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
OG002	Placebo and Tiotropium/Olodaterol on Day 3	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

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	75	0	75	15	75
EG001	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 RPL554 Suspension: A PDE3/4 inhibitor Tiotropium/olodaterol (Respimat): An anticholinergic/β-agonist combination medication	74	1	74	15	74
EG002	Placebo and Tiotropium/Olodaterol	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	76	0	76	8	76

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Headache	Nervous system disorders	MedDRA 21.0	Non-systematic Assessment	EG0005 affected75 at risk EG0015 affected74 at risk EG0021 affected76 at risk
Ventricular extrasystoles	Cardiac disorders	MedDRA 21.0	Non-systematic Assessment	EG0002 affected75 at risk EG0013 affected74 at risk EG0020 affected76 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0012 affected74 at risk EG0021 affected76 at risk
Hypertension	Vascular disorders	MedDRA 21.0	Non-systematic Assessment	EG0000 affected75 at risk EG0012 affected74 at risk EG0021 affected76 at risk
syncope	Nervous system disorders	MedDRA 21.0	Non-systematic Assessment	EG0000 affected75 at risk EG0010 affected74 at risk EG0021 affected76 at risk
Accelerated idioventricular rhythm	Cardiac disorders	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0010 affected74 at risk EG0020 affected76 at risk
Atrioventricular block second degree	Cardiac disorders	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0010 affected74 at risk EG0021 affected76 at risk
Tachycardia	Cardiac disorders	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0010 affected74 at risk EG0020 affected76 at risk
Ventricular tachycardia	Cardiac disorders	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0010 affected74 at risk EG0020 affected76 at risk
Bronchospasm	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Non-systematic Assessment	EG0000 affected75 at risk EG0011 affected74 at risk EG0021 affected76 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Non-systematic Assessment	EG0000 affected75 at risk EG0010 affected74 at risk EG0021 affected76 at risk
Oral candidiasis	Infections and infestations	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0010 affected74 at risk EG0021 affected76 at risk
Bronchitis	Infections and infestations	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0010 affected74 at risk EG0020 affected76 at risk
Constipation	Gastrointestinal disorders	MedDRA 21.0	Non-systematic Assessment	EG0000 affected75 at risk EG0011 affected74 at risk EG0020 affected76 at risk
Nausea	Gastrointestinal disorders	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0010 affected74 at risk EG0020 affected76 at risk
Blood glucose increased	Investigations	MedDRA 21.0	Non-systematic Assessment	EG0000 affected75 at risk EG0011 affected74 at risk EG0020 affected76 at risk
Electrocardiogram QT prolonged	Investigations	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0011 affected74 at risk EG0020 affected76 at risk
Medical device site rash	General disorders	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0010 affected74 at risk EG0020 affected76 at risk
Upper limb fracture	Injury, poisoning and procedural complications	MedDRA 21.0	Non-systematic Assessment	EG0000 affected75 at risk EG0011 affected74 at risk EG0020 affected76 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Non-systematic Assessment	EG0001 affected75 at risk EG0011 affected74 at risk EG0021 affected76 at risk

ID	Term
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012140	Respiratory Tract Diseases
D002908	Chronic Disease
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D012602	Scopolamine Derivatives
D014326	Tropanes
D053961	Azabicyclo Compounds
D001372	Aza Compounds
D009930	Organic Chemicals
D000470	Alkaloids
D006571	Heterocyclic Compounds
D019086	Bridged Bicyclo Compounds, Heterocyclic
D006572	Heterocyclic Compounds, Bridged-Ring