Trial Outcomes & Findings for Bronchodilator Effect of RPL554 Administered in Addition to Tiotropium/Olodaterol in Patients With COPD (NCT NCT03673670)

Last Updated: 2019-10-10

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

79 participants

Primary outcome timeframe

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

Results posted on

2019-10-10

Participant Flow

Participant milestones

Participant milestones
Measure	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	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	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	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	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	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
Treatment Period 1 (3 Days) STARTED	14	14	13	12	13	13
Treatment Period 1 (3 Days) COMPLETED	13	14	12	12	13	11
Treatment Period 1 (3 Days) NOT COMPLETED	1	0	1	0	0	2
Washout Period 1 (7-14 Days) STARTED	13	14	12	12	13	11
Washout Period 1 (7-14 Days) COMPLETED	13	14	12	12	13	11
Washout Period 1 (7-14 Days) NOT COMPLETED	0	0	0	0	0	0
Treatment Period 2 (3 Days) STARTED	13	14	12	12	13	11
Treatment Period 2 (3 Days) COMPLETED	13	14	11	12	12	11
Treatment Period 2 (3 Days) NOT COMPLETED	0	0	1	0	1	0
Washout Period 2 (7-14 Days) STARTED	13	14	11	12	12	11
Washout Period 2 (7-14 Days) COMPLETED	13	14	11	12	11	11
Washout Period 2 (7-14 Days) NOT COMPLETED	0	0	0	0	1	0
Treatment Period 3 (3 Days) STARTED	13	14	11	12	11	11
Treatment Period 3 (3 Days) COMPLETED	13	14	11	12	10	11
Treatment Period 3 (3 Days) NOT COMPLETED	0	0	0	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	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	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	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	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
Treatment Period 1 (3 Days) Withdrawal by Subject	1	0	0	0
Treatment Period 1 (3 Days) Physician Decision	0	1	0	0
Treatment Period 1 (3 Days) Adverse Event	0	0	0	1
Treatment Period 1 (3 Days) Alpha 1 antitrypsin deficiency	0	0	0	1
Treatment Period 2 (3 Days) Adverse Event	0	1	1	0
Washout Period 2 (7-14 Days) Pre-dose FEV1 not 20% baseline	0	0	1	0
Treatment Period 3 (3 Days) Adverse Event	0	0	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Low Dose RPL554 Then High Dose RPL554 Then Placebo n=14 Participants 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	Low Dose RPL554 Then Placebo Then High Dose RPL554 n=14 Participants 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	High Dose RPL554 Then Low Dose RPL554 Then Placebo n=13 Participants 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	High Dose RPL554 Then Placebo Then Low Dose RPL554 n=12 Participants 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 Then Low Dose RPL554 Then High Dose RPL554 n=13 Participants 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 Then High Dose RPL554 Then Low Dose RPL554 n=13 Participants 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 n=79 Participants Total of all reporting groups
Age, Continuous	65.5 years n=5 Participants	64.5 years n=7 Participants	63.0 years n=5 Participants	63.0 years n=4 Participants	67.0 years n=21 Participants	61.0 years n=10 Participants	64.0 years n=115 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	9 Participants n=7 Participants	8 Participants n=5 Participants	7 Participants n=4 Participants	8 Participants n=21 Participants	8 Participants n=10 Participants	49 Participants n=115 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	5 Participants n=7 Participants	5 Participants n=5 Participants	5 Participants n=4 Participants	5 Participants n=21 Participants	5 Participants n=10 Participants	30 Participants n=115 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	1 Participants n=115 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants	6 Participants n=115 Participants
Race (NIH/OMB) White	13 Participants n=5 Participants	13 Participants n=7 Participants	12 Participants n=5 Participants	10 Participants n=4 Participants	13 Participants n=21 Participants	11 Participants n=10 Participants	72 Participants n=115 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants

PRIMARY outcome

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

Population: Full analysis set

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

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Change From Baseline in Peak FEV1 on Day 3	0.565 Liters Standard Deviation 0.2783	0.506 Liters Standard Deviation 0.2506	0.519 Liters Standard Deviation 0.2809

SECONDARY outcome

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

Population: Full analysis set

Change from baseline to morning trough FEV1 on Day 4

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Change From Baseline to Trough FEV1 on Day 4	0.186 Liters Standard Deviation 0.2496	0.178 Liters Standard Deviation 0.2123	0.150 Liters Standard Deviation 0.2218

SECONDARY outcome

Timeframe: 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)

Population: Full analysis set

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.)

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Change From Baseline in AUC0-4h FEV1 on Day 3	0.429 Liters Standard Deviation 0.2518	0.390 Liters Standard Deviation 0.2246	0.377 Liters Standard Deviation 0.2485

SECONDARY outcome

Timeframe: 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)

Population: Full analysis set

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.)

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Change From Baseline in AUC0-12h FEV1 on Day 3	0.390 Liters Standard Deviation 0.2426	0.347 Liters Standard Deviation 0.2219	0.337 Liters Standard Deviation 0.2447

SECONDARY outcome

Timeframe: 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

Population: Full analysis set

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

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Change From Baseline in Peak FEV1 on Day 1	0.490 Liters Standard Deviation 0.2219	0.467 Liters Standard Deviation 0.2393	0.445 Liters Standard Deviation 0.2306

SECONDARY outcome

Timeframe: 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

Population: Full analysis set

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

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Change From Baseline in Peak FEV1 After Evening Dose on Day 3	0.453 Liters Standard Deviation 0.2625	0.405 Liters Standard Deviation 0.2581	0.324 Liters Standard Deviation 0.2211

SECONDARY outcome

Timeframe: 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)

Population: Full analysis set

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.)

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Change From Baseline in AUC0-12h FEV1 on Day 1	0.333 Liters Standard Deviation 0.1815	0.308 Liters Standard Deviation 0.1854	0.303 Liters Standard Deviation 0.1920

SECONDARY outcome

Timeframe: 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)

Population: Full analysis set

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

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Determination of Onset of Action on Day 1	10.0 minutes Interval 1.0 to 86.0	6.0 minutes Interval 4.0 to 117.0	11.0 minutes Interval 7.0 to 120.0

SECONDARY outcome

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

Population: Full analysis set

Change in residual volume during treatment

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=74 Participants 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
Residual Volume on Day 1	-0.469 Liters Standard Deviation 0.5521	-0.408 Liters Standard Deviation 0.4803	-0.377 Liters Standard Deviation 0.4810

SECONDARY outcome

Timeframe: 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)

Population: Full analysis set

Change in residual volume during treatment

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Residual Volume on Day 3 Pre-dose Day 3	-0.323 Liters Standard Deviation 0.4548	-0.313 Liters Standard Deviation 0.8946	-0.184 Liters Standard Deviation 0.6274
Residual Volume on Day 3 1.25 hours	-0.648 Liters Standard Deviation 0.5173	-0.510 Liters Standard Deviation 0.6304	-0.510 Liters Standard Deviation 0.6257
Residual Volume on Day 3 8.25 hours	-0.526 Liters Standard Deviation 0.5594	-0.481 Liters Standard Deviation 0.4994	-0.471 Liters Standard Deviation 0.6186
Residual Volume on Day 3 12.25 hours	-0.353 Liters Standard Deviation 0.4561	-0.236 Liters Standard Deviation 0.7566	-0.094 Liters Standard Deviation 0.7118

SECONDARY outcome

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

Population: Full analysis set

Change in functional residual capacity during treatment

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Functional Residual Capacity on Day 1	-0.344 Liters Standard Deviation 0.5097	-0.294 Liters Standard Deviation 0.4524	-0.277 Liters Standard Deviation 0.4279

SECONDARY outcome

Timeframe: 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)

Population: Full analysis set

Change in functional residual capacity during treatment

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Functional Residual Capacity on Day 3 1.25 hours	-0.490 Liters Standard Deviation 0.4654	-0.408 Liters Standard Deviation 0.6102	-0.382 Liters Standard Deviation 0.5610
Functional Residual Capacity on Day 3 8.25 hours	-0.420 Liters Standard Deviation 0.5003	-0.405 Liters Standard Deviation 0.6111	-0.355 Liters Standard Deviation 0.6004
Functional Residual Capacity on Day 3 12.25 hours	-0.255 Liters Standard Deviation 0.4003	-0.155 Liters Standard Deviation 0.7788	-0.075 Liters Standard Deviation 0.5881
Functional Residual Capacity on Day 3 Pre-dose on Day 3	-0.278 Liters Standard Deviation 0.4340	-0.206 Liters Standard Deviation 0.5925	-0.163 Liters Standard Deviation 0.5742

SECONDARY outcome

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

Population: Full analysis set

Change in specific airway conductance during treatment

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Specific Airway Conductance on Day 1	0.064 1/kPa*sec Standard Deviation 0.1148	0.042 1/kPa*sec Standard Deviation 0.0483	0.043 1/kPa*sec Standard Deviation 0.1072

SECONDARY outcome

Timeframe: 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)

Population: Full analysis set

Change in specific airway conductance during treatment

Outcome measures

Outcome measures
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=74 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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 and Tiotropium/Olodaterol n=73 Participants 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
Specific Airway Conductance on Day 3 Pre-dose Day 3	0.021 1/kPa*sec Standard Deviation 0.608	0.046 1/kPa*sec Standard Deviation 0.1060	0.016 1/kPa*sec Standard Deviation 0.0890
Specific Airway Conductance on Day 3 1.25 hours	0.064 1/kPa*sec Standard Deviation 0.0824	0.050 1/kPa*sec Standard Deviation 0.0682	0.049 1/kPa*sec Standard Deviation 0.1193
Specific Airway Conductance on Day 3 8.25 hours	0.059 1/kPa*sec Standard Deviation 0.1312	0.048 1/kPa*sec Standard Deviation 0.0733	0.037 1/kPa*sec Standard Deviation 0.1125
Specific Airway Conductance on Day 3 12.25 hours	0.029 1/kPa*sec Standard Deviation 0.0774	0.032 1/kPa*sec Standard Deviation 0.0629	0.021 1/kPa*sec Standard Deviation 0.1071

Adverse Events

1.5 mg RPL554 and Tiotropium/Olodaterol

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

6 mg RPL554 and Tiotropium/Olodaterol

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Placebo and Tiotropium/Olodaterol

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=75 participants at risk 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 and Tiotropium/Olodaterol n=74 participants at risk 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 and Tiotropium/Olodaterol n=76 participants at risk 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
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.4% 1/74 • Number of events 1 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.

Other adverse events

Additional Information

Brian Maurer

Verona Pharma plc

Phone: +19147675037

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER

Measure	1.5 mg RPL554 and Tiotropium/Olodaterol n=75 participants at risk 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 and Tiotropium/Olodaterol n=74 participants at risk 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 and Tiotropium/Olodaterol n=76 participants at risk 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
Nervous system disorders Headache	6.7% 5/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	6.8% 5/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.3% 1/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Cardiac disorders Ventricular extrasystoles	2.7% 2/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	4.1% 3/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	2.7% 2/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.3% 1/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Vascular disorders Hypertension	0.00% 0/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	2.7% 2/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.3% 1/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Nervous system disorders syncope	0.00% 0/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.3% 1/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Cardiac disorders Accelerated idioventricular rhythm	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Cardiac disorders Atrioventricular block second degree	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.3% 1/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Cardiac disorders Tachycardia	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Cardiac disorders Ventricular tachycardia	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.00% 0/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.4% 1/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.3% 1/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.3% 1/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Infections and infestations Oral candidiasis	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.3% 1/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Infections and infestations Bronchitis	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Gastrointestinal disorders Constipation	0.00% 0/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.4% 1/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Gastrointestinal disorders Nausea	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Investigations Blood glucose increased	0.00% 0/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.4% 1/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Investigations Electrocardiogram QT prolonged	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.4% 1/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
General disorders Medical device site rash	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.4% 1/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	0.00% 0/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.
Musculoskeletal and connective tissue disorders Muscle spasms	1.3% 1/75 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.4% 1/74 • From informed consent until the end of the study, approximately 2 months for each patient 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.	1.3% 1/76 • From informed consent until the end of the study, approximately 2 months for each patient 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.