COPD
Conditions
Keywords
COPD, Bronchodilation, FEV1
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
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).
Interventions
DRUGPlacebo
A placebo solution
A PDE3/4 inhibitor
DRUGTiotropium/olodaterol (Respimat)
An anticholinergic/β-agonist combination medication
Sponsors
Verona Pharma plc
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, 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.
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
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 10. 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
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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.) |
| 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.) |
| 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 |
| 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 |
| 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.) |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
Countries
United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 14 |
| 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 | 14 |
| 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 | 13 |
| 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 | 12 |
| 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 | 13 |
| 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 | 13 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (3 Days) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Period 1 (3 Days) | Alpha 1 antitrypsin deficiency | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Period 1 (3 Days) | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 |
| Treatment Period 1 (3 Days) | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 2 (3 Days) | Adverse Event | 0 | 0 | 1 | 0 | 1 | 0 |
| Treatment Period 3 (3 Days) | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
| Washout Period 2 (7-14 Days) | Pre-dose FEV1 not 20% baseline | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Low Dose RPL554 Then High Dose RPL554 Then Placebo | Total | Placebo Then High Dose RPL554 Then Low Dose RPL554 | Placebo Then Low Dose RPL554 Then High Dose RPL554 | High Dose RPL554 Then Placebo Then Low Dose RPL554 | High Dose RPL554 Then Low Dose RPL554 Then Placebo | Low Dose RPL554 Then Placebo Then High Dose RPL554 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.5 years | 64.0 years | 61.0 years | 67.0 years | 63.0 years | 63.0 years | 64.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 6 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 72 Participants | 11 Participants | 13 Participants | 10 Participants | 12 Participants | 13 Participants |
| Sex: Female, Male Female | 9 Participants | 49 Participants | 8 Participants | 8 Participants | 7 Participants | 8 Participants | 9 Participants |
| Sex: Female, Male Male | 5 Participants | 30 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 74 | 0 / 76 |
| other Total, other adverse events | 15 / 75 | 15 / 74 | 8 / 76 |
| serious Total, serious adverse events | 0 / 75 | 1 / 74 | 0 / 76 |
Outcome results
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
Time frame: Change from pre-dose at 5, 15 and 30 minutes and 1, 1.5, 2 & 4 hours on Day 3
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in Peak FEV1 on Day 3 | 0.565 Liters | Standard Deviation 0.2783 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in Peak FEV1 on Day 3 | 0.506 Liters | Standard Deviation 0.2506 |
| Placebo and Tiotropium/Olodaterol | Change From Baseline in Peak FEV1 on Day 3 | 0.519 Liters | Standard Deviation 0.2809 |
p-value: 0.16895% CI: [0.991, 1.052]ANCOVA
p-value: 0.73195% CI: [0.966, 1.025]ANCOVA
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.)
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)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in AUC0-12h FEV1 on Day 1 | 0.333 Liters | Standard Deviation 0.1815 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in AUC0-12h FEV1 on Day 1 | 0.308 Liters | Standard Deviation 0.1854 |
| Placebo and Tiotropium/Olodaterol | Change From Baseline in AUC0-12h FEV1 on Day 1 | 0.303 Liters | Standard Deviation 0.192 |
p-value: 0.09695% CI: [0.997, 1.043]ANCOVA
p-value: 0.86295% CI: [0.979, 1.025]ANCOVA
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.)
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)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in AUC0-12h FEV1 on Day 3 | 0.390 Liters | Standard Deviation 0.2426 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in AUC0-12h FEV1 on Day 3 | 0.347 Liters | Standard Deviation 0.2219 |
| Placebo and Tiotropium/Olodaterol | Change From Baseline in AUC0-12h FEV1 on Day 3 | 0.337 Liters | Standard Deviation 0.2447 |
p-value: 0.06795% CI: [0.998, 1.057]ANCOVA
p-value: 0.39595% CI: [0.984, 1.042]ANCOVA
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.)
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)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in AUC0-4h FEV1 on Day 3 | 0.429 Liters | Standard Deviation 0.2518 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in AUC0-4h FEV1 on Day 3 | 0.390 Liters | Standard Deviation 0.2246 |
| Placebo and Tiotropium/Olodaterol | Change From Baseline in AUC0-4h FEV1 on Day 3 | 0.377 Liters | Standard Deviation 0.2485 |
p-value: 0.30395% CI: [0.987, 1.043]ANCOVA
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
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
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in Peak FEV1 After Evening Dose on Day 3 | 0.453 Liters | Standard Deviation 0.2625 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in Peak FEV1 After Evening Dose on Day 3 | 0.405 Liters | Standard Deviation 0.2581 |
| Placebo and Tiotropium/Olodaterol | Change From Baseline in Peak FEV1 After Evening Dose on Day 3 | 0.324 Liters | Standard Deviation 0.2211 |
p-value: 0.00195% CI: [1.043, 1.123]ANCOVA
p-value: 0.00295% CI: [1.023, 1.101]ANCOVA
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
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
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in Peak FEV1 on Day 1 | 0.490 Liters | Standard Deviation 0.2219 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline in Peak FEV1 on Day 1 | 0.467 Liters | Standard Deviation 0.2393 |
| Placebo and Tiotropium/Olodaterol | Change From Baseline in Peak FEV1 on Day 1 | 0.445 Liters | Standard Deviation 0.2306 |
p-value: 0.40495% CI: [0.984, 1.039]ANCOVA
Secondary
Change From Baseline to Trough FEV1 on Day 4
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
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline to Trough FEV1 on Day 4 | 0.186 Liters | Standard Deviation 0.2496 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Change From Baseline to Trough FEV1 on Day 4 | 0.178 Liters | Standard Deviation 0.2123 |
| Placebo and Tiotropium/Olodaterol | Change From Baseline to Trough FEV1 on Day 4 | 0.150 Liters | Standard Deviation 0.2218 |
p-value: 0.11595% CI: [0.994, 1.055]ANCOVA
p-value: 0.11195% CI: [0.994, 1.055]ANCOVA
Secondary
Determination of Onset of Action on Day 1
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)
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Determination of Onset of Action on Day 1 | 10.0 minutes |
| 6 mg RPL554 and Tiotropium/Olodaterol | Determination of Onset of Action on Day 1 | 6.0 minutes |
| Placebo and Tiotropium/Olodaterol | Determination of Onset of Action on Day 1 | 11.0 minutes |
p-value: 0.945Wilcoxon (Mann-Whitney)
p-value: 0.501Wilcoxon (Mann-Whitney)
Secondary
Functional Residual Capacity on Day 1
Change in functional residual capacity during treatment
Time frame: Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 1 | -0.344 Liters | Standard Deviation 0.5097 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 1 | -0.294 Liters | Standard Deviation 0.4524 |
| Placebo and Tiotropium/Olodaterol | Functional Residual Capacity on Day 1 | -0.277 Liters | Standard Deviation 0.4279 |
Secondary
Functional Residual Capacity on Day 3
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)
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | 8.25 hours | -0.420 Liters | Standard Deviation 0.5003 |
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | Pre-dose on Day 3 | -0.278 Liters | Standard Deviation 0.434 |
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | 1.25 hours | -0.490 Liters | Standard Deviation 0.4654 |
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | 12.25 hours | -0.255 Liters | Standard Deviation 0.4003 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | 12.25 hours | -0.155 Liters | Standard Deviation 0.7788 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | 1.25 hours | -0.408 Liters | Standard Deviation 0.6102 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | Pre-dose on Day 3 | -0.206 Liters | Standard Deviation 0.5925 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | 8.25 hours | -0.405 Liters | Standard Deviation 0.6111 |
| Placebo and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | Pre-dose on Day 3 | -0.163 Liters | Standard Deviation 0.5742 |
| Placebo and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | 8.25 hours | -0.355 Liters | Standard Deviation 0.6004 |
| Placebo and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | 1.25 hours | -0.382 Liters | Standard Deviation 0.561 |
| Placebo and Tiotropium/Olodaterol | Functional Residual Capacity on Day 3 | 12.25 hours | -0.075 Liters | Standard Deviation 0.5881 |
Secondary
Residual Volume on Day 1
Change in residual volume during treatment
Time frame: Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 1 | -0.469 Liters | Standard Deviation 0.5521 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 1 | -0.408 Liters | Standard Deviation 0.4803 |
| Placebo and Tiotropium/Olodaterol | Residual Volume on Day 1 | -0.377 Liters | Standard Deviation 0.481 |
Secondary
Residual Volume on Day 3
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)
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 3 | Pre-dose Day 3 | -0.323 Liters | Standard Deviation 0.4548 |
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 3 | 1.25 hours | -0.648 Liters | Standard Deviation 0.5173 |
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 3 | 8.25 hours | -0.526 Liters | Standard Deviation 0.5594 |
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 3 | 12.25 hours | -0.353 Liters | Standard Deviation 0.4561 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 3 | 12.25 hours | -0.236 Liters | Standard Deviation 0.7566 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 3 | Pre-dose Day 3 | -0.313 Liters | Standard Deviation 0.8946 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 3 | 8.25 hours | -0.481 Liters | Standard Deviation 0.4994 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Residual Volume on Day 3 | 1.25 hours | -0.510 Liters | Standard Deviation 0.6304 |
| Placebo and Tiotropium/Olodaterol | Residual Volume on Day 3 | 12.25 hours | -0.094 Liters | Standard Deviation 0.7118 |
| Placebo and Tiotropium/Olodaterol | Residual Volume on Day 3 | 1.25 hours | -0.510 Liters | Standard Deviation 0.6257 |
| Placebo and Tiotropium/Olodaterol | Residual Volume on Day 3 | 8.25 hours | -0.471 Liters | Standard Deviation 0.6186 |
| Placebo and Tiotropium/Olodaterol | Residual Volume on Day 3 | Pre-dose Day 3 | -0.184 Liters | Standard Deviation 0.6274 |
Secondary
Specific Airway Conductance on Day 1
Change in specific airway conductance during treatment
Time frame: Change from pre-dose to 1.25 hours on Day 1 (after the morning dose)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 1 | 0.064 1/kPa*sec | Standard Deviation 0.1148 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 1 | 0.042 1/kPa*sec | Standard Deviation 0.0483 |
| Placebo and Tiotropium/Olodaterol | Specific Airway Conductance on Day 1 | 0.043 1/kPa*sec | Standard Deviation 0.1072 |
Secondary
Specific Airway Conductance on Day 3
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)
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | 12.25 hours | 0.029 1/kPa*sec | Standard Deviation 0.0774 |
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | Pre-dose Day 3 | 0.021 1/kPa*sec | Standard Deviation 0.608 |
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | 8.25 hours | 0.059 1/kPa*sec | Standard Deviation 0.1312 |
| 1.5 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | 1.25 hours | 0.064 1/kPa*sec | Standard Deviation 0.0824 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | 8.25 hours | 0.048 1/kPa*sec | Standard Deviation 0.0733 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | 12.25 hours | 0.032 1/kPa*sec | Standard Deviation 0.0629 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | 1.25 hours | 0.050 1/kPa*sec | Standard Deviation 0.0682 |
| 6 mg RPL554 and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | Pre-dose Day 3 | 0.046 1/kPa*sec | Standard Deviation 0.106 |
| Placebo and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | 12.25 hours | 0.021 1/kPa*sec | Standard Deviation 0.1071 |
| Placebo and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | 1.25 hours | 0.049 1/kPa*sec | Standard Deviation 0.1193 |
| Placebo and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | 8.25 hours | 0.037 1/kPa*sec | Standard Deviation 0.1125 |
| Placebo and Tiotropium/Olodaterol | Specific Airway Conductance on Day 3 | Pre-dose Day 3 | 0.016 1/kPa*sec | Standard Deviation 0.089 |