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| Name | Class |
|---|---|
| IQVIA Pty Ltd | INDUSTRY |
| LGC Limited | INDUSTRY |
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The purpose of this study is to investigate the dose response of RPL554 in patients with moderate to severe CHRONIC OBSTRUCTIVE PULMONARY DISEASE that are still symptomatic despite treatment with a stable background of tiotropium over 4 weeks of treatment. This study is intended to support optimal dose selection for a Phase III program evaluating RPL554 as an add-on treatment to standard of care therapy.
This is a Phase IIb, randomized, double-blind, placebo controlled, multiple dose, parallel group study to investigate the effects of 4 weeks of treatment with nebulized RPL554 (at different dose levels) compared to placebo in patients with moderate to severe CHRONIC OBSTRUCTIVE PULMONARY DISEASE on a stable background therapy of open-label tiotropium. The study comprises seven visits: Pre-screening (Visit 0), Screening (Visit 1) and then a Treatment Period consisting of Randomization (Visit 2), and weekly visits for 4 weeks (Visit 3 to Visit 6).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| RPL554 0.375 mg twice daily | Experimental | RPL554 0.375 mg twice daily |
|
| RPL554 0.75 mg twice daily | Experimental | RPL554 0.75 mg twice daily |
|
| RPL554 1.5 mg twice daily | Experimental | RPL554 1.5 mg twice daily |
|
| RPL554 3.0 mg twice daily | Experimental | RPL554 3.0 mg twice daily |
|
| Placebo twice daily | Placebo Comparator | Placebo twice daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ensifentrine (formerly RPL554) 0.375 mg twice daily plus placebo, in addition to tiotropium | Drug | Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● RPL554 0.375 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication. |
| Measure | Description | Time Frame |
|---|---|---|
| Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. | Baseline and Week 4 |
| Measure | Description | Time Frame |
|---|---|---|
| LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-3h FEV1 was defined as area under the curve over 3 hours of the FEV1, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. |
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Inclusion Criteria:
Sign an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study.
Male or female aged between 40 and 80 years inclusive, at the time of informed consent.
Must agree to meet the following from the first dose up to 1 month after the last dose of study medication:
If male:
If female:
Have a 12-lead ECG recording at Screening showing the following (and no changes in the pre-dose value at the first treatment deemed clinically significant by the Investigator):
Capable of complying with study restrictions and procedures, including ability to use the nebulizer correctly.
Body mass index (BMI) between 18 and 35 kg/m2 (inclusive) with a minimum weight of 45 kg.
COPD diagnosis: Patients with a diagnosis of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines (Celli and MacNee, 2004) with symptoms compatible with COPD for at least 1 year prior to Screening.
Ability to perform acceptable and reproducible spirometry.
Post-bronchodilator (four puffs of albuterol) spirometry at Screening demonstrating the following:
Clinically stable COPD in the 4 weeks prior to Screening (Visit 1) and during the period between Visits 1 and 2.
A score of ≥2 on the modified Medical Research Council (mMRC) dyspnea scale at Screening.
A chest X-ray (posterior-anterior) at Screening, or in the 12 months prior to Screening showing no clinically significant abnormalities unrelated to COPD.
Meet the concomitant medication restrictions and be expected to do so for the rest of the study.
Current and former smokers with smoking history of ≥10 pack years.
Capable of withdrawing from long acting bronchodilators (other than tiotropium) for the duration of the study, and short acting bronchodilators for 6 hours prior to dosing.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gary Ferguson | Pulmonary Research Institute of Southeast Michigan | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pinnacle Research Group, LLC | Anniston | Alabama | 36207 | United States | ||
| California Research Medical Group, Inc |
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Following Screening on Visit 1, eligible patients entered a 14-day run-in period, where they received tiotropium once daily. At Visit 2, patients were re-assessed for eligibility according to randomization criteria. Patients were randomized equally across 5 double-blind treatment groups (4 doses of RPL554 or placebo).
The study was conducted at 49 study centers in the United States of America between 01 May 2019 and 15 November 2019. Overall, 416 adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) on a stable background therapy of open-label tiotropium were randomized and 413 patients received double-blind study treatment.
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| ID | Title | Description |
|---|---|---|
| FG000 | RPL554 0.375 mg | Patients were administered 0.375 milligram (mg) RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| FG001 | RPL554 0.75 mg |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Dec 5, 2019 | Aug 21, 2020 |
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|
| Ensifentrine (formerly RPL554) 0.75 mg twice daily plus placebo, in addition to tiotropium | Drug | Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● RPL554 0.75 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication. |
|
| Ensifentrine (formerly RPL554) 1.5 mg twice daily plus placebo, in addition to tiotropium | Drug | Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● RPL554 1.5 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication. |
|
| Ensifentrine (formerly RPL554) 3.0 mg twice daily plus placebo, in addition to tiotropium | Drug | Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● RPL554 3.0 mg twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication. |
|
| Ensifentrine (formerly RPL554) placebo twice daily, in addition to tiotropium | Drug | Patients will be randomized to receive one of the following treatment arms plus tiotropiuim: ● Placebo twice daily The approximate planned duration for each completed patient will be 14 days of run-in and 28 days of treatment with study medication. |
|
| Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4 |
| LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-12h FEV1 was defined as area under the curve over 12 hours of the FEV1, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4 |
| LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2 and 3 |
| LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and morning trough FEV1 was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4 |
| LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS:COPD scale has a scoring range of 0 to 40. Higher scores indicates severe respiratory symptoms. Baseline was the mean over the 7 days prior to first intake of study treatment. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS:COPD was measured by daily electronic diary (e-diary). | Baseline and Weeks 1, 2, 3 and 4 |
| LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Patients completed the SGRQ-C consisting of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome. The SGRQ-C was measured at Week 2 and 4 visits. | Baseline, Weeks 2 and 4 |
| LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | The TDI is a questionnaire that focussed on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome. | Weeks 2 and 4 |
| LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | The PGAC is a single question assessment to determine whether patients noticed a change in their breathing since the start of the study. Patients were asked to respond to a PGAC question asking, "Compared with prior to the study start, how do you feel your breathing is?" on a scale of '1=much worse' to '5=much better', with '3=no change'. Higher scores indicate better outcome. | Weeks 2 and 4 |
| LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Use of rescue medication (albuterol) per visit was calculated as the LS mean use daily over total number of days between previous visit (inclusive) and the following visit. Baseline use was the mean over the last 7 days of the run-in phase (calculated as the sum of puffs taken, divided by number of days data has been recorded). | Baseline and Weeks 1, 2, 3 and 4 |
| LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and peak FVC was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2, 3 and 4 |
| LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-3h FVC was defined as area under the curve over 3 hours of the FVC, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4 |
| LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-12h FVC was defined as area under the curve over 12 hours of the FVC, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4 |
| LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and morning trough FVC was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4 |
| Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Blood samples were taken to determine steady-state plasma concentrations of tiotropium prior to and following 14 days of treatment with RPL554. | Pre-dose on Day 1 and Week 2 |
| Steady-State Plasma Concentrations of RPL554 at Week 2 | Blood samples were taken to determine steady-state plasma concentrations of RPL554 following 14 days of treatment with RPL554. | Pre-dose at Week 2 |
| Number of Patients With Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any undesirable experience occurring to a patient, or worsening in a patient, whether considered related to the study medication or not. All AEs which started after the first dose of study treatment or started prior to first dose of study treatment and worsened, based on the Investigator's assessment of severity, on or after first dose of study treatment were considered to be treatment-emergent. A serious adverse event is any adverse experience that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events. | TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. |
| Fullerton |
| California |
| 92835 |
| United States |
| Southern California Institute For Respiratory Diseases, Inc. | Los Angeles | California | 90048 | United States |
| Innovative Clinical Research | Lafayette | Colorado | 80026 | United States |
| Meris Clinical Research | Brandon | Florida | 33511 | United States |
| Clinical Research of West Florida | Clearwater | Florida | 33765 | United States |
| Pulmonary Disease Specialists, PA d/b/a PDS Research | Kissimmee | Florida | 34741 | United States |
| Medical Research of Central Florida, LLC | Leesburg | Florida | 34748 | United States |
| Clinical Trials of Florida, LLC | Miami | Florida | 33186 | United States |
| Peninsula Research, Ormond Beach, LLC | Ormond Beach | Florida | 32174 | United States |
| Medsol Clinical Research Center, Inc | Port Charlotte | Florida | 33952 | United States |
| Progressive Medical Research | Port Orange | Florida | 32127 | United States |
| Pasadena Center for Medical Research, LLC | St. Petersburg | Florida | 33707 | United States |
| Florida Pulmonary Research Institute, LLC | Winter Park | Florida | 32789 | United States |
| Columbus Regional Research Institute | Columbus | Georgia | 31904 | United States |
| VitaLink Research - Hamilton Mill | Dacula | Georgia | 30019 | United States |
| VitaLink Research - Duluth | Duluth | Georgia | 30096 | United States |
| Gwinnett Biomedical Research | Lawrenceville | Georgia | 30046 | United States |
| IACT Health | Rincon | Georgia | 31326 | United States |
| Vitalink | Winder | Georgia | 30680 | United States |
| Genesis Clinical Research and Consulting, LLC | Fall River | Massachusetts | 02723 | United States |
| Pulmonary Research Institute of Southeast Michigan | Farmington Hills | Michigan | 48336 | United States |
| Cities Research Center | Fridley | Minnesota | 34741 | United States |
| American Health Research | Charlotte | North Carolina | 28078 | United States |
| Clinical Research of Gastonia | Gastonia | North Carolina | 28054 | United States |
| Research Carolina of Huntersville | Huntersville | North Carolina | 28078 | United States |
| Clinical Research of Lake Norman | Mooresville | North Carolina | 28117 | United States |
| New Horizons Clinical Research | Cincinnati | Ohio | 45242 | United States |
| Aventiv Research, Inc | Columbus | Ohio | 43213 | United States |
| Aventiv Research, Inc | Dublin | Ohio | 43016 | United States |
| Crisor, LLC | Medford | Oregon | 97504 | United States |
| Vitalink Research - Anderson | Anderson | South Carolina | 29621 | United States |
| Lowcountry Lung and Critical Care, PA | Charleston | South Carolina | 29406 | United States |
| VitaLink-Columbia | Columbia | South Carolina | 33765 | United States |
| VitaLink Research - Easley | Easley | South Carolina | 29640 | United States |
| Piedmont Research Partners, LLC | Fort Mill | South Carolina | 29707 | United States |
| VitaLink Research-Gaffney | Gaffney | South Carolina | 29340 | United States |
| VitaLink Research-Greenville | Greenville | South Carolina | 29615 | United States |
| VitaLink Research-UPSTATE | Greenville | South Carolina | 29615 | United States |
| Clinical Research of Charleston | Mt. Pleasant | South Carolina | 29464 | United States |
| Clinical Research of Rock Hill | Rock Hill | South Carolina | 29732 | United States |
| Vitalink Research-Seneca | Seneca | South Carolina | 29678 | United States |
| Fusion Clinical Research of Spartanburg, LLC | Spartanburg | South Carolina | 29301 | United States |
| Spartanburg Medical Research | Spartanburg | South Carolina | 29301 | United States |
| Vitalink Research-Spartanburg | Spartanburg | South Carolina | 29303 | United States |
| VitaLink Research - Union | Union | South Carolina | 29379 | United States |
| New Phase Research & Development | Knoxville | Tennessee | 37909 | United States |
| FMC Science, LLC | Lampasas | Texas | 76550 | United States |
| DCOL Center for Clinical Research | Longview | Texas | 75605 | United States |
| Metroplex Pulmonary and Sleep Center | McKinney | Texas | 75069 | United States |
Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
| FG002 | RPL554 1.5 mg | Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| FG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| FG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| Received Treatment |
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| COMPLETED |
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| NOT COMPLETED |
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|
All Patients Randomized Set included all patients who provided informed consent and who were randomized to study treatment.
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| ID | Title | Description |
|---|---|---|
| BG000 | RPL554 0.375 mg | Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| BG001 | RPL554 0.75 mg | Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| BG002 | RPL554 1.5 mg | Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| BG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| BG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| BG005 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants | No |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants | No |
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| Race/Ethnicity, Customized | Count of Participants | Participants | No |
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| 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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Least Square (LS) Mean Change From Baseline Forced Expiratory Volume in 1 Second (FEV1) to Peak FEV1 at Week 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. | The Full Analysis Set (FAS) included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Only patients with valid values at baseline and Week 4 are included in the analysis. | Posted | Least Squares Mean | Standard Error | liters | Baseline and Week 4 |
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| Secondary | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 3 Hours (AUC0-3h) FEV1 on Day 1 and at Weeks 1 to 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-3h FEV1 was defined as area under the curve over 3 hours of the FEV1, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | liters | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4 |
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| Secondary | LS Mean Change From Baseline FEV1 to Average Area Under the Curve Over 12 Hours (AUC0-12h) FEV1 on Day 1 and at Week 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and average AUC0-12h FEV1 was defined as area under the curve over 12 hours of the FEV1, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | liters | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4 |
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| Secondary | LS Mean Change From Baseline FEV1 to Peak FEV1 on Day 1 and at Weeks 1 to 3 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and peak FEV1 was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | liters | Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2 and 3 |
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| Secondary | LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 1 to 4 | Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Baseline FEV1 was defined as the value of FEV1 assessed 30 minutes before first administration and morning trough FEV1 was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | liters | Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4 |
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| Secondary | LS Mean Change From Baseline to the Mean Weekly Evaluating Respiratory Symptoms of COPD (E-RS:COPD) Total Score at Weeks 1 to 4 | The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS:COPD scale has a scoring range of 0 to 40. Higher scores indicates severe respiratory symptoms. Baseline was the mean over the 7 days prior to first intake of study treatment. Scores were derived weekly as the mean over 7 days prior to the visit, using only days where data was recorded. The E-RS:COPD was measured by daily electronic diary (e-diary). | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline and Weeks 1, 2, 3 and 4 |
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| Secondary | LS Mean Change From Baseline in the St George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score at Weeks 2 and 4 | Patients completed the SGRQ-C consisting of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome. The SGRQ-C was measured at Week 2 and 4 visits. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline, Weeks 2 and 4 |
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| Secondary | LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 2 and 4 | The TDI is a questionnaire that focussed on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | units on a scale | Weeks 2 and 4 |
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| Secondary | LS Mean Patient Global Assessment of Change (PGAC) Questionnaire Total Score at Weeks 2 and 4 | The PGAC is a single question assessment to determine whether patients noticed a change in their breathing since the start of the study. Patients were asked to respond to a PGAC question asking, "Compared with prior to the study start, how do you feel your breathing is?" on a scale of '1=much worse' to '5=much better', with '3=no change'. Higher scores indicate better outcome. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | units on a scale | Weeks 2 and 4 |
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| Secondary | LS Mean Change From Baseline to the Mean Weekly Values Over Weeks 1 to 4 in Number of Puffs of Rescue Medication | Use of rescue medication (albuterol) per visit was calculated as the LS mean use daily over total number of days between previous visit (inclusive) and the following visit. Baseline use was the mean over the last 7 days of the run-in phase (calculated as the sum of puffs taken, divided by number of days data has been recorded). | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | number of rescue medication puffs | Baseline and Weeks 1, 2, 3 and 4 |
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| Secondary | LS Mean Change From Baseline Forced Vital Capacity (FVC) to Peak FVC on Day 1 and at Weeks 1 to 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and peak FVC was defined as the maximum value in the 3 hours after dosing. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | liters | Baseline (30 minutes before first administration on Day 1); 30 minutes post-dose on Day 1 and Weeks 1, 2, 3 and 4 |
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| Secondary | LS Mean Change From Baseline FVC to Average AUC0-3h FVC on Day 1 and at Weeks 1 to 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-3h FVC was defined as area under the curve over 3 hours of the FVC, divided by 3 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | liters | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, and 3 hours post-dose on Day 1 and Weeks 1, 2, 3 and 4 |
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| Secondary | LS Mean Change From Baseline FVC to Average AUC0-12h FVC on Day 1 and at Week 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and average AUC0-12h FVC was defined as area under the curve over 12 hours of the FVC, divided by 12 hours. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | liters | Baseline (30 minutes before first administration on Day 1); 30 minutes and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 and at Week 4 |
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| Secondary | LS Mean Change From Baseline FVC to Morning Trough FVC at Weeks 1 to 4 | Forced spirometry maneuvers including the FVC were used to assess pulmonary function. Baseline FVC was defined as the value of FVC assessed 30 minutes before first administration and morning trough FVC was defined as the last pre-dose value. Spirometry assessments were performed in accordance with ATS/ERS guidelines. | The FAS included all randomized patients with sufficient data collected after intake of study treatment to compute any of the FEV1 parameters on at least 1 occasion. Number of patients with valid values at baseline and at the specific visit were analyzed. | Posted | Least Squares Mean | Standard Error | liters | Baseline (30 minutes before first administration on Day 1) and morning pre-dose on Weeks 1, 2, 3 and 4 |
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| Secondary | Steady-State Plasma Concentrations of Tiotropium on Day 1 and at Week 2 | Blood samples were taken to determine steady-state plasma concentrations of tiotropium prior to and following 14 days of treatment with RPL554. | The Pharmacokinetic (PK) analysis set included all randomized patients who had blood sampling performed and quantitative values of study treatment concentrations determined. Patients were classified according to actual treatment received for PK analysis set. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Number of patients with values available at the specific visit were analyzed. | Posted | Mean | Standard Deviation | picogram per milliliter (pg/mL) | Pre-dose on Day 1 and Week 2 |
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| Secondary | Steady-State Plasma Concentrations of RPL554 at Week 2 | Blood samples were taken to determine steady-state plasma concentrations of RPL554 following 14 days of treatment with RPL554. | The PK analysis set included all randomized patients who had blood sampling performed and quantitative values of study treatment concentrations determined. Patients were classified according to actual treatment received for PK analysis set. Number of patients with values available at the specific visit were analyzed. | Posted | Mean | Standard Deviation | pg/mL | Pre-dose at Week 2 |
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| Secondary | Number of Patients With Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any undesirable experience occurring to a patient, or worsening in a patient, whether considered related to the study medication or not. All AEs which started after the first dose of study treatment or started prior to first dose of study treatment and worsened, based on the Investigator's assessment of severity, on or after first dose of study treatment were considered to be treatment-emergent. A serious adverse event is any adverse experience that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or other important medical events. | The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set. | Posted | Count of Participants | Participants | No | TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks. |
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TEAEs were collected from the first dose of study treatment up to 1 week after the final study visit at Week 4, approximately 5 weeks.
The safety analysis set included all randomized patients who received at least 1 dose of study treatment. One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to actual treatment received for safety analysis set.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | RPL554 0.375 mg | Patients were administered 0.375 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set. | 0 | 82 | 0 | 82 | 6 | 82 |
| EG001 | RPL554 0.75 mg | Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set. | 0 | 83 | 1 | 83 | 9 | 83 |
| EG002 | RPL554 1.5 mg | Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set. | 0 | 81 | 0 | 81 | 4 | 81 |
| EG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set. | 0 | 83 | 2 | 83 | 8 | 83 |
| EG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. Patients were classified according to actual treatment received for safety analysis set. | 0 | 84 | 0 | 84 | 5 | 84 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Jaw fracture | Injury, poisoning and procedural complications | MedDRA 22.0 | Systematic Assessment |
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| Syncope | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
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| Alcohol abuse | Psychiatric disorders | MedDRA 22.0 | Systematic Assessment |
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| Chronic kidney disease | Renal and urinary disorders | MedDRA 22.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Oral candidiasis | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
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| Gastroenteritis | Infections and infestations | MedDRA 22.0 | Systematic Assessment |
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| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 22.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 22.0 | Systematic Assessment |
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| Blood creatinine increased | Investigations | MedDRA 22.0 | Systematic Assessment |
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| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 22.0 | Systematic Assessment |
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One patient who was randomized to RPL554 0.375 mg group was dispensed wrong treatment kit and received RPL554 3 mg. Patients were classified according to randomized treatment for the FAS and actual treatment received for safety and PK analysis sets.
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Nancy Herje | Verona Pharma Plc | +1 646-951-0961 | nancy.herje@veronapharma.com |
| SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol | Jul 22, 2019 | Aug 21, 2020 | Prot_001.pdf |
| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| 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 |
Not provided
Not provided
| ID | Term |
|---|---|
| C512996 | ensifentrine |
Not provided
Not provided
Not provided
| Between 18 and 65 years |
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| >=65 years |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Black or African American |
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| Native Hawaiian or Other Pacific Islander |
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| White |
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| Other |
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| Superiority |
| Comparison was done using a closed testing procedure; testing began at the highest dose of RPL554 compared with placebo. If found statistically significant then the next highest dose was compared with placebo. This continued until a result was found to be non-significant or all RPL554 doses were compared with placebo. | MMRM | 0.0040 | The MMRM model was used to model the change from baseline FEV1 to peak FEV1 using treatment, visit and treatment by visit interaction as fixed effect, patient as random effect and baseline FEV1 as the covariate. | LS mean difference | 0.1072 | Standard Error of the Mean | 0.03703 | 2-Sided | 95 | 0.0344 | 0.1800 | Estimates refer to the Week 4 from treatment by visit interaction. | Superiority |
| Comparison was done using a closed testing procedure; testing began at the highest dose of RPL554 compared with placebo. If found statistically significant then the next highest dose was compared with placebo. This continued until a result was found to be non-significant or all RPL554 doses were compared with placebo. | MMRM | 0.0148 | The MMRM model was used to model the change from baseline FEV1 to peak FEV1 using treatment, visit and treatment by visit interaction as fixed effect, patient as random effect and baseline FEV1 as the covariate. | LS mean difference | 0.0912 | Standard Error of the Mean | 0.03723 | 2-Sided | 95 | 0.0180 | 0.1643 | Estimates refer to the Week 4 from treatment by visit interaction. | Superiority |
| Comparison was done using a closed testing procedure; testing began at the highest dose of RPL554 compared with placebo. If found statistically significant then the next highest dose was compared with placebo. This continued until a result was found to be non-significant or all RPL554 doses were compared with placebo. | MMRM | 0.0368 | The MMRM model was used to model the change from baseline FEV1 to peak FEV1 using treatment, visit and treatment by visit interaction as fixed effect, patient as random effect and baseline FEV1 as the covariate. | LS mean difference | 0.0775 | Standard Error of the Mean | 0.03697 | 2-Sided | 95 | 0.0048 | 0.1501 | Estimates refer to the Week 4 from treatment by visit interaction. | Superiority |
| RPL554 1.5 mg |
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
| RPL554 1.5 mg |
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
| OG002 | RPL554 1.5 mg | Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
| OG002 | RPL554 1.5 mg | Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
| RPL554 1.5 mg |
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
| RPL554 1.5 mg |
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
| RPL554 1.5 mg |
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning.
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
|
|
Patients were administered 0.75 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG002 | RPL554 1.5 mg | Patients were administered 1.5 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG003 | RPL554 3.0 mg | Patients were administered 3.0 mg RPL554 by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
| OG004 | Placebo | Patients were administered placebo (matching with RPL554) by jet nebulizer twice daily (morning and evening) for 4 weeks. Open-label tiotropium was administered once daily in the morning. |
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