COPD
Conditions
Keywords
COPD, Adults, Phase II, RPL554, Ensifentrine
Brief summary
The purpose of this study is to investigate 5 doses of RPL554 and placebo, administered by pressurized metered dose inhaler (pMDI), in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
Detailed description
The study will consist of two parts. Part A is a parallel group, placebo-controlled single dose study to ascertain the Pharmacokinetics (PK) profile, safety and bronchodilator effect of a single dose of RPL554 administered via pMDI. Five of the 6 treatment arms will be double-blind and one will be single-blind (due to the different number of capsules administered). Part B is a 7-day placebo-controlled, complete block cross-over, repeat dose study to assess the bronchodilator effect of repeat doses of RPL554 delivered via pMDI.
Interventions
DRUGPart A: RPL554
Single dose RPL554 via metered dose inhaler.
DRUGPlacebos
Part A: Single dose placebo via metered dose inhaler. Part B: Repeat doses of placebo via metered dose inhaler in crossover fashion. One dose administered twice daily over 7 days.
DRUGPart B: RPL554
Part B: Repeat doses via metered dose inhaler in crossover fashion. One dose administered twice daily over 7 days.
Sponsors
Iqvia Pty Ltd
Verona Pharma plc
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double blind
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients with moderate to severe COPD, with a post bronchodilator FEV1 of 40 to 80% of predicted and FEV1/FVC ratio of ≤0.70. * They must have a baseline increase in FEV1 of \>150 mL following four puffs of salbutamol. * They must have at least a 10 pack-year smoking history, and may be either a current or former smoker.
Exclusion criteria
* Patients must be clinically stable without recent COPD exacerbations or hospitalisations. * They must not have uncontrolled disease or chronic heart failure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Pharmacokinetic Parameter AUC0-12 | Day 1 | Area under the curve from 0 to 12 hours after single dose drug administration. |
| Part A: Pharmacokinetic Parameter Cmax | Day 1 | Pharmacokinetic Parameter Cmax after a Single Dose |
| Part A: Pharmacokinetic Parameter AUC0-t | Day 1 | Area under the curve at maximum concentration 0-24 hrs after single dose drug administration |
| Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life) | Day 1 | RPL554 Plasma Pharmacokinetics concentration after single dose |
| Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) on Day 7 | Day 7 | Change from Baseline FEV1 to Peak FEV1 (over 4 hours) after morning dosing on Day 7 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Safety and Tolerability / Urinalysis Safety Assessments: Number of Patients With Treatment-emergent Urinalysis Abnormal Laboratory Assessments | 1 day | Number of patients with treatment-emergent urinalysis abnormal laboratory assessments |
| Part A: Safety and Tolerability / Supine Vitals Signs - Pulse Rate | Start of treatment to day 1 | Number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm) |
| Part A: Safety and Tolerability / Supine Vitals Signs - Blood Pressure | Start of treatment to day 1 | Number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg) |
| Part A: Safety and Tolerability / ECG - QTcF | Start of treatment to day 1 | Number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec |
| Part A: Safety and Tolerability / ECG - Heart Rate | Start of treatment to day 1 | Number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm |
| Part B: Change From Baseline in Average FEV1 (Over 4 Hrs) After 7 Days | Day 7 | Change from baseline in average FEV1 (over 4 hours) on Day 7 after morning dose |
| Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 7 Days | Day 7 | Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 7 after morning dose |
| Part B: Change From Baseline in Trough FEV1 After 7 Days | Day 7 | Change from Baseline FEV1 to Morning Trough FEV1 on Day 7 after morning dose |
| Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1st Dose | Day 1 | Change from baseline FEV1 in peak FEV1 (over 4 hours) after first dose |
| Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1 Dose | Day 1 | Change from Baseline FEV1 to Peak FEV1 (over 4 hours) After Single Dose |
| Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 1st Dose | Day 1 | Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 1 |
| Part B: RPL554 Plasma Pharmacokinetic Parameter (Onset of Action) | Day 1 | Determination of onset of action (\>10% increase in FEV1 from pre- to post-first dose, censored at 120 minutes) on Day 1 |
| Part B: Safety and Tolerability / Hematology Safety Assessments | 1 day | Number of patients with treatment-emergent hematology abnormal laboratory assessments |
| Part B: Safety and Tolerability / Blood Chemistry Safety Assessments | 1 day | Number of patients with treatment-emergent blood chemistry abnormal laboratory assessments |
| Part B: Safety and Tolerability / Urinalysis Safety Assessments | 1 day | Number of patients with treatment-emergent urinalysis abnormal laboratory assessments |
| Part B: Safety and Tolerability / Supine Vital Signs - Pulse Rate | Start of treatment to day 1 | Number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm) |
| Part B: Safety and Tolerability / Supine Vital Signs - Blood Pressure | Start of treatment to day 1 | Number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg) |
| Part B: Safety and Tolerability / ECG - QTcF | Start of treatment to day 70 | Number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec |
| Part B: Safety and Tolerability / ECG - Heart Rate | Start of treatment to day 70 | Number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm |
| Part B: Change From Baseline in Average FEV1 (Over 4 Hours) After 1st Dose | Day 1 | Change from baseline FEV1 in average FEV1 (over 4 hours) on Day 1 |
| Part A: Change From Baseline in Average FEV1 (Over 4 Hours) After 1 Dose | Day 1 | Change from Baseline FEV1 to Average FEV1 (over 4 hours) After Single Dose |
| Part A: Change From Baseline in Average FEV1 (Over 12 Hours) After 1 Dose | Day 1 | Change from Baseline FEV1 to Average FEV1 (over 12 hours) After Single Dose |
| Part A: Safety and Tolerability / Hematology Safety Assessments | 1 day | Number of patients with treatment-emergent hematology abnormal laboratory assessments |
| Part A: Safety and Tolerability / Blood Chemistry Safety Assessments: Number of Patients With Treatment-emergent Blood Chemistry Abnormal Laboratory Assessments | 1 day | Number of patients with treatment-emergent blood chemistry abnormal laboratory assessments |
Countries
United Kingdom
Participant flow
Recruitment details
40 subjects enrolled for Part A and eligible to continue into Part B.
Pre-assignment details
Part A: 40 Patients randomized equally to receive a single dose of RPL554 (0.10, 0.30, 1, 3, or 6 mg) or matching placebo via pressurized metered dose inhaler (pMDI). Patients continued to Part B after Part A completed. Part B: 28 Patients continued to Part B and randomly assigned to 1 of 4 treatment sequences in a crossover design (1-week treatment periods separated by 7-10 day washout). Each sequence included twice daily RPL554 (0.30, 1, or 3 mg) or matching placebo via pMDI.
Participants by arm
| Arm | Count |
|---|---|
| 0.10 mg Single dose of RPL554 via pMDI (double-blind) | 6 |
| 0.30 mg Single dose of RPL554 via pMDI (double-blind) | 7 |
| 1 mg Single dose of RPL554 via pMDI (double-blind) | 6 |
| 3 mg Single dose of RPL554 via pMDI (double-blind) | 7 |
| 6 mg Single dose of RPL554 via pMDI (single-blind) | 7 |
| Placebo Single dose of placebo via pMDI (double-blind) | 7 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Part B (R, PC, XO) Twice Daily for 7 Day | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Part B (R, PC, XO) Twice Daily for 7 Day | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Part B (R, PC, XO) Twice Daily for 7 Day | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | 0.10 mg | Total | Placebo | 6 mg | 3 mg | 1 mg | 0.30 mg |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 66.8 years STANDARD_DEVIATION 4.92 | 66.3 years STANDARD_DEVIATION 6.67 | 64.4 years STANDARD_DEVIATION 6.6 | 63.1 years STANDARD_DEVIATION 8.71 | 67.1 years STANDARD_DEVIATION 6.72 | 64.3 years STANDARD_DEVIATION 7.87 | 71.4 years STANDARD_DEVIATION 1.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 40 Participants | 7 Participants | 7 Participants | 7 Participants | 6 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 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 | 6 Participants | 40 Participants | 7 Participants | 7 Participants | 7 Participants | 6 Participants | 7 Participants |
| Region of Enrollment United Kingdom | 6 participants | 40 participants | 7 participants | 7 participants | 7 participants | 6 participants | 7 participants |
| Sex: Female, Male Female | 2 Participants | 16 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 24 Participants | 4 Participants | 5 Participants | 4 Participants | 4 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 7 | 0 / 7 | 0 / 7 | 0 / 24 | 0 / 23 | 0 / 23 | 0 / 25 |
| other Total, other adverse events | 2 / 6 | 1 / 7 | 1 / 6 | 2 / 7 | 4 / 7 | 2 / 7 | 3 / 24 | 4 / 23 | 2 / 23 | 3 / 25 |
| serious Total, serious adverse events | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 7 | 0 / 7 | 0 / 7 | 0 / 24 | 0 / 23 | 0 / 23 | 0 / 25 |
Outcome results
Primary
Part A: Pharmacokinetic Parameter AUC0-12
Area under the curve from 0 to 12 hours after single dose drug administration.
Time frame: Day 1
Population: Pharmacokinetic (PK) Analysis Set in Part A: all randomized patients who had blood sampling performed after the single dose of RPL554 and had evaluable PK parameter data. The PK Analysis Set included the 33 patients who received RPL554 in Part A but not the 7 patients in the placebo group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part A: Pharmacokinetic Parameter AUC0-12 | 175 h*pg/mL | Standard Deviation 96.7 |
| 0.30 mg | Part A: Pharmacokinetic Parameter AUC0-12 | 611 h*pg/mL | Standard Deviation 183 |
| 1 mg | Part A: Pharmacokinetic Parameter AUC0-12 | 1550 h*pg/mL | Standard Deviation 443 |
| 3 mg | Part A: Pharmacokinetic Parameter AUC0-12 | 5860 h*pg/mL | Standard Deviation 3120 |
| 6 mg | Part A: Pharmacokinetic Parameter AUC0-12 | 9360 h*pg/mL | Standard Deviation 8100 |
Primary
Part A: Pharmacokinetic Parameter AUC0-t
Area under the curve at maximum concentration 0-24 hrs after single dose drug administration
Time frame: Day 1
Population: Pharmacokinetic (PK) Analysis Set in Part A: all randomized patients who had blood sampling performed after the single dose of RPL554 and had evaluable PK parameter data. The PK Analysis Set included the 33 patients who received RPL554 in Part A but not the 7 patients in the placebo group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part A: Pharmacokinetic Parameter AUC0-t | 208 h*pg/mL | Standard Deviation 119 |
| 0.30 mg | Part A: Pharmacokinetic Parameter AUC0-t | 692 h*pg/mL | Standard Deviation 229 |
| 1 mg | Part A: Pharmacokinetic Parameter AUC0-t | 1680 h*pg/mL | Standard Deviation 559 |
| 3 mg | Part A: Pharmacokinetic Parameter AUC0-t | 6800 h*pg/mL | Standard Deviation 3770 |
| 6 mg | Part A: Pharmacokinetic Parameter AUC0-t | 10800 h*pg/mL | Standard Deviation 10100 |
Primary
Part A: Pharmacokinetic Parameter Cmax
Pharmacokinetic Parameter Cmax after a Single Dose
Time frame: Day 1
Population: Pharmacokinetic (PK) Analysis Set in Part A: all randomized patients who had blood sampling performed after the single dose of RPL554 and had evaluable PK parameter data. The PK Analysis Set included the 33 patients who received RPL554 in Part A but not the 7 patients in the placebo group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part A: Pharmacokinetic Parameter Cmax | 39.4 pg/mL | Standard Deviation 16.4 |
| 0.30 mg | Part A: Pharmacokinetic Parameter Cmax | 138 pg/mL | Standard Deviation 40.9 |
| 1 mg | Part A: Pharmacokinetic Parameter Cmax | 467 pg/mL | Standard Deviation 57.8 |
| 3 mg | Part A: Pharmacokinetic Parameter Cmax | 1520 pg/mL | Standard Deviation 1050 |
| 6 mg | Part A: Pharmacokinetic Parameter Cmax | 2360 pg/mL | Standard Deviation 1430 |
Primary
Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life)
RPL554 Plasma Pharmacokinetics concentration after single dose
Time frame: Day 1
Population: Pharmacokinetic (PK) Analysis Set in Part A: all randomized patients who had blood sampling performed after the single dose of RPL554 and had evaluable PK parameter data. The PK Analysis Set included the 33 patients who received RPL554 in Part A but not the 7 patients in the placebo group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life) | 6.31 h | Standard Deviation 5.18 |
| 0.30 mg | Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life) | 5.32 h | Standard Deviation 3.36 |
| 1 mg | Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life) | 3.47 h | Standard Deviation 1.44 |
| 3 mg | Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life) | 5.62 h | Standard Deviation 1.7 |
| 6 mg | Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life) | 4.44 h | Standard Deviation 2.03 |
Primary
Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) on Day 7
Change from Baseline FEV1 to Peak FEV1 (over 4 hours) after morning dosing on Day 7
Time frame: Day 7
Population: Full Analysis Set = number of patients with at least one on treatment value who contributed to the model estimation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) on Day 7 | 0.189 L | Standard Deviation 0.1624 |
| 0.30 mg | Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) on Day 7 | 0.261 L | Standard Deviation 0.1597 |
| 1 mg | Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) on Day 7 | 0.310 L | Standard Deviation 0.1511 |
| 3 mg | Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) on Day 7 | -0.016 L | Standard Deviation 0.1485 |
p-value: <0.000195% CI: [1.163, 1.281]ANCOVA
p-value: <0.000195% CI: [1.146, 1.263]ANCOVA
p-value: <0.000195% CI: [1.085, 1.195]ANCOVA
Secondary
Part A: Change From Baseline in Average FEV1 (Over 12 Hours) After 1 Dose
Change from Baseline FEV1 to Average FEV1 (over 12 hours) After Single Dose
Time frame: Day 1
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part A: Change From Baseline in Average FEV1 (Over 12 Hours) After 1 Dose | 0.018 L | Standard Deviation 0.0643 |
| 0.30 mg | Part A: Change From Baseline in Average FEV1 (Over 12 Hours) After 1 Dose | 0.061 L | Standard Deviation 0.0429 |
| 1 mg | Part A: Change From Baseline in Average FEV1 (Over 12 Hours) After 1 Dose | 0.010 L | Standard Deviation 0.0408 |
| 3 mg | Part A: Change From Baseline in Average FEV1 (Over 12 Hours) After 1 Dose | 0.121 L | Standard Deviation 0.1321 |
| 6 mg | Part A: Change From Baseline in Average FEV1 (Over 12 Hours) After 1 Dose | 0.190 L | Standard Deviation 0.1053 |
| Placebo | Part A: Change From Baseline in Average FEV1 (Over 12 Hours) After 1 Dose | -0.031 L | Standard Deviation 0.074 |
p-value: <0.000195% CI: [1.073, 1.204]ANCOVA
p-value: 0.004195% CI: [1.03, 1.155]ANCOVA
p-value: 0.5395% CI: [0.96, 1.081]ANCOVA
Secondary
Part A: Change From Baseline in Average FEV1 (Over 4 Hours) After 1 Dose
Change from Baseline FEV1 to Average FEV1 (over 4 hours) After Single Dose
Time frame: Day 1
Population: Full analysis set. () () () () () ()
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part A: Change From Baseline in Average FEV1 (Over 4 Hours) After 1 Dose | 0.058 L | Standard Deviation 0.0889 |
| 0.30 mg | Part A: Change From Baseline in Average FEV1 (Over 4 Hours) After 1 Dose | 0.161 L | Standard Deviation 0.065 |
| 1 mg | Part A: Change From Baseline in Average FEV1 (Over 4 Hours) After 1 Dose | 0.153 L | Standard Deviation 0.0653 |
| 3 mg | Part A: Change From Baseline in Average FEV1 (Over 4 Hours) After 1 Dose | 0.240 L | Standard Deviation 0.1677 |
| 6 mg | Part A: Change From Baseline in Average FEV1 (Over 4 Hours) After 1 Dose | 0.334 L | Standard Deviation 0.1147 |
| Placebo | Part A: Change From Baseline in Average FEV1 (Over 4 Hours) After 1 Dose | -0.011 L | Standard Deviation 0.0805 |
p-value: <0.000195% CI: [1.142, 1.319]ANCOVA
p-value: 0.000295% CI: [1.075, 1.24]ANCOVA
p-value: 0.012995% CI: [1.022, 1.184]ANCOVA
p-value: 0.007995% CI: [1.03, 1.201]ANCOVA
p-value: 0.3995% CI: [0.957, 1.116]ANCOVA
Secondary
Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1 Dose
Change from Baseline FEV1 to Peak FEV1 (over 4 hours) After Single Dose
Time frame: Day 1
Population: Full analysis includes patients with values at baseline and peak FEV1 (0-4h).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1 Dose | 0.133 L | Standard Deviation 0.1144 |
| 0.30 mg | Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1 Dose | 0.264 L | Standard Deviation 0.1012 |
| 1 mg | Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1 Dose | 0.255 L | Standard Deviation 0.0994 |
| 3 mg | Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1 Dose | 0.332 L | Standard Deviation 0.2095 |
| 6 mg | Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1 Dose | 0.477 L | Standard Deviation 0.1469 |
| Placebo | Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1 Dose | 0.086 L | Standard Deviation 0.0694 |
p-value: <0.000195% CI: [1.151, 1.363]ANCOVA
p-value: 0.002295% CI: [1.054, 1.246]ANCOVA
p-value: 0.029595% CI: [1.01, 1.202]ANCOVA
p-value: 0.009895% CI: [1.032, 1.235]ANCOVA
p-value: 0.5495% CI: [0.939, 1.125]ANCOVA
Secondary
Part A: Safety and Tolerability / Blood Chemistry Safety Assessments: Number of Patients With Treatment-emergent Blood Chemistry Abnormal Laboratory Assessments
Number of patients with treatment-emergent blood chemistry abnormal laboratory assessments
Time frame: 1 day
Secondary
Part A: Safety and Tolerability / ECG - Heart Rate
Number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm
Time frame: Start of treatment to day 1
Secondary
Part A: Safety and Tolerability / ECG - QTcF
Number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec
Time frame: Start of treatment to day 1
Secondary
Part A: Safety and Tolerability / Hematology Safety Assessments
Number of patients with treatment-emergent hematology abnormal laboratory assessments
Time frame: 1 day
Secondary
Part A: Safety and Tolerability / Supine Vitals Signs - Blood Pressure
Number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg)
Time frame: Start of treatment to day 1
Secondary
Part A: Safety and Tolerability / Supine Vitals Signs - Pulse Rate
Number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm)
Time frame: Start of treatment to day 1
Secondary
Part A: Safety and Tolerability / Urinalysis Safety Assessments: Number of Patients With Treatment-emergent Urinalysis Abnormal Laboratory Assessments
Number of patients with treatment-emergent urinalysis abnormal laboratory assessments
Time frame: 1 day
Secondary
Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 1st Dose
Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 1
Time frame: Day 1
Population: number of patients with at least one on treatment value who contributed to the model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 1st Dose | 0.047 L | Standard Deviation 0.0914 |
| 0.30 mg | Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 1st Dose | 0.102 L | Standard Deviation 0.1306 |
| 1 mg | Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 1st Dose | 0.085 L | Standard Deviation 0.0659 |
| 3 mg | Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 1st Dose | -0.058 L | Standard Deviation 0.1444 |
p-value: <0.000195% CI: [1.059, 1.137]ANCOVA
p-value: <0.000195% CI: [1.072, 1.15]ANCOVA
p-value: 0.00035% CI: [1.033, 1.109]ANCOVA
Secondary
Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 7 Days
Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 7 after morning dose
Time frame: Day 7
Population: Full analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 7 Days | 0.008 L | Standard Deviation 0.1421 |
| 0.30 mg | Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 7 Days | 0.075 L | Standard Deviation 0.1472 |
| 1 mg | Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 7 Days | 0.085 L | Standard Deviation 0.1411 |
| 3 mg | Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 7 Days | -0.112 L | Standard Deviation 0.1662 |
p-value: 0.001895% CI: [1.031, 1.132]ANCOVA
p-value: <0.000195% CI: [1.087, 1.194]ANCOVA
p-value: <0.000195% CI: [1.089, 1.197]ANCOVA
Secondary
Part B: Change From Baseline in Average FEV1 (Over 4 Hours) After 1st Dose
Change from baseline FEV1 in average FEV1 (over 4 hours) on Day 1
Time frame: Day 1
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part B: Change From Baseline in Average FEV1 (Over 4 Hours) After 1st Dose | 0.144 L | Standard Deviation 0.0762 |
| 0.30 mg | Part B: Change From Baseline in Average FEV1 (Over 4 Hours) After 1st Dose | 0.204 L | Standard Deviation 0.1162 |
| 1 mg | Part B: Change From Baseline in Average FEV1 (Over 4 Hours) After 1st Dose | 0.224 L | Standard Deviation 0.0905 |
| 3 mg | Part B: Change From Baseline in Average FEV1 (Over 4 Hours) After 1st Dose | -0.017 L | Standard Deviation 0.1284 |
p-value: <0.000195% CI: [1.119, 1.196]ANCOVA
p-value: <0.000195% CI: [1.11, 1.186]ANCOVA
p-value: <0.000195% CI: [1.068, 1.142]ANCOVA
Secondary
Part B: Change From Baseline in Average FEV1 (Over 4 Hrs) After 7 Days
Change from baseline in average FEV1 (over 4 hours) on Day 7 after morning dose
Time frame: Day 7
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part B: Change From Baseline in Average FEV1 (Over 4 Hrs) After 7 Days | 0.083 L | Standard Deviation 0.1223 |
| 0.30 mg | Part B: Change From Baseline in Average FEV1 (Over 4 Hrs) After 7 Days | 0.161 L | Standard Deviation 0.1686 |
| 1 mg | Part B: Change From Baseline in Average FEV1 (Over 4 Hrs) After 7 Days | 0.206 L | Standard Deviation 0.147 |
| 3 mg | Part B: Change From Baseline in Average FEV1 (Over 4 Hrs) After 7 Days | -0.095 L | Standard Deviation 0.1702 |
p-value: <0.000195% CI: [1.153, 1.27]ANCOVA
p-value: <0.000195% CI: [1.136, 1.252]ANCOVA
p-value: <0.000195% CI: [1.071, 1.179]ANCOVA
Secondary
Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1st Dose
Change from baseline FEV1 in peak FEV1 (over 4 hours) after first dose
Time frame: Day 1
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1st Dose | 0.253 L | Standard Deviation 0.0772 |
| 0.30 mg | Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1st Dose | 0.311 L | Standard Deviation 0.1532 |
| 1 mg | Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1st Dose | 0.337 L | Standard Deviation 0.1108 |
| 3 mg | Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1st Dose | 0.079 L | Standard Deviation 0.0914 |
p-value: <0.000195% CI: [1.122, 1.203]ANCOVA
p-value: <0.000195% CI: [1.111, 1.19]ANCOVA
p-value: <0.000195% CI: [1.074, 1.152]ANCOVA
Secondary
Part B: Change From Baseline in Trough FEV1 After 7 Days
Change from Baseline FEV1 to Morning Trough FEV1 on Day 7 after morning dose
Time frame: Day 7
Population: Full analysis set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.10 mg | Part B: Change From Baseline in Trough FEV1 After 7 Days | -0.051 L | Standard Deviation 0.1254 |
| 0.30 mg | Part B: Change From Baseline in Trough FEV1 After 7 Days | -0.017 L | Standard Deviation 0.1783 |
| 1 mg | Part B: Change From Baseline in Trough FEV1 After 7 Days | 0.013 L | Standard Deviation 0.1631 |
| 3 mg | Part B: Change From Baseline in Trough FEV1 After 7 Days | -0.097 L | Standard Deviation 0.1389 |
p-value: 0.006695% CI: [1.022, 1.14]ANCOVA
p-value: 0.011595% CI: [1.017, 1.134]ANCOVA
p-value: 0.1895% CI: [0.982, 1.096]ANCOVA
Secondary
Part B: RPL554 Plasma Pharmacokinetic Parameter (Onset of Action)
Determination of onset of action (\>10% increase in FEV1 from pre- to post-first dose, censored at 120 minutes) on Day 1
Time frame: Day 1
Population: Patients with onset of action
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 0.10 mg | Part B: RPL554 Plasma Pharmacokinetic Parameter (Onset of Action) | 37.0 mins |
| 0.30 mg | Part B: RPL554 Plasma Pharmacokinetic Parameter (Onset of Action) | 27.5 mins |
| 1 mg | Part B: RPL554 Plasma Pharmacokinetic Parameter (Onset of Action) | 19.0 mins |
p-value: 0.47Hodges-Lehmann
p-value: 0.0059Hodges-Lehmann
Secondary
Part B: Safety and Tolerability / Blood Chemistry Safety Assessments
Number of patients with treatment-emergent blood chemistry abnormal laboratory assessments
Time frame: 1 day
Secondary
Part B: Safety and Tolerability / ECG - Heart Rate
Number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm
Time frame: Start of treatment to day 70
Secondary
Part B: Safety and Tolerability / ECG - QTcF
Number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec
Time frame: Start of treatment to day 70
Secondary
Part B: Safety and Tolerability / Hematology Safety Assessments
Number of patients with treatment-emergent hematology abnormal laboratory assessments
Time frame: 1 day
Secondary
Part B: Safety and Tolerability / Supine Vital Signs - Blood Pressure
Number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg)
Time frame: Start of treatment to day 1
Secondary
Part B: Safety and Tolerability / Supine Vital Signs - Pulse Rate
Number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm)
Time frame: Start of treatment to day 1
Secondary
Part B: Safety and Tolerability / Urinalysis Safety Assessments
Number of patients with treatment-emergent urinalysis abnormal laboratory assessments
Time frame: 1 day