Clincosm LogoSign in Get a demo

A Study of RPL554 Drug Administered by Metered Dose Inhaler to Treat Chronic Obstructive Pulmonary Disease

Sponsor
Verona Pharma plc (Industry)
Overall Status
Completed
CT.gov ID
NCT04091360
Collaborator
Iqvia Pty Ltd (Industry)
40
Enrollment
2
Locations
6
Arms
20.8
Actual Duration (Months)
20
Patients Per Site
1
Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease Intervention/Treatment Phase
  • Drug: Part A: RPL554
  • Drug: Placebos
  • Drug: Part B: RPL554
 Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
40 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Double (Participant, Investigator)
Masking Description:
Double blind
Primary Purpose:
Treatment
Official Title:
A Phase II, Randomised Study to Assess the Pharmacokinetics, Safety and Pharmacodynamics of Single and Repeat Doses of RPL554 Administered by Pressurised Metered Dose Inhaler in Patients With COPD
Actual Study Start Date :
Apr 29, 2019
Actual Primary Completion Date :
Dec 10, 2020
Actual Study Completion Date :
Jan 21, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: RPL554 100 mcg

Part A: Patients receive 1 dose of either RPL554 100mcg via metered dose inhaler. Part B: not applicable

Drug: Part A: RPL554
Single dose RPL554 via metered dose inhaler.
Other Names:
  • Part A

    • Drug: Placebos
    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.
    Experimental: RPL554 300 mcg

    Part A: Patients receive 1 dose of RPL554 300mcg via metered dose inhaler. Part B: Patients receive repeat doses of RPL554 300mcg via metered dose inhaler in crossover fashion.

    Drug: Part A: RPL554
    Single dose RPL554 via metered dose inhaler.
    Other Names:
  • Part A

    • Drug: Placebos
    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.

    Drug: Part B: RPL554
    Part B: Repeat doses via metered dose inhaler in crossover fashion. One dose administered twice daily over 7 days.
    Other Names:
  • Part B

    		•
    Experimental: RPL554 1000 mcg

    Part A: Patients receive 1 dose of RPL554 1000mcg via metered dose inhaler. Part B: Patients receive repeat doses of RPL554 3000mcg via metered dose inhaler in crossover fashion.

    Drug: Part A: RPL554
    Single dose RPL554 via metered dose inhaler.
    Other Names:
  • Part A

    • Drug: Placebos
    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.

    Drug: Part B: RPL554
    Part B: Repeat doses via metered dose inhaler in crossover fashion. One dose administered twice daily over 7 days.
    Other Names:
  • Part B

    		•
    Experimental: RPL554 3000 mcg

    Part A: Patients receive 1 dose of either RPL554 3000mcg via metered dose inhaler. Part B: Patients receive repeat doses of RPL554 3000mcg via metered dose inhaler in crossover fashion.

    Drug: Part A: RPL554
    Single dose RPL554 via metered dose inhaler.
    Other Names:
  • Part A

    • Drug: Placebos
    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.

    Drug: Part B: RPL554
    Part B: Repeat doses via metered dose inhaler in crossover fashion. One dose administered twice daily over 7 days.
    Other Names:
  • Part B

    		•
    Experimental: RPL554 6000 mcg

    Part A: Patients receive 1 dose of either RPL554 6000mcg via metered dose inhaler. Part B: not applicable

    Drug: Part A: RPL554
    Single dose RPL554 via metered dose inhaler.
    Other Names:
  • Part A

    • Drug: Placebos
    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.
    Placebo Comparator: RPL554 Placebo

    Part A: Patients receive 1 dose of RPL554 placebo via metered dose inhaler. Part B: Patients receive repeat doses of RPL554 placebo via metered dose inhaler in crossover fashion.

    Drug: Part A: RPL554
    Single dose RPL554 via metered dose inhaler.
    Other Names:
  • Part A

    • Drug: Placebos
    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.

    Outcome Measures

    Primary Outcome Measures

    1. Part A: Pharmacokinetic Parameter AUC0-12 [Day 1]

      Area under the curve from 0 to 12 hours after single dose drug administration.

    2. Part A: Pharmacokinetic Parameter Cmax [Day 1]

      Pharmacokinetic Parameter Cmax after a Single Dose

    3. Part A: Pharmacokinetic Parameter AUC0-t [Day 1]

      Area under the curve at maximum concentration 0-24 hrs after single dose drug administration

    4. Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life) [Day 1]

      RPL554 Plasma Pharmacokinetics concentration after single dose

    5. 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 Outcome Measures

    1. 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

    2. 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

    3. 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

    4. Part A: Safety and Tolerability / Hematology Safety Assessments [1 day]

      Number of patients with treatment-emergent hematology abnormal laboratory assessments

    5. 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

    6. 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

    7. 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)

    8. 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)

    9. 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

    10. 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

    11. 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

    12. 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

    13. 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

    14. 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

    15. 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

    16. 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

    17. 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

    18. Part B: Safety and Tolerability / Hematology Safety Assessments [1 day]

      Number of patients with treatment-emergent hematology abnormal laboratory assessments

    19. Part B: Safety and Tolerability / Blood Chemistry Safety Assessments [1 day]

      Number of patients with treatment-emergent blood chemistry abnormal laboratory assessments

    20. Part B: Safety and Tolerability / Urinalysis Safety Assessments [1 day]

      Number of patients with treatment-emergent urinalysis abnormal laboratory assessments

    21. 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)

    22. 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)

    23. 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

    24. 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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    40 Years to 80 Years
    Sexes Eligible for Study:
    All
    Accepts 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Respiratory Clinical Trials Ltd London United Kingdom W1G 8HU
    2 Medicines Evaluation Unit Limited Wythenshawe United Kingdom M23 9QZ

    Sponsors and Collaborators

    • Verona Pharma plc
    • Iqvia Pty Ltd

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Verona Pharma plc
    ClinicalTrials.gov Identifier:
    NCT04091360
    Other Study ID Numbers:
    • RPL554-MD-201
    First Posted:
    Sep 16, 2019
    Last Update Posted:
    Jul 25, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Verona Pharma plc
    COPD
    Adults
    Phase II
    RPL554
    Ensifentrine

    Study Results

    Participant Flow

    Recruitment Details 40 subjects enrolled for Part A and eligible to continue into Part B.
    Pre-assignment Detail 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.
    Arm/Group Title 0.10 mg/Part A 0.30 mg/Part A 1 mg/Part A 3 mg/Part A 6 mg/Part A Placebo/Part A Seq 1/Part B Seq 2/Part B Seq 3/Part B Seq 4/Part B
    Arm/Group Description Part A: single dose of RPL554 via pMDI (double-blind) Part A: single dose of RPL554 via pMDI (double-blind) Part A: single dose of RPL554 via pMDI (double-blind) Part A: single dose of RPL554 via pMDI (double-blind) Part A: single dose of RPL554 via pMDI (single-blind) Part A: single dose via pMDI (double-blind) Part B: 7 day, twice daily dose of RPL554 via pMDI (double-blind) complete block, cross-over. Seq 1= RPL554 0.30 mg / RPL554 3 mg / Placebo / RPL554 1 mg Part B: 7 day, twice daily dose of RPL554 via pMDI (double-blind) complete block, cross-over. Seq 2= RPL554 1 mg / Placebo / RPL554 3 mg / RPL554 0.30 mg. Part B: 7 day, twice daily dose of RPL554 via pMDI (double-blind) complete block, cross-over. Seq 3= RPL554 3 mg / RPL554 1 mg / RPL554 0.30 mg / Placebo. Part B: 7 day, twice daily dose of RPL554 via pMDI (double-blind) complete block, cross-over. Seq 4= Placebo / RPL554 0.30 mg / RPL554 1 mg / RPL554 3 mg.
    Period Title: Part A (R, PC, PG) Single Dose
    STARTED 6 7 6 7 7 7 0 0 0 0
    COMPLETED 6 7 6 7 7 7 0 0 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0
    Period Title: Part A (R, PC, PG) Single Dose
    STARTED 0 0 0 0 0 0 8 7 7 6
    COMPLETED 0 0 0 0 0 0 6 6 6 4
    NOT COMPLETED 0 0 0 0 0 0 2 1 1 2

    Baseline Characteristics

    Arm/Group Title 0.10 mg 0.30 mg 1 mg 3 mg 6 mg Placebo Total
    Arm/Group Description Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (single-blind) Single dose of placebo via pMDI (double-blind) Total of all reporting groups
    Overall Participants 6 7 6 7 7 7 40
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    66.8
    (4.92)
    71.4
    (1.27)
    64.3
    (7.87)
    67.1
    (6.72)
    63.1
    (8.71)
    64.4
    (6.60)
    66.3
    (6.67)
    Sex: Female, Male (Count of Participants)
    Female
    2
    33.3%
    4
    57.1%
    2
    33.3%
    3
    42.9%
    2
    28.6%
    3
    42.9%
    16
    40%
    Male
    4
    66.7%
    3
    42.9%
    4
    66.7%
    4
    57.1%
    5
    71.4%
    4
    57.1%
    24
    60%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Not Hispanic or Latino
    6
    100%
    7
    100%
    6
    100%
    7
    100%
    7
    100%
    7
    100%
    40
    100%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    White
    6
    100%
    7
    100%
    6
    100%
    7
    100%
    7
    100%
    7
    100%
    40
    100%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (participants) [Number]
    United Kingdom
    6
    100%
    7
    100%
    6
    100%
    7
    100%
    7
    100%
    7
    100%
    40
    100%

    Outcome Measures

    1. Primary Outcome
    Title Part A: Pharmacokinetic Parameter AUC0-12
    Description Area under the curve from 0 to 12 hours after single dose drug administration.
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    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/Group Title 0.10 mg 0.30 mg 1 mg 3 mg 6 mg
    Arm/Group Description Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (single-blind)
    Measure Participants 6 7 6 7 7
    Mean (Standard Deviation) [h*pg/mL]
    175
    (96.7)
    611
    (183)
    1550
    (443)
    5860
    (3120)
    9360
    (8100)
    2. Primary Outcome
    Title Part A: Pharmacokinetic Parameter Cmax
    Description Pharmacokinetic Parameter Cmax after a Single Dose
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    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/Group Title 0.10 mg 0.30 mg 1 mg 3 mg 6 mg
    Arm/Group Description Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (single-blind)
    Measure Participants 6 7 6 7 7
    Mean (Standard Deviation) [pg/mL]
    39.4
    (16.4)
    138
    (40.9)
    467
    (57.8)
    1520
    (1050)
    2360
    (1430)
    3. Primary Outcome
    Title Part A: Pharmacokinetic Parameter AUC0-t
    Description Area under the curve at maximum concentration 0-24 hrs after single dose drug administration
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    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/Group Title 0.10 mg 0.30 mg 1 mg 3 mg 6 mg
    Arm/Group Description Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (single-blind)
    Measure Participants 5 7 6 7 7
    Mean (Standard Deviation) [h*pg/mL]
    208
    (119)
    692
    (229)
    1680
    (559)
    6800
    (3770)
    10800
    (10100)
    4. Primary Outcome
    Title Part A: RPL554 Plasma Pharmacokinetic Parameter (Half-life)
    Description RPL554 Plasma Pharmacokinetics concentration after single dose
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    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/Group Title 0.10 mg 0.30 mg 1 mg 3 mg 6 mg
    Arm/Group Description Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (single-blind)
    Measure Participants 4 7 6 7 7
    Mean (Standard Deviation) [h]
    6.31
    (5.18)
    5.32
    (3.36)
    3.47
    (1.44)
    5.62
    (1.7)
    4.44
    (2.03)
    5. Primary Outcome
    Title Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) on Day 7
    Description Change from Baseline FEV1 to Peak FEV1 (over 4 hours) after morning dosing on Day 7
    Time Frame Day 7

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set = number of patients with at least one on treatment value who contributed to the model estimation.
    Arm/Group Title 0.30 mg 1 mg 3 mg Placebo
    Arm/Group Description 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of placebo via MPI (double-blind) complete block, cross-over
    Measure Participants 22 22 22 23
    Mean (Standard Deviation) [L]
    0.189
    (0.1624)
    0.261
    (0.1597)
    0.310
    (0.1511)
    -0.016
    (0.1485)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 1 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.221
    Confidence Interval (2-Sided) 95%
    1.163 to 1.281
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.203
    Confidence Interval (2-Sided) 95%
    1.146 to 1.263
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.139
    Confidence Interval (2-Sided) 95%
    1.085 to 1.195
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Part A: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1 Dose
    Description Change from Baseline FEV1 to Peak FEV1 (over 4 hours) After Single Dose
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Full analysis includes patients with values at baseline and peak FEV1 (0-4h).
    Arm/Group Title 0.10 mg 0.30 mg 1 mg 3 mg 6 mg Placebo
    Arm/Group Description Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (single-blind) Single dose of placebo via pMDI (double-blind)
    Measure Participants 6 7 6 7 7 7
    Mean (Standard Deviation) [L]
    0.133
    (0.1144)
    0.264
    (0.1012)
    0.255
    (0.0994)
    0.332
    (0.2095)
    0.477
    (0.1469)
    0.086
    (0.0694)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 6 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.253
    Confidence Interval (2-Sided) 95%
    1.151 to 1.363
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 3 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0022
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.146
    Confidence Interval (2-Sided) 95%
    1.054 to 1.246
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0295
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.102
    Confidence Interval (2-Sided) 95%
    1.010 to 1.202
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0098
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.129
    Confidence Interval (2-Sided) 95%
    1.032 to 1.235
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.54
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.028
    Confidence Interval (2-Sided) 95%
    0.939 to 1.125
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Part A: Change From Baseline in Average FEV1 (Over 4 Hours) After 1 Dose
    Description Change from Baseline FEV1 to Average FEV1 (over 4 hours) After Single Dose
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Full analysis set. () () () () () ()
    Arm/Group Title 0.10 mg 0.30 mg 1 mg 3 mg 6 mg Placebo
    Arm/Group Description Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (single-blind) Single dose of placebo via pMDI (double-blind)
    Measure Participants 6 7 6 7 7 7
    Mean (Standard Deviation) [L]
    0.058
    (0.0889)
    0.161
    (0.0650)
    0.153
    (0.0653)
    0.240
    (0.1677)
    0.334
    (0.1147)
    -0.011
    (0.0805)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 6 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.228
    Confidence Interval (2-Sided) 95%
    1.142 to 1.319
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 3 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.155
    Confidence Interval (2-Sided) 95%
    1.075 to 1.240
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0129
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.100
    Confidence Interval (2-Sided) 95%
    1.022 to 1.184
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0079
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.112
    Confidence Interval (2-Sided) 95%
    1.030 to 1.201
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.39
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.033
    Confidence Interval (2-Sided) 95%
    0.957 to 1.116
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Part A: Change From Baseline in Average FEV1 (Over 12 Hours) After 1 Dose
    Description Change from Baseline FEV1 to Average FEV1 (over 12 hours) After Single Dose
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Full analysis set.
    Arm/Group Title 0.10 mg 0.30 mg 1 mg 3 mg 6 mg Placebo
    Arm/Group Description Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (double-blind) Single dose of RPL554 via pMDI (single-blind) Single dose of placebo via pMDI (double-blind)
    Measure Participants 6 7 6 7 7 7
    Mean (Standard Deviation) [L]
    0.018
    (0.0643)
    0.061
    (0.0429)
    0.010
    (0.0408)
    0.121
    (0.1321)
    0.190
    (0.1053)
    -0.031
    (0.0740)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 6 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.137
    Confidence Interval (2-Sided) 95%
    1.073 to 1.204
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 3 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0041
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.091
    Confidence Interval (2-Sided) 95%
    1.030 to 1.155
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 1 mg, Placebo
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.53
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.019
    Confidence Interval (2-Sided) 95%
    0.960 to 1.081
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Part A: Safety and Tolerability / Hematology Safety Assessments
    Description Number of patients with treatment-emergent hematology abnormal laboratory assessments
    Time Frame 1 day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Secondary Outcome
    Title Part A: Safety and Tolerability / Blood Chemistry Safety Assessments: Number of Patients With Treatment-emergent Blood Chemistry Abnormal Laboratory Assessments
    Description Number of patients with treatment-emergent blood chemistry abnormal laboratory assessments
    Time Frame 1 day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Secondary Outcome
    Title Part A: Safety and Tolerability / Urinalysis Safety Assessments: Number of Patients With Treatment-emergent Urinalysis Abnormal Laboratory Assessments
    Description Number of patients with treatment-emergent urinalysis abnormal laboratory assessments
    Time Frame 1 day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    12. Secondary Outcome
    Title Part A: Safety and Tolerability / Supine Vitals Signs - Pulse Rate
    Description Number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm)
    Time Frame Start of treatment to day 1

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    13. Secondary Outcome
    Title Part A: Safety and Tolerability / Supine Vitals Signs - Blood Pressure
    Description Number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg)
    Time Frame Start of treatment to day 1

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    14. Secondary Outcome
    Title Part A: Safety and Tolerability / ECG - QTcF
    Description Number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec
    Time Frame Start of treatment to day 1

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    15. Secondary Outcome
    Title Part A: Safety and Tolerability / ECG - Heart Rate
    Description Number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm
    Time Frame Start of treatment to day 1

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    16. Secondary Outcome
    Title Part B: Change From Baseline in Average FEV1 (Over 4 Hrs) After 7 Days
    Description Change from baseline in average FEV1 (over 4 hours) on Day 7 after morning dose
    Time Frame Day 7

    Outcome Measure Data

    Analysis Population Description
    Full analysis set.
    Arm/Group Title 0.30 mg 1 mg 3 mg Placebo
    Arm/Group Description 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of placebo via MPI (double-blind) complete block, cross-over
    Measure Participants 22 22 22 23
    Mean (Standard Deviation) [L]
    0.083
    (0.1223)
    0.161
    (0.1686)
    0.206
    (0.1470)
    -0.095
    (0.1702)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 1 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.210
    Confidence Interval (2-Sided) 95%
    1.153 to 1.270
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.193
    Confidence Interval (2-Sided) 95%
    1.136 to 1.252
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.124
    Confidence Interval (2-Sided) 95%
    1.071 to 1.179
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    17. Secondary Outcome
    Title Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 7 Days
    Description Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 7 after morning dose
    Time Frame Day 7

    Outcome Measure Data

    Analysis Population Description
    Full analysis Set.
    Arm/Group Title 0.30 mg 1 mg 3 mg Placebo
    Arm/Group Description 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of placebo via MPI (double-blind) complete block, cross-over
    Measure Participants 22 22 22 23
    Mean (Standard Deviation) [L]
    0.008
    (0.1421)
    0.075
    (0.1472)
    0.085
    (0.1411)
    -0.112
    (0.1662)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 1 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.139
    Confidence Interval (2-Sided) 95%
    1.087 to 1.194
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.142
    Confidence Interval (2-Sided) 95%
    1.089 to 1.197
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0018
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.080
    Confidence Interval (2-Sided) 95%
    1.031 to 1.132
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    18. Secondary Outcome
    Title Part B: Change From Baseline in Trough FEV1 After 7 Days
    Description Change from Baseline FEV1 to Morning Trough FEV1 on Day 7 after morning dose
    Time Frame Day 7

    Outcome Measure Data

    Analysis Population Description
    Full analysis set.
    Arm/Group Title 0.30 mg 1 mg 3 mg Placebo
    Arm/Group Description 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of placebo via MPI (double-blind) complete block, cross-over
    Measure Participants 22 22 22 23
    Mean (Standard Deviation) [L]
    -0.051
    (0.1254)
    -0.017
    (0.1783)
    0.013
    (0.1631)
    -0.097
    (0.1389)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 1 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0066
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.080
    Confidence Interval (2-Sided) 95%
    1.022 to 1.140
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0115
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.074
    Confidence Interval (2-Sided) 95%
    1.017 to 1.134
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.18
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.037
    Confidence Interval (2-Sided) 95%
    0.982 to 1.096
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    19. Secondary Outcome
    Title Part B: Change From Baseline in Peak FEV1 (Over 4 Hours) After 1st Dose
    Description Change from baseline FEV1 in peak FEV1 (over 4 hours) after first dose
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Full analysis set.
    Arm/Group Title 0.30 mg 1 mg 3 mg Placebo
    Arm/Group Description 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of placebo via MPI (double-blind) complete block, cross-over
    Measure Participants 22 23 22 23
    Mean (Standard Deviation) [L]
    0.253
    (0.0772)
    0.311
    (0.1532)
    0.337
    (0.1108)
    0.079
    (0.0914)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 1 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.162
    Confidence Interval (2-Sided) 95%
    1.122 to 1.203
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.150
    Confidence Interval (2-Sided) 95%
    1.111 to 1.190
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.112
    Confidence Interval (2-Sided) 95%
    1.074 to 1.152
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    20. Secondary Outcome
    Title Part B: Change From Baseline in Average FEV1 (Over 4 Hours) After 1st Dose
    Description Change from baseline FEV1 in average FEV1 (over 4 hours) on Day 1
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    Full analysis set.
    Arm/Group Title 0.30 mg 1 mg 3 mg Placebo
    Arm/Group Description 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of placebo via MPI (double-blind) complete block, cross-over
    Measure Participants 22 23 22 23
    Mean (Standard Deviation) [L]
    0.144
    (0.0762)
    0.204
    (0.1162)
    0.224
    (0.0905)
    -0.017
    (0.1284)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 1 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.157
    Confidence Interval (2-Sided) 95%
    1.119 to 1.196
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.147
    Confidence Interval (2-Sided) 95%
    1.110 to 1.186
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.105
    Confidence Interval (2-Sided) 95%
    1.068 to 1.142
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    21. Secondary Outcome
    Title Part B: Change From Baseline in Average FEV1 (Over 12 Hours) After 1st Dose
    Description Change from baseline FEV1 in average FEV1 (over 12 hours) on Day 1
    Time Frame Day 1

    Outcome Measure Data

    Analysis Population Description
    number of patients with at least one on treatment value who contributed to the model.
    Arm/Group Title 0.30 mg 1 mg 3 mg Placebo
    Arm/Group Description 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of placebo via MPI (double-blind) complete block, cross-over
    Measure Participants 22 23 22 23
    Mean (Standard Deviation) [L]
    0.047
    (0.0914)
    0.102
    (0.1306)
    0.085
    (0.0659)
    -0.058
    (0.1444)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 1 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.098
    Confidence Interval (2-Sided) 95%
    1.059 to 1.137
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.111
    Confidence Interval (2-Sided) 95%
    1.072 to 1.150
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, 3 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0003
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter GeoMean Ratio
    Estimated Value 1.070
    Confidence Interval (2-Sided) 5%
    1.033 to 1.109
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    22. Secondary Outcome
    Title Part B: RPL554 Plasma Pharmacokinetic Parameter (Onset of Action)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Patients with onset of action
    Arm/Group Title 0.30 mg 1 mg 3 mg
    Arm/Group Description 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over 7 day, twice daily dose of RPL554 via MPI (double-blind) complete block, cross-over
    Measure Participants 18 19 22
    Median (Full Range) [mins]
    37.0
    27.5
    19.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection 0.30 mg, 1 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.47
    Comments
    Method Hodges-Lehmann
    Comments
    Method of Estimation Estimation Parameter Median Difference (Final Values)
    Estimated Value 8.5
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection 0.10 mg, 1 mg
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0059
    Comments
    Method Hodges-Lehmann
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 18.0
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    23. Secondary Outcome
    Title Part B: Safety and Tolerability / Hematology Safety Assessments
    Description Number of patients with treatment-emergent hematology abnormal laboratory assessments
    Time Frame 1 day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    24. Secondary Outcome
    Title Part B: Safety and Tolerability / Blood Chemistry Safety Assessments
    Description Number of patients with treatment-emergent blood chemistry abnormal laboratory assessments
    Time Frame 1 day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    25. Secondary Outcome
    Title Part B: Safety and Tolerability / Urinalysis Safety Assessments
    Description Number of patients with treatment-emergent urinalysis abnormal laboratory assessments
    Time Frame 1 day

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    26. Secondary Outcome
    Title Part B: Safety and Tolerability / Supine Vital Signs - Pulse Rate
    Description Number of patients with treatment-emergent abnormal vital signs (pulse rate in bpm)
    Time Frame Start of treatment to day 1

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    27. Secondary Outcome
    Title Part B: Safety and Tolerability / Supine Vital Signs - Blood Pressure
    Description Number of patients with treatment-emergent abnormal vital signs (blood pressure in mm Hg)
    Time Frame Start of treatment to day 1

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    28. Secondary Outcome
    Title Part B: Safety and Tolerability / ECG - QTcF
    Description Number of patients with treatment-emergent abnormal ECG parameters, QTcF in msec
    Time Frame Start of treatment to day 70

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    29. Secondary Outcome
    Title Part B: Safety and Tolerability / ECG - Heart Rate
    Description Number of patients with treatment-emergent abnormal ECG parameters, heart rate in bpm
    Time Frame Start of treatment to day 70

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame Part A: 24 hours. Part B: Approximately 70 days
    Adverse Event Reporting Description
    Arm/Group Title 0.10 mg/Part A 0.30 mg/Part A 1 mg/Part A 3 mg/Part A 6 mg/Part A Placebo/Part A Part B/0.30 mg Part B/1 mg Part B/3 mg Part B/Placebo
    Arm/Group Description Part A: single dose of RPL554 via pMDI (double-blind) Part A: single dose of RPL554 via pMDI (double-blind) Part A: single dose of RPL554 via pMDI (double-blind) Part A: single dose of RPL554 via pMDI (double-blind) Part A: single dose of RPL554 via pMDI (single-blind) Part A: single dose via pMDI (double-blind) Part B: 7 day, twice daily dose of RPL554 via pMDI (double-blind) complete block, cross-over. Part B: 7 day, twice daily dose of RPL554 via pMDI (double-blind) complete block, cross-over. Part B: 7 day, twice daily dose of RPL554 via pMDI (double-blind) complete block, cross-over. Part B: 7 day, twice daily dose of placebo via pMDI (double-blind) complete block, cross-over.
    All Cause Mortality
    0.10 mg/Part A 0.30 mg/Part A 1 mg/Part A 3 mg/Part A 6 mg/Part A Placebo/Part A Part B/0.30 mg Part B/1 mg Part B/3 mg Part B/Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Serious Adverse Events
    0.10 mg/Part A 0.30 mg/Part A 1 mg/Part A 3 mg/Part A 6 mg/Part A Placebo/Part A Part B/0.30 mg Part B/1 mg Part B/3 mg Part B/Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Other (Not Including Serious) Adverse Events
    0.10 mg/Part A 0.30 mg/Part A 1 mg/Part A 3 mg/Part A 6 mg/Part A Placebo/Part A Part B/0.30 mg Part B/1 mg Part B/3 mg Part B/Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/6 (33.3%) 1/7 (14.3%) 1/6 (16.7%) 2/7 (28.6%) 4/7 (57.1%) 2/7 (28.6%) 3/24 (12.5%) 4/23 (17.4%) 2/23 (8.7%) 3/25 (12%)
    Gastrointestinal disorders
    Dental caries 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 1/23 (4.3%) 0/23 (0%) 0/25 (0%)
    Flatulence 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 1/25 (4%)
    General disorders
    Catheter site bruise 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 1/23 (4.3%) 0/25 (0%)
    Infections and infestations
    Nasopharyngitis 0/6 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 1/7 (14.3%) 1/7 (14.3%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Rhinitis 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/7 (14.3%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Upper respiratory tract infection 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 1/7 (14.3%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Kidney infection 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 1/23 (4.3%) 0/25 (0%)
    Injury, poisoning and procedural complications
    Contusion 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/7 (14.3%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 1/23 (4.3%) 0/23 (0%) 0/25 (0%)
    Nervous system disorders
    Headache 0/6 (0%) 0/7 (0%) 1/6 (16.7%) 1/7 (14.3%) 2/7 (28.6%) 1/7 (14.3%) 1/24 (4.2%) 1/23 (4.3%) 0/23 (0%) 0/25 (0%)
    Syncope 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Dizziness postural 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 1/24 (4.2%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Renal and urinary disorders
    Renal cyst 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 1/23 (4.3%) 0/25 (0%)
    Reproductive system and breast disorders
    Dysmenorrhoea 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 1/23 (4.3%) 0/23 (0%) 0/25 (0%)
    Respiratory, thoracic and mediastinal disorders
    COPD 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 1/25 (4%)
    Dry throat 1/6 (16.7%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Productive cough 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 1/7 (14.3%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)
    Dyspnoea 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 1/24 (4.2%) 0/23 (0%) 0/23 (0%) 1/25 (4%)
    Haemoptysis 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 1/23 (4.3%) 0/25 (0%)
    Sputum increased 0/6 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 1/25 (4%)
    Skin and subcutaneous tissue disorders
    Dermatitis contact 0/6 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/7 (0%) 0/7 (0%) 0/24 (0%) 0/23 (0%) 0/23 (0%) 0/25 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Medical Science Director
    Organization Verona Pharma
    Phone 6464130307
    Email margot.macdonald-berko@veronapharma.com
    Responsible Party:
    Verona Pharma plc
    ClinicalTrials.gov Identifier:
    NCT04091360
    Other Study ID Numbers:
    • RPL554-MD-201
    First Posted:
    Sep 16, 2019
    Last Update Posted:
    Jul 25, 2022
    Last Verified:
    Jul 1, 2022