Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A PHASE II, RANDOMISED, DOUBLE BLIND, PLACEBO CONTROLLED, THREE WAY CROSSOVER STUDY TO ASSESS THE BRONCHODILATOR EFFECT OF RPL554 ADMINISTERED IN ADDITION TO OPEN LABEL TIOTROPIUM/OLODATEROL IN PATIENTS WITH COPD

    Summary
    EudraCT number
    		 2018-001037-41
    Trial protocol
    		 GB  
    Global end of trial date
    13 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Aug 2019
    First version publication date
    18 Aug 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RPL554-CO-204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03673670
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Verona Pharma plc
    Sponsor organisation address
    3 More London Riverside, London, United Kingdom, SE12RE
    Public contact
    Paula Siu, Verona Pharma plc, 44 2032834200, paula.siu@veronapharma.com
    Scientific contact
    Paula Siu, Verona Pharma plc, 44 2032834200, paula.siu@veronapharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the bronchodilator effect on peak forced expired volume in 1 second (FEV1) (measured in the first 4 hours after dosing) of nebulised RPL554 dosed twice daily for 3 days, as compared to placebo, when administered in addition to once daily tiotropium/olodaterol. The peak FEV1 is measured after the morning dose on Day 3.)
    Protection of trial subjects
    Standard procedures for emergency care were followed for any individual adverse events if clinically needed. Short acting bronchodilators could be used as rescue medication.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jul 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 75
    Worldwide total number of subjects
    79
    EEA total number of subjects
    4
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    41
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were recruited in the United States of America and the United Kingdom. The first patient was consented on 16 July 2018.

    Pre-assignment
    Screening details
    		 A total of 142 patients were screened, of which 63 screen failed and 79 were treated

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1.5 mg RPL554: 6 mg RPL554: Placebo
    Arm description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    1.5 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    1.5 mg administered using a jet nebuliser

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Arm title
    		 1.5 mg RPL554: Placebo: 6 mg RPL554
    Arm description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    1.5 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    1.5 mg administered using a jet nebuliser

    Arm title
    		 6 mg RPL554: 1.5 mg RPL554: Placebo
    Arm description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    6 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    6 mg RPL554 administered using a Jet nebuliser

    Arm title
    		 6 mg RPL554: Placebo: 1.5 mg RPL554
    Arm description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    6 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    6 mg RPL554 administered using a Jet nebuliser

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Arm title
    		 Placebo: 1.5 mg RPL554: 6 mg RPL554
    Arm description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo administered using a Jet nebulider

    Arm title
    		 Placebo: 6 mg RPL554: 1.5 mg RPL554
    Arm description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo administered using a Jet nebulider

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Number of subjects in period 1
    		1.5 mg RPL554: 6 mg RPL554: Placebo 1.5 mg RPL554: Placebo: 6 mg RPL554 6 mg RPL554: 1.5 mg RPL554: Placebo 6 mg RPL554: Placebo: 1.5 mg RPL554 Placebo: 1.5 mg RPL554: 6 mg RPL554 Placebo: 6 mg RPL554: 1.5 mg RPL554
    Started
    14
    14
    13
    12
    13
    13
    Completed
    13
    14
    12
    12
    13
    11
    Not completed
    1
    0
    1
    0
    0
    2
         Consent withdrawn by subject
    1
    -
    -
    -
    -
    -
         Physician decision
    -
    -
    1
    -
    -
    -
         Alpha 1 antitrypsin deficiency
    -
    -
    -
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    1
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1.5 mg RPL554: 6 mg RPL554: Placebo
    Arm description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    6 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    6 mg RPL554 administered using a Jet nebuliser

    Arm title
    		 1.5 mg RPL554: Placebo: 6 mg RPL554
    Arm description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo administered using a Jet nebulider

    Arm title
    		 6 mg RPL554: 1.5 mg RPL554: Placebo
    Arm description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    1.5 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    1.5 mg administered using a jet nebuliser

    Arm title
    		 6 mg RPL554: Placebo: 1.5 mg RPL554
    Arm description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo administered using a Jet nebulider

    Arm title
    		 Placebo: 1.5 mg RPL554: 6 mg RPL554
    Arm description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    1.5 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    1.5 mg administered using a jet nebuliser

    Arm title
    		 Placebo: 6 mg RPL554: 1.5 mg RPL554
    Arm description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    6 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    6 mg RPL554 administered using a Jet nebuliser

    Number of subjects in period 2
    		1.5 mg RPL554: 6 mg RPL554: Placebo 1.5 mg RPL554: Placebo: 6 mg RPL554 6 mg RPL554: 1.5 mg RPL554: Placebo 6 mg RPL554: Placebo: 1.5 mg RPL554 Placebo: 1.5 mg RPL554: 6 mg RPL554 Placebo: 6 mg RPL554: 1.5 mg RPL554
    Started
    13
    14
    12
    12
    13
    11
    Completed
    13
    14
    11
    12
    12
    11
    Not completed
    0
    0
    1
    0
    1
    0
         Adverse event, non-fatal
    -
    -
    1
    -
    1
    -
    Period 3
    Period 3 title
    Treatment Period 3
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1.5 mg RPL554: 6 mg RPL554: Placebo
    Arm description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo administered using a Jet nebulider

    Arm title
    		 1.5 mg RPL554: Placebo: 6 mg RPL554
    Arm description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    6 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    6 mg RPL554 administered using a Jet nebuliser

    Arm title
    		 6 mg RPL554: 1.5 mg RPL554: Placebo
    Arm description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo administered using a Jet nebulider

    Arm title
    		 6 mg RPL554: Placebo: 1.5 mg RPL554
    Arm description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    1.5 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    1.5 mg administered using a jet nebuliser

    Arm title
    		 Placebo: 1.5 mg RPL554: 6 mg RPL554
    Arm description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    6 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    6 mg RPL554 administered using a Jet nebuliser

    Arm title
    		 Placebo: 6 mg RPL554: 1.5 mg RPL554
    Arm description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    5/5 mcg from a Respimat device

    Investigational medicinal product name
    1.5 mg RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    1.5 mg administered using a jet nebuliser

    Number of subjects in period 3
    		1.5 mg RPL554: 6 mg RPL554: Placebo 1.5 mg RPL554: Placebo: 6 mg RPL554 6 mg RPL554: 1.5 mg RPL554: Placebo 6 mg RPL554: Placebo: 1.5 mg RPL554 Placebo: 1.5 mg RPL554: 6 mg RPL554 Placebo: 6 mg RPL554: 1.5 mg RPL554
    Started
    13
    14
    11
    12
    12
    11
    Completed
    13
    14
    11
    12
    10
    11
    Not completed
    0
    0
    0
    0
    2
    0
         Adverse event, non-fatal
    -
    -
    -
    -
    1
    -
         Pre-dose FEV1 not 20% of baseline
    -
    -
    -
    -
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period 1 Total
    Number of subjects
    		 79 79
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age at the time of informed consent
    Units: years
        median (full range (min-max))
    		 64.0 (43 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 49 49
        Male
    		 30 30

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    1.5 mg RPL554: 6 mg RPL554: Placebo
    Reporting group description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    1.5 mg RPL554: Placebo: 6 mg RPL554
    Reporting group description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    6 mg RPL554: 1.5 mg RPL554: Placebo
    Reporting group description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    6 mg RPL554: Placebo: 1.5 mg RPL554
    Reporting group description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    Placebo: 1.5 mg RPL554: 6 mg RPL554
    Reporting group description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    Placebo: 6 mg RPL554: 1.5 mg RPL554
    Reporting group description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Reporting group title
    1.5 mg RPL554: 6 mg RPL554: Placebo
    Reporting group description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    1.5 mg RPL554: Placebo: 6 mg RPL554
    Reporting group description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    6 mg RPL554: 1.5 mg RPL554: Placebo
    Reporting group description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    6 mg RPL554: Placebo: 1.5 mg RPL554
    Reporting group description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    Placebo: 1.5 mg RPL554: 6 mg RPL554
    Reporting group description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    Placebo: 6 mg RPL554: 1.5 mg RPL554
    Reporting group description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods
    Reporting group title
    1.5 mg RPL554: 6 mg RPL554: Placebo
    Reporting group description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    1.5 mg RPL554: Placebo: 6 mg RPL554
    Reporting group description
    		 Patients received 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    6 mg RPL554: 1.5 mg RPL554: Placebo
    Reporting group description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    6 mg RPL554: Placebo: 1.5 mg RPL554
    Reporting group description
    		 Patients received 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    Placebo: 1.5 mg RPL554: 6 mg RPL554
    Reporting group description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Reporting group title
    Placebo: 6 mg RPL554: 1.5 mg RPL554
    Reporting group description
    		 Patients received placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 1, 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 2 then 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days in Treatment Period 3 with a 7-14 day washout between treatment periods

    Subject analysis set title
    1.5 mg RPL554
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who received 1.5 mg RPL554 and had data to compute the pharmacodynamic parameters

    Subject analysis set title
    6 mg RPL554
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who received 6 mg RPL554 and had data to compute the pharmacodynamic parameters

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients who received placebo and had data to compute the pharmacodynamic parameters

    Primary: Change From Baseline in Peak FEV1 on Day 3

    		 Close Top of page
    End point title
    		 Change From Baseline in Peak FEV1 on Day 3
    End point description
    Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the morning dose on Day 3
    End point type
    Primary
    End point timeframe
    Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4 on Day 3 (after the morning dose)
    End point values
    		 1.5 mg RPL554 6 mg RPL554 Placebo
    Number of subjects analysed
    74
    73
    73
    Units: Litres
        arithmetic mean (standard deviation)
    0.565 ( 0.2783 )
    0.506 ( 0.2506 )
    0.519 ( 0.2809 )
    Statistical analysis title
    		 1.5 mg RPL554 placebo-corrected treatment effect
    Comparison groups
    Placebo v 1.5 mg RPL554
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.168
    Method
    		 ANCOVA
    Parameter type
    		 Geomean ratio
    Point estimate
    1.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.991
         upper limit
    		 1.052
    Notes
    [1] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 placebo-corrected treatment effect
    Comparison groups
    6 mg RPL554 v Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.731
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    0.995
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.966
         upper limit
    		 1.025
    Notes
    [2] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 lower-dose corrected treatment effect
    Comparison groups
    1.5 mg RPL554 v 6 mg RPL554
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.088
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    0.974
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.946
         upper limit
    		 1.004
    Notes
    [3] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.

    Secondary: Change From Baseline to Trough FEV1 on Day 4

    		 Close Top of page
    End point title
    		 Change From Baseline to Trough FEV1 on Day 4
    End point description
    Change from baseline to morning trough FEV1 on Day 4
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 4
    End point values
    		 1.5 mg RPL554 6 mg RPL554 Placebo
    Number of subjects analysed
    74
    73
    73
    Units: Litres
        arithmetic mean (standard deviation)
    0.186 ( 0.2496 )
    0.178 ( 0.2123 )
    0.150 ( 0.2218 )
    Statistical analysis title
    		 1.5 mg RPL554 placebo-corrected treatment effect
    Comparison groups
    1.5 mg RPL554 v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.115
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.994
         upper limit
    		 1.055
    Notes
    [4] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 placebo-corrected treatme...
    Comparison groups
    Placebo v 6 mg RPL554
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.111
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.994
         upper limit
    		 1.055
    Notes
    [5] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 lower dose-corrected treatme...
    Comparison groups
    6 mg RPL554 v 1.5 mg RPL554
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.978
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.971
         upper limit
    		 1.03
    Notes
    [6] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.

    Secondary: Change From Baseline in AUC0-4h FEV1 on Day 3

    		 Close Top of page
    End point title
    		 Change From Baseline in AUC0-4h FEV1 on Day 3
    End point description
    Change from baseline FEV1 to AUC FEV1 over 4 hours post-dose after the morning dose on Day 3
    End point type
    Secondary
    End point timeframe
    Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the morning dose)
    End point values
    		 1.5 mg RPL554 6 mg RPL554 Placebo
    Number of subjects analysed
    74
    73
    73
    Units: Litres
        arithmetic mean (standard deviation)
    0.429 ( 0.2518 )
    0.390 ( 0.2246 )
    0.377 ( 0.2485 )
    Statistical analysis title
    		 1.5 mg RPL554 placebo-corrected treatment effect
    Comparison groups
    1.5 mg RPL554 v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.039
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.002
         upper limit
    		 1.058
    Notes
    [7] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 placebo-corrected treatme...
    Comparison groups
    Placebo v 6 mg RPL554
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.303
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.987
         upper limit
    		 1.043
    Notes
    [8] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 lower dose-corrected treatme...
    Comparison groups
    6 mg RPL554 v 1.5 mg RPL554
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.294
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    0.985
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.958
         upper limit
    		 1.013
    Notes
    [9] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.

    Secondary: Change From Baseline in Peak FEV1 on Day 1

    		 Close Top of page
    End point title
    		 Change From Baseline in Peak FEV1 on Day 1
    End point description
    Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the morning dose on Day 1
    End point type
    Secondary
    End point timeframe
    Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 1 (after the morning dose)
    End point values
    		 1.5 mg RPL554 6 mg RPL554 Placebo
    Number of subjects analysed
    74
    73
    73
    Units: Litres
        arithmetic mean (standard deviation)
    0.490 ( 0.2219 )
    0.467 ( 0.2393 )
    0.445 ( 0.2306 )
    Statistical analysis title
    		 1.5 mg RPL554 placebo-corrected treatment effect
    Comparison groups
    1.5 mg RPL554 v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.02
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.005
         upper limit
    		 1.061
    Notes
    [10] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 placebo-corrected treatme...
    Comparison groups
    Placebo v 6 mg RPL554
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.404
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.012
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.984
         upper limit
    		 1.039
    Notes
    [11] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 lower dose-corrected treatme...
    Comparison groups
    6 mg RPL554 v 1.5 mg RPL554
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.134
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.953
         upper limit
    		 1.006
    Notes
    [12] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.

    Secondary: Change From Baseline in AUC0-12h FEV1 on Day 3

    		 Close Top of page
    End point title
    		 Change From Baseline in AUC0-12h FEV1 on Day 3
    End point description
    Change from baseline in AUC over 12 hours post-dose after the morning dose on Day 3
    End point type
    Secondary
    End point timeframe
    Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 3 (after the morning dose)
    End point values
    		 1.5 mg RPL554 6 mg RPL554 Placebo
    Number of subjects analysed
    74
    73
    73
    Units: Litres
        arithmetic mean (standard deviation)
    0.390 ( 0.2426 )
    0.347 ( 0.2219 )
    0.337 ( 0.2447 )
    Statistical analysis title
    		 1.5 mg RPL554 placebo-corrected treatment effect
    Comparison groups
    1.5 mg RPL554 v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.067
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean Ratio
    Point estimate
    1.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.998
         upper limit
    		 1.057
    Notes
    [13] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 placebo-corrected treatme...
    Comparison groups
    Placebo v 6 mg RPL554
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.395
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean Ratio
    Point estimate
    1.012
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.984
         upper limit
    		 1.042
    Notes
    [14] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 lower dose-corrected treatme...
    Comparison groups
    6 mg RPL554 v 1.5 mg RPL554
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.324
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean Ratio
    Point estimate
    0.986
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.958
         upper limit
    		 1.015
    Notes
    [15] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.

    Secondary: Change From Baseline in Peak FEV1 After Evening Dose on Day 3

    		 Close Top of page
    End point title
    		 Change From Baseline in Peak FEV1 After Evening Dose on Day 3
    End point description
    Change from baseline FEV1 to peak FEV1 in the 4 hours post-dose after the evening dose on Day 3
    End point type
    Secondary
    End point timeframe
    Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4 hours on Day 3 (after the evening dose)
    End point values
    		 1.5 mg RPL554 6 mg RPL554 Placebo
    Number of subjects analysed
    74
    73
    73
    Units: Litres
        arithmetic mean (standard deviation)
    0.453 ( 0.2625 )
    0.405 ( 0.2581 )
    0.324 ( 0.2211 )
    Statistical analysis title
    		 1.5 mg RPL554 placebo-corrected treatment effect
    Comparison groups
    1.5 mg RPL554 v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.043
         upper limit
    		 1.123
    Notes
    [16] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 placebo-corrected treatme...
    Comparison groups
    Placebo v 6 mg RPL554
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.023
         upper limit
    		 1.101
    Notes
    [17] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 lower dose-corrected treatme...
    Comparison groups
    6 mg RPL554 v 1.5 mg RPL554
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.288
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.945
         upper limit
    		 1.017
    Notes
    [18] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.

    Secondary: Change From Baseline in AUC0-12h FEV1 on Day 1

    		 Close Top of page
    End point title
    		 Change From Baseline in AUC0-12h FEV1 on Day 1
    End point description
    Change from baseline FEV1 to AUC FEV1 over 12 hours post-dose after the morning dose on Day 1
    End point type
    Secondary
    End point timeframe
    Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8, 12 hours on Day 1 (after the morning dose)
    End point values
    		 1.5 mg RPL554 6 mg RPL554 Placebo
    Number of subjects analysed
    74
    73
    73
    Units: Litres
        arithmetic mean (standard deviation)
    0.333 ( 0.1815 )
    0.308 ( 0.1854 )
    0.303 ( 0.1920 )
    Statistical analysis title
    		 1.5 mg RPL554 placebo-corrected treatment effect
    Comparison groups
    1.5 mg RPL554 v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.096
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.997
         upper limit
    		 1.043
    Notes
    [19] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 placebo-corrected treatme...
    Comparison groups
    Placebo v 6 mg RPL554
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.862
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    1.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.979
         upper limit
    		 1.025
    Notes
    [20] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.
    Statistical analysis title
    		 6 mg RPL554 lower dose-corrected treatme...
    Comparison groups
    6 mg RPL554 v 1.5 mg RPL554
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.135
    Method
    		 ANCOVA
    Parameter type
    		 GeoMean ratio
    Point estimate
    0.983
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.006
    Notes
    [21] - A hierarchical fixed-sequence testing strategy was employed to test the significance of the treatment effect for each of the two RPL554 doses against placebo, starting with the highest dose (6 mg). If a statistically significant difference was found at the 2-sided α level of 5%, the testing proceeded with the next highest dose. Otherwise, testing was stopped, and the remaining null hypotheses were accepted without testing.

    Secondary: Determination of Onset of Action on Day 1

    		 Close Top of page
    End point title
    		 Determination of Onset of Action on Day 1
    End point description
    Time to >10% increase in FEV1 from pre-first dose, censored at 2 hours
    End point type
    Secondary
    End point timeframe
    Pre-dose; 5, 15 and 30 minutes and 1, 1.5, 2 hours on Day 1 (after the morning dose)
    End point values
    		 1.5 mg RPL554 6 mg RPL554 Placebo
    Number of subjects analysed
    74
    73
    73
    Units: Hours
        median (full range (min-max))
    10 (5 to 15)
    6 (5 to 12)
    11 (6 to 14)
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From informed consent until the end of the study
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    1.5 mg RPL554
    Reporting group description
    		 1.5 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days

    Reporting group title
    6 mg Dose RPL554
    Reporting group description
    		 6 mg RPL554 twice daily plus tiotropium 5/5 mcg once daily for 3 days

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo twice daily plus tiotropium 5/5 mcg once daily for 3 days

    Serious adverse events
    		 1.5 mg RPL554 6 mg Dose RPL554 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 76 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 1.5 mg RPL554 6 mg Dose RPL554 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 75 (20.00%)
    15 / 74 (20.27%)
    8 / 76 (10.53%)
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
    0 / 76 (0.00%)
         occurrences all number
    1
    1
    0
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 75 (0.00%)
    2 / 74 (2.70%)
    1 / 76 (1.32%)
         occurrences all number
    0
    2
    1
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 75 (2.67%)
    3 / 74 (4.05%)
    0 / 76 (0.00%)
         occurrences all number
    3
    3
    0
    Accelerated idioventricular rhythm
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    1
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 75 (6.67%)
    5 / 74 (6.76%)
    1 / 76 (1.32%)
         occurrences all number
    5
    6
    1
    Syncope
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Medical device site rash
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    0 / 76 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 74 (1.35%)
    1 / 76 (1.32%)
         occurrences all number
    0
    1
    1
    Chronic onstructive pulmonary disease
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 74 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 74 (1.35%)
    1 / 76 (1.32%)
         occurrences all number
    1
    1
    1
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    1 / 76 (1.32%)
         occurrences all number
    1
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 74 (0.00%)
    0 / 76 (0.00%)
         occurrences all number
    1
    0
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2018
    • Inclusion Criterion 3 clarified to specify that the time frames indicated for contraception use applied to both males and females. • Exclusion Criterion 4 updated to add atropine to list of drugs with known hypersensitivity.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Mon May 05 14:11:48 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA