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    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 in patients with COPD.

    Summary
    EudraCT number
    		 2016-004450-15
    Trial protocol
    		 GB  
    Global end of trial date
    24 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Aug 2018
    First version publication date
    09 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RPL554-CO-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Verona Pharma Plc
    Sponsor organisation address
    3 More London Riverside, London, United Kingdom, SE1 2RE
    Public contact
    Brian Maurer, Verona Pharma plc, +44 203 283 4200, brian.maurer@veronapharma.com
    Scientific contact
    Brian Maurer, Verona Pharma plc, +44 203 283 4200, brian.maurer@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
    25 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the bronchodilator effect on peak FEV1 measured in first 4 hours after dosing and average FEV1 over 12 hours of nebulised RPL554, dosed twice daily for 3 days (five total doses), as compared to placebo when administered in addition to once daily tiotropium.
    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
    27 Jan 2017
    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: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    15
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was consented on 27 January 2017. Overall, 74 patients were screened for the study and 30 were treated. Patients received study treatment between 14 February 2017 and 07 July 2017. A total of 26 patients completed the study and 4 were withdrawn.

    Pre-assignment
    Screening details
    		 74 were screened. The main reasons for screen failure were reversibility test criteria not met (21 patients), withdrew consent (5 patients) and unsuitable COPD history (4 patients). Patients had to discontinue long acting bronchodilators on the day prior to screening and short acting bronchodilators for 8 hours before all spirometry assessments

    Period 1
    Period 1 title
    Overall trial (overall period)
    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
    No

    Arm title
    		 Tiotropium+1.5 mg RPL554
    Arm description
    		 18 mcg tiotropium once daily and 1.5 mg RPL554 twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    18 mcg tiotropium administered by dry powder inhaler

    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 RPL554 administered using a nebuliser

    Arm title
    		 Tiotropium+6 mg RPL554
    Arm description
    		 18 mcg tiotropium once daily and 6 mg RPL554 twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    18 mcg tiotropium administered by dry powder inhaler

    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 nebuliser

    Arm title
    		 Tiotropium+placebo
    Arm description
    		 18 mcg tiotropium once daily and placebo twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    18 mcg tiotropium administered by dry powder inhaler

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

    Number of subjects in period 1
    		Tiotropium+1.5 mg RPL554 Tiotropium+6 mg RPL554 Tiotropium+placebo
    Started
    29
    27
    28
    Completed
    29
    27
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 30 30
    Age categorical
    Age at time of informed consent
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 15 15
        From 65-84 years
    		 15 15
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 64.5 (47 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 13 13
        Male
    		 17 17

    End points

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    End points reporting groups
    Reporting group title
    Tiotropium+1.5 mg RPL554
    Reporting group description
    		 18 mcg tiotropium once daily and 1.5 mg RPL554 twice daily

    Reporting group title
    Tiotropium+6 mg RPL554
    Reporting group description
    		 18 mcg tiotropium once daily and 6 mg RPL554 twice daily

    Reporting group title
    Tiotropium+placebo
    Reporting group description
    		 18 mcg tiotropium once daily and placebo twice daily

    Primary: Peak FEV1 on Day 3

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    End point title
    		 Peak FEV1 on Day 3
    End point description
    Change from baseline in peak FEV1
    End point type
    Primary
    End point timeframe
    Over 4 hours after morning dosing on Day 3
    End point values
    		 Tiotropium+1.5 mg RPL554 Tiotropium+6 mg RPL554 Tiotropium+placebo
    Number of subjects analysed
    28
    27
    27
    Units: Litres
        arithmetic mean (standard deviation)
    0.477 ( 0.1673 )
    0.500 ( 0.2157 )
    0.373 ( 0.1970 )
    Statistical analysis title
    		 Tiotropium+1.5 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+1.5 mg RPL554 v Tiotropium+placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0022
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.09
    Statistical analysis title
    		 Tiotropium+6 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+placebo v Tiotropium+6 mg RPL554
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Ratio
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 1.12

    Primary: Area under the curve over 12 hours for FEV1 on Day 3

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    End point title
    		 Area under the curve over 12 hours for FEV1 on Day 3
    End point description
    Change from baseline in area under the curve for FEV1 over 12 hours
    End point type
    Primary
    End point timeframe
    Over 12 hours after morning dosing on Day 3
    End point values
    		 Tiotropium+1.5 mg RPL554 Tiotropium+6 mg RPL554 Tiotropium+placebo
    Number of subjects analysed
    28
    27
    27
    Units: Litres*hour
        arithmetic mean (standard deviation)
    3.804 ( 1.8512 )
    3.967 ( 2.2134 )
    3.197 ( 2.2826 )
    Statistical analysis title
    		 Tiotropium+1.5 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+1.5 mg RPL554 v Tiotropium+placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0988
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.06
    Statistical analysis title
    		 Tiotropium+6 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+6 mg RPL554 v Tiotropium+placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0009
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.09

    Secondary: Peak FEV1 on Day 1

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    End point title
    		 Peak FEV1 on Day 1
    End point description
    Change from baseline in peak FEV1
    End point type
    Secondary
    End point timeframe
    Over 4 hours after morning dosing on Day 1
    End point values
    		 Tiotropium+1.5 mg RPL554 Tiotropium+6 mg RPL554 Tiotropium+placebo
    Number of subjects analysed
    28
    27
    27
    Units: Litres
        arithmetic mean (standard deviation)
    0.383 ( 0.1448 )
    0.432 ( 0.1720 )
    0.337 ( 0.1854 )
    Statistical analysis title
    		 Tiotropium+1.5 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+placebo v Tiotropium+1.5 mg RPL554
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2496
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.06
    Statistical analysis title
    		 Tiotropium+6 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+6 mg RPL554 v Tiotropium+placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0039
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.1

    Secondary: Area under the curve over 12 hours for FEV1 on Day 1

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    End point title
    		 Area under the curve over 12 hours for FEV1 on Day 1
    End point description
    Change from baseline in area under the curve for FEV1 over 12 hours
    End point type
    Secondary
    End point timeframe
    Over 12 hours after morning dosing on Day 1
    End point values
    		 Tiotropium+1.5 mg RPL554 Tiotropium+6 mg RPL554 Tiotropium+placebo
    Number of subjects analysed
    28
    27
    27
    Units: Litres*hour
        arithmetic mean (standard deviation)
    3.058 ( 1.4851 )
    3.094 ( 1.9624 )
    2.510 ( 1.9381 )
    Statistical analysis title
    		 Tiotropium+1.5 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+1.5 mg RPL554 v Tiotropium+placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1404
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.06
    Statistical analysis title
    		 Tiotropium+6 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+6 mg RPL554 v Tiotropium+placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0228
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 1.08

    Secondary: Area under the curve over 4 hours on Day 1

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    End point title
    		 Area under the curve over 4 hours on Day 1
    End point description
    Change from baseline in area under the curve for FEV1 over 4 hours
    End point type
    Secondary
    End point timeframe
    Over 4 hours after morning dosing on Day 1
    End point values
    		 Tiotropium+1.5 mg RPL554 Tiotropium+6 mg RPL554 Tiotropium+placebo
    Number of subjects analysed
    28
    27
    27
    Units: Litres*hour
        arithmetic mean (standard deviation)
    1.208 ( 0.5740 )
    1.376 ( 0.6630 )
    0.894 ( 0.6161 )
    Statistical analysis title
    		 Tiotropium+1.5 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+1.5 mg RPL554 v Tiotropium+placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0073
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 1.08
    Statistical analysis title
    		 Tiotropium+6 mg RPL554 versus tiotropium+placebo
    Comparison groups
    Tiotropium+6 mg RPL554 v Tiotropium+placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 1.12

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent until the end of the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Tiotropium+1.5 mg RPL554
    Reporting group description
    		 -

    Reporting group title
    Tiotropium+6 mg RPL554
    Reporting group description
    		 -

    Reporting group title
    Tiotropium+placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Tiotropium+1.5 mg RPL554 Tiotropium+6 mg RPL554 Tiotropium+placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Tiotropium+1.5 mg RPL554 Tiotropium+6 mg RPL554 Tiotropium+placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 29 (41.38%)
    12 / 27 (44.44%)
    12 / 28 (42.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 29 (6.90%)
    5 / 27 (18.52%)
    3 / 28 (10.71%)
         occurrences all number
    2
    8
    3
    General disorders and administration site conditions
    Medical device site reaction
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 27 (3.70%)
    4 / 28 (14.29%)
         occurrences all number
    4
    1
    4
    Chest discomfort
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 27 (3.70%)
    2 / 28 (7.14%)
         occurrences all number
    1
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 27 (3.70%)
    2 / 28 (7.14%)
         occurrences all number
    1
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2017
    The exclusion criteria were amended to remove the prohibition against prior exposure to RPL554.

    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.

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