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    Clinical Trial Results:
    A Phase IIb, randomized, double blind, placebo controlled, dose ranging study to assess the effect of RPL554 in patients with moderate to severe COPD.

    Summary
    EudraCT number
    2016-005205-40
    Trial protocol
    DE   CZ   BG   GB  
    Global end of trial date
    07 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Mar 2019
    First version publication date
    13 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RPL554-CO-203
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03443414
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Verona Pharma plc
    Sponsor organisation address
    3 More Riverside, London, United Kingdom, SE12RE
    Public contact
    Paula Siu, Verona Pharma plc, +44 203 283 4200, paula.siu@veronapharma.com
    Scientific contact
    Paula Siu, Verona Pharma plc, +44 203 283 4200, 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
    07 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of RPL554 or placebo on change from baseline in peak forced expiratory volume in 1 second (FEV1) when administered to patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD)
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jun 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
    Poland: 93
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Bulgaria: 76
    Country: Number of subjects enrolled
    Czech Republic: 65
    Country: Number of subjects enrolled
    Germany: 111
    Country: Number of subjects enrolled
    Romania: 45
    Worldwide total number of subjects
    405
    EEA total number of subjects
    405
    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)
    221
    From 65 to 84 years
    184
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    405 adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) were randomized into this double-blind, multicenter study, and 403 received study medication. Patients were recruited to 47 study centers in Bulgaria, Czech Republic, Germany, Poland, Romania and the United Kingdom.

    Pre-assignment
    Screening details
    Patients with a clinical diagnosis of COPD as defined by the American Thoracic Society/European Respiratory Society guidelines with symptoms compatible with COPD for at least 1 year prior to screening, and with clinically stable symptoms in the 4 weeks prior to screening and randomization were screened for inclusion.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    0.75 mg RPL554
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    0.75 mg RPL554 administered using a jet nebuliser for 5-10 minutes until sputtering

    Arm title
    1.5 mg RPL554
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    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 jet nebuliser for 5-10 minutes until sputtering

    Arm title
    3.0 mg RPL554
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    3.0 mg RPL554 administered using a jet nebuliser for 5-10 minutes until sputtering

    Arm title
    6.0 mg RPL554
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    RPL554
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    6.0 mg RPL554 administered using a jet nebuliser for 5-10 minutes until sputtering

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    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 for 5-10 minutes until sputtering

    Number of subjects in period 1
    0.75 mg RPL554 1.5 mg RPL554 3.0 mg RPL554 6.0 mg RPL554 Placebo
    Started
    82
    81
    82
    80
    80
    Completed
    71
    78
    76
    75
    75
    Not completed
    11
    3
    6
    5
    5
         Adverse event, serious fatal
    -
    1
    -
    1
    -
         Adverse event, non-fatal
    6
    -
    4
    2
    3
         Consent withdrawn by subject
    3
    2
    2
    2
    1
         Reason not specified
    2
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Whole study
    Reporting group description
    -

    Reporting group values
    Whole study Total
    Number of subjects
    405 405
    Age categorical
    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)
    221 221
        From 65-84 years
    184 184
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.3 ± 6.61 -
    Gender categorical
    Units: Subjects
        Female
    160 160
        Male
    245 245
    Race
    Units: Subjects
        White
    405 405
        American Indian or Alaska Native
    0 0
        Asian
    0 0
        Native Hawaiian or Other Pacific Islander
    0 0
        Black or African American
    0 0
        Unknown or Not Reported
    0 0
        More than One Race
    0 0
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    405 405
        Hispanic or Latino
    0 0
        Unknown or Not Reported
    0 0

    End points

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    End points reporting groups
    Reporting group title
    0.75 mg RPL554
    Reporting group description
    -

    Reporting group title
    1.5 mg RPL554
    Reporting group description
    -

    Reporting group title
    3.0 mg RPL554
    Reporting group description
    -

    Reporting group title
    6.0 mg RPL554
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Mean Change From Baseline in Peak FEV1 (Over 3 Hours) at Week 4

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    End point title
    Mean Change From Baseline in Peak FEV1 (Over 3 Hours) at Week 4
    End point description
    Spirometry assessments were used to assess pulmonary function including the forced expiratory volume in 1 second (FEV1). Peak FEV1 at Week 4 was defined as the maximum post-dose value among the 30 minutes, 1, 2 and 3 hour assessments collected at Visit 6. Baseline was defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. A mixed model for repeated measures (MMRM) was used to model the change from baseline FEV1 using baseline FEV1 as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect. The least squares (LS) mean change from baseline FEV1 to peak FEV1 (as measured over 3 hours) at Week 4 is presented.
    End point type
    Primary
    End point timeframe
    15 minutes pre-dose; 30 minutes and 1, 2 and 3 hours post-dose
    End point values
    0.75 mg RPL554 1.5 mg RPL554 3.0 mg RPL554 6.0 mg RPL554 Placebo
    Number of subjects analysed
    81
    81
    82
    80
    79
    Units: Litres
        least squares mean (confidence interval 95%)
    0.203 (0.152 to 0.253)
    0.209 (0.160 to 0.258)
    0.257 (0.208 to 0.306)
    0.196 (0.147 to 0.246)
    0.057 (0.007 to 0.106)
    Statistical analysis title
    RPL554 6.0 mg versus Placebo
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 6.0 mg - Placebo)
    Comparison groups
    6.0 mg RPL554 v Placebo
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.139
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.069
         upper limit
    0.21
    Notes
    [1] - A fixed sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 3.0 mg versus Placebo
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 3.0 mg - Placebo)
    Comparison groups
    3.0 mg RPL554 v Placebo
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.131
         upper limit
    0.27
    Notes
    [2] - A fixed sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 1.5 mg versus Placebo
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 1.5 mg - Placebo)
    Comparison groups
    1.5 mg RPL554 v Placebo
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.153
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.083
         upper limit
    0.222
    Notes
    [3] - A fixed sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 0.75 mg versus Placebo
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 0.75 mg - Placebo)
    Comparison groups
    0.75 mg RPL554 v Placebo
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.146
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.075
         upper limit
    0.216
    Notes
    [4] - A fixed sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.

    Secondary: Mean Change from Baseline FEV1 to Morning Trough at Week 4

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    End point title
    Mean Change from Baseline FEV1 to Morning Trough at Week 4
    End point description
    Morning trough FEV1 was defined as the last pre-dose value at Visit 6. Baseline was defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. MMRM was used to model the change from baseline FEV1 using baseline FEV1 as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect. The LS mean change from baseline FEV1 to morning trough FEV1 at Week 4 is presented.
    End point type
    Secondary
    End point timeframe
    Pre-dose at baseline and pre-dose at Week 4
    End point values
    0.75 mg RPL554 1.5 mg RPL554 3.0 mg RPL554 6.0 mg RPL554 Placebo
    Number of subjects analysed
    77
    80
    82
    77
    78
    Units: Litres
        least squares mean (confidence interval 95%)
    0.007 (-0.038 to 0.053)
    -0.019 (-0.063 to 0.025)
    0.040 (-0.003 to 0.084)
    -0.026 (-0.071 to 0.018)
    -0.028 (-0.072 to 0.016)
    Statistical analysis title
    RPL554 6.0 mg versus Placebo
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 6.0 mg - Placebo)
    Comparison groups
    6.0 mg RPL554 v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.953
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.061
         upper limit
    0.065
    Notes
    [5] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 3.0 mg versus Placebo
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 3.0 mg - Placebo)
    Comparison groups
    Placebo v 3.0 mg RPL554
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.032
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.068
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.006
         upper limit
    0.13
    Notes
    [6] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 1.5 mg versus Placebo
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 1.5 mg - Placebo)
    Comparison groups
    Placebo v 1.5 mg RPL554
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.773
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.053
         upper limit
    0.072
    Notes
    [7] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 0.75 mg versus Placebo
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 0.75 mg - Placebo)
    Comparison groups
    Placebo v 0.75 mg RPL554
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    P-value
    = 0.272
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.035
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.028
         upper limit
    0.099
    Notes
    [8] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.

    Secondary: Number of Patients with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    Number of Patients with Treatment Emergent Adverse Events (TEAEs)
    End point description
    The number of patients with TEAEs for each the following categories are presented: any TEAE, any drug-related TEAE, any severe TEAE, any serious TEAE, serious drug-related TEAE, any TEAE leading to drug interruption, any TEAE leading to drug discontinuation, and any TEAE leading to death. All adverse events which started after the first dose of investigational product or started prior to first dose and worsened, based on the Investigator assessment of severity, on or after first dose were considered to be treatment-emergent
    End point type
    Secondary
    End point timeframe
    Up to end of Study (Approximately 6 weeks)
    End point values
    0.75 mg RPL554 1.5 mg RPL554 3.0 mg RPL554 6.0 mg RPL554 Placebo
    Number of subjects analysed
    81
    81
    82
    80
    79
    Units: Number of Patients
        Any TEAE
    27
    36
    29
    29
    31
        Any drug-related TEAE
    8
    11
    12
    8
    10
        Any severe TEAE
    4
    1
    2
    1
    2
        Any serious TEAE
    2
    2
    1
    1
    1
        Any serious drug-related TEAE
    1
    1
    0
    0
    0
        Any TEAE leading to drug interruption
    1
    0
    1
    0
    0
        Any TEAE leading to drug discontinuation
    6
    1
    4
    2
    2
        Any TEAE leading to death
    0
    1
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in COPD Symptoms Using the Exacerbations of Chronic Pulmonary Disease Tool Patient- Reported Outcome (EXACT-PRO) Scoring at Week 4

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    End point title
    Mean Change From Baseline in COPD Symptoms Using the Exacerbations of Chronic Pulmonary Disease Tool Patient- Reported Outcome (EXACT-PRO) Scoring at Week 4
    End point description
    Patients completed an electronic diary (e-diary) once daily which used the 14-item EXACT-PRO instrument to assess COPD symptoms. The EXACT-PRO instrument contains 11 respiratory symptom questions that comprise the derivative Evaluating Respiratory Symptoms (E-RS) instrument that was used to measure the effect of treatment with RPL554 on the severity of COPD symptoms overall. The E-RS tool contains 3 subscales to assess breathlessness, cough/sputum and chest symptoms. In addition to the subscale scores, a total score for the E-RS part was obtained. The raw totals for the E-RS score and for each of the subscales were converted to a scale range of 0 to 100 (least symptomatic to most symptomatic). MMRM was used to model the change from baseline using baseline as a continuous fixed effect, randomised treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose, Visit 2) and Week 4 (Visit 6)
    End point values
    0.75 mg RPL554 1.5 mg RPL554 3.0 mg RPL554 6.0 mg RPL554 Placebo
    Number of subjects analysed
    71
    74
    76
    74
    76
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        E-RS Total Score
    -1.07 (-2.00 to -0.14)
    -1.26 (-2.16 to -0.35)
    -0.80 (-1.69 to 0.10)
    -0.92 (-1.81 to -0.02)
    1.19 (0.30 to 2.08)
        E-RS Breathlessness Score
    -0.46 (-0.92 to -0.01)
    -0.63 (-1.07 to -0.18)
    -0.48 (-0.92 to -0.04)
    -0.48 (-0.92 to -0.04)
    0.47 (0.03 to 0.90)
        E-RS Cough/Sputum Score
    -0.22 (-0.50 to 0.07)
    -0.30 (-0.58 to -0.03)
    -0.14 (-0.41 to 0.13)
    -0.21 (-0.48 to 0.06)
    0.36 (0.09 to 0.63)
        E-RS Chest Symptom Score
    -0.39 (-0.70 to -0.08)
    -0.32 (-0.62 to -0.02)
    -0.19 (-0.48 to 0.11)
    -0.22 (-0.52 to 0.07)
    0.35 (0.05 to 0.64)
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Breathlessness as Assessed Using the St George's Respiratory Questionnaire (SGRQ) at Week 4

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    End point title
    Mean Change From Baseline in Breathlessness as Assessed Using the St George's Respiratory Questionnaire (SGRQ) at Week 4
    End point description
    Patients completed the COPD specific SGRQ (SGRQ-C) which consisted of 14 questions in 2 parts. Part 1 produced the symptoms score, and Part 2 gave the activity and impacts scores. Each of the component scores was calculated separately by dividing the summed weights by the maximum possible weight for that component and expressing the score as a percentage (0 for least symptomatic and 100 for most symptomatic). A total score was also produced which was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms. Baseline assessment was pre-dose at Visit 2. MMRM was used to model the change from baseline using baseline as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, patient as random effect.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose, Visit 2) and Week 4 (Visit 6)
    End point values
    0.75 mg RPL554 1.5 mg RPL554 3.0 mg RPL554 6.0 mg RPL554 Placebo
    Number of subjects analysed
    74
    75
    71
    77
    73
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        SGRQ-C Total Score
    -2.56 (-5.13 to 0.02)
    -3.18 (-5.72 to -0.65)
    -2.63 (-5.24 to -0.01)
    -3.01 (-5.51 to -0.51)
    -0.33 (-2.90 to 2.23)
        SGRQ-C Symptoms Score
    -4.73 (-7.99 to -1.46)
    -1.89 (-5.11 to 1.33)
    -2.17 (-5.50 to 1.17)
    -4.33 (-7.51 to -1.16)
    1.25 (-2.02 to 4.51)
        SGRQ-C Activity Score
    -2.19 (-5.30 to 0.91)
    -4.28 (-7.34 to -1.23)
    -2.70 (-5.85 to 0.46)
    -2.75 (-5.76 to 0.27)
    -2.16 (-5.25 to 0.94)
        SGRQ-C Impact Score
    -1.73 (-4.91 to 1.46)
    -2.93 (-6.06 to 0.20)
    -2.96 (-6.20 to 0.28)
    -2.80 (-5.89 to 0.29)
    0.11 (-3.07 to 3.28)
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline FEV1 to Average FEV1 (Over 12 Hours) at Day 1 and Week 4

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    End point title
    Mean Change From Baseline FEV1 to Average FEV1 (Over 12 Hours) at Day 1 and Week 4
    End point description
    Average FEV1 over 12 hours was defined as the area under the curve from 0 to 12 hours post-dose (AUC[0-12]) of the FEV1 values collected during Day 1 or Week 4, divided by the length of the time interval of interest (in hours). The AUC was calculated using the trapezoidal rule. Baseline was defined as the FEV1 pre-dose assessment (-15 minutes) collected at Visit 2. MMRM was used to model the change from baseline FEV1 using baseline FEV1 as a continuous fixed effect, randomized treatment, week and treatment-by-week as categorical fixed effect, and patient as random effect. The LS mean change from baseline FEV1 to average FEV1 over 12 hours at Day 1 and Week 4 are presented
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose, Visit 2), up to 12 hours post-dose at Visit 2 (Day 1) and Visit 6 (Week 4)
    End point values
    0.75 mg RPL554 1.5 mg RPL554 3.0 mg RPL554 6.0 mg RPL554 Placebo
    Number of subjects analysed
    80
    81
    82
    79
    78
    Units: Litres
    least squares mean (confidence interval 95%)
        Day 1
    0.088 (0.058 to 0.117)
    0.077 (0.048 to 0.107)
    0.103 (0.074 to 0.132)
    0.095 (0.065 to 0.125)
    0.008 (-0.022 to 0.038)
        Week 4
    0.039 (-0.007 to 0.085)
    0.052 (0.008 to 0.096)
    0.085 (0.040 to 0.130)
    0.031 (-0.014 to 0.076)
    -0.033 (-0.079 to 0.012)
    Statistical analysis title
    RPL554 6.0 mg versus Placebo At Day 1
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 6.0 mg - Placebo) at Day 1
    Comparison groups
    6.0 mg RPL554 v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.087
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.045
         upper limit
    0.129
    Notes
    [9] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 3.0 mg versus Placebo At Day 1
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 3.0 mg - Placebo) at Day 1
    Comparison groups
    Placebo v 3.0 mg RPL554
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.095
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.053
         upper limit
    0.137
    Notes
    [10] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 1.5 mg versus Placebo At Day 1
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 1.5 mg - Placebo) at Day 1
    Comparison groups
    Placebo v 1.5 mg RPL554
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    = 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.028
         upper limit
    0.112
    Notes
    [11] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 0.75 mg versus Placebo At Day 1
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 0.75 mg - Placebo) at Day 1
    Comparison groups
    Placebo v 0.75 mg RPL554
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.038
         upper limit
    0.122
    Notes
    [12] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 6.0 mg versus Placebo At Week 4
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 6.0 mg - Placebo) at Week 4
    Comparison groups
    6.0 mg RPL554 v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    other [13]
    P-value
    = 0.048
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.001
         upper limit
    0.129
    Notes
    [13] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 3.0 mg versus Placebo At Week 4
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 3.0 mg - Placebo) at Week 4
    Comparison groups
    Placebo v 3.0 mg RPL554
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    P-value
    < 0.001
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.119
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.055
         upper limit
    0.183
    Notes
    [14] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 1.5 mg versus Placebo At Week 4
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 1.5 mg - Placebo) at Week 4
    Comparison groups
    Placebo v 1.5 mg RPL554
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    = 0.008
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.085
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.022
         upper limit
    0.149
    Notes
    [15] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.
    Statistical analysis title
    RPL554 0.75 mg versus Placebo At Week 4
    Statistical analysis description
    Placebo corrected treatment effect: LS mean difference (RPL554 0.75 mg - Placebo) at Week 4
    Comparison groups
    Placebo v 0.75 mg RPL554
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    other [16]
    P-value
    = 0.028
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    0.072
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.008
         upper limit
    0.137
    Notes
    [16] - A fixed-sequence testing approach was used, starting with the highest dose versus placebo. If a statistically significant difference was found at the 2-sided alpha level of 5%, the testing proceeded to the next highest dose.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs were collected from the first dose of investigational product up to 2 weeks after the end of the study (approximately 6 weeks).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    RPL554 0.75 mg
    Reporting group description
    -

    Reporting group title
    RPL554 1.5 mg
    Reporting group description
    -

    Reporting group title
    RPL554 3.0 mg
    Reporting group description
    -

    Reporting group title
    RPL554 6.0 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    RPL554 0.75 mg RPL554 1.5 mg RPL554 3.0 mg RPL554 6.0 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 81 (2.47%)
    1 / 82 (1.22%)
    1 / 80 (1.25%)
    1 / 79 (1.27%)
         number of deaths (all causes)
    0
    1
    0
    1
    0
         number of deaths resulting from adverse events
    0
    1
    0
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 80 (1.25%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    RPL554 0.75 mg RPL554 1.5 mg RPL554 3.0 mg RPL554 6.0 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 81 (33.33%)
    36 / 81 (44.44%)
    29 / 82 (35.37%)
    29 / 80 (36.25%)
    31 / 79 (39.24%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 81 (1.23%)
    4 / 82 (4.88%)
    3 / 80 (3.75%)
    1 / 79 (1.27%)
         occurrences all number
    3
    1
    4
    4
    1
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 80 (1.25%)
    2 / 79 (2.53%)
         occurrences all number
    0
    0
    0
    1
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 81 (1.23%)
    1 / 82 (1.22%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    1 / 80 (1.25%)
    2 / 79 (2.53%)
         occurrences all number
    0
    1
    0
    1
    2
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 81 (1.23%)
    1 / 82 (1.22%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 81 (4.94%)
    5 / 81 (6.17%)
    3 / 82 (3.66%)
    3 / 80 (3.75%)
    6 / 79 (7.59%)
         occurrences all number
    4
    5
    3
    3
    6
    Cough
         subjects affected / exposed
    4 / 81 (4.94%)
    4 / 81 (4.94%)
    6 / 82 (7.32%)
    1 / 80 (1.25%)
    1 / 79 (1.27%)
         occurrences all number
    4
    4
    6
    1
    1
    Dyspnoea
         subjects affected / exposed
    3 / 81 (3.70%)
    1 / 81 (1.23%)
    1 / 82 (1.22%)
    1 / 80 (1.25%)
    5 / 79 (6.33%)
         occurrences all number
    3
    1
    1
    1
    7
    Productive cough
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 81 (3.70%)
    1 / 82 (1.22%)
    0 / 80 (0.00%)
    0 / 79 (0.00%)
         occurrences all number
    0
    5
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 81 (2.47%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    2
    0
    0
    2
    Headache
         subjects affected / exposed
    4 / 81 (4.94%)
    4 / 81 (4.94%)
    7 / 82 (8.54%)
    4 / 80 (5.00%)
    3 / 79 (3.80%)
         occurrences all number
    4
    4
    8
    5
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    2 / 82 (2.44%)
    0 / 80 (0.00%)
    1 / 79 (1.27%)
         occurrences all number
    0
    0
    2
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    2 / 82 (2.44%)
    1 / 80 (1.25%)
    0 / 79 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Nausea
         subjects affected / exposed
    3 / 81 (3.70%)
    2 / 81 (2.47%)
    2 / 82 (2.44%)
    0 / 80 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    3
    2
    3
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    2 / 82 (2.44%)
    1 / 80 (1.25%)
    1 / 79 (1.27%)
         occurrences all number
    0
    0
    2
    1
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 81 (2.47%)
    4 / 81 (4.94%)
    4 / 82 (4.88%)
    5 / 80 (6.25%)
    7 / 79 (8.86%)
         occurrences all number
    2
    5
    4
    5
    7
    Rhinitis
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 80 (0.00%)
    2 / 79 (2.53%)
         occurrences all number
    1
    1
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2017
    • Inclusion criterion 3 updated to the reduce duration of contraception requirements after the last dose of study medication from 1 month to 2 weeks • Inclusion criterion 12 updated to add ‘current and former smokers’ to the smoking pack history criteria • If necessary, the Investigator could unblind the investigational product without prior contact with the Sponsor. In addition, study personnel were instructed not to discuss the medication appearance with patients, and patients were instructed to seal the medication kit before returning it at their next visit • Schedule for post-dose assessments of vital signs updated to include a 30 minute (post dose) time point • Schedule of pre-dose assessments updated to include 12-lead ECGs and vital signs • Statistical analysis amended to include details of consolidation of data from sites to the country level. A closed testing procedure to test active dose vs. placebo for the primary endpoint was added. • Statistical analysis amended to include details of how PD parameters were to be calculated for each visit with missing visit values imputed • Sample size determination amended to state the detectable limit was considered sufficient to conclusively identify a minimal effective dose of RPL554. • A definition of ‘woman of childbearing potential’ added
    15 Sep 2017
    • Number of study centres increased from 45 to 50 • Text clarified to state that the number of patients was ‘approximately 400’ • Historical MRI or CT scans were permitted, in addition to historical chest X-rays, in the 12 months prior to Screening (with equivalent results) • Exclusion criterion 14 amended to state: Patients with a history of current chronic uncontrolled disease including, but not limited to, endocrine, active hyperthyroidism thyroid disease, neurological, hepatic, gastrointestinal, renal, hematological, urological, immunological, or ophthalmic diseases that the Investigator believes are clinically significant • Exclusion criterion 16 clarified to be specific for oral beta blockers • Albuterol/salbutamol could be used on an as needed basis • Ocular beta blockers added to oral mucolytics as specified allowed therapies • Rescue medications should only be used during treatment visits when absolutely necessary • Requirement to discuss the re screening of patients with the Sponsor removed • Holter monitor removal was to occur at least 23 hours after placement and the number of PVCs seen in the screening Holter monitor assessment was to be standardized to 24 hours for the exclusion criterion of >1000 PVCs per 24 hours • Serum and urine pregnancy tests were to be performed on all females not just those of childbearing potential • Short acting bronchodilators were not to be used within 8 hours prior to the reversibility test

    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
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