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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind, Placebo- Controlled Study to Evaluate the Efficacy and Safety of Ensifentrine over 24 Weeks (With a 48-Week Safety Subset) in Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease.

    Summary
    EudraCT number
    		 2020-002086-34
    Trial protocol
    		 CZ   DE   SK   HU   BG   GR   RO  
    Global end of trial date
    02 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Sep 2023
    First version publication date
    15 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RPL554-CO-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04535986
    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
    Chief Medical Officer, Verona Pharma plc, info@veronapharma.com
    Scientific contact
    Chief Medical Officer, Verona Pharma plc, info@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
    02 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of ensifentrine on lung function compared to placebo over a 12-hour dosing interval in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
    Protection of trial subjects
    The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organisations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice and other Guidelines, and applicable laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Sep 2020
    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
    Bulgaria: 45
    Country: Number of subjects enrolled
    Czechia: 106
    Country: Number of subjects enrolled
    Germany: 190
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 39
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Romania: 39
    Country: Number of subjects enrolled
    Russian Federation: 104
    Country: Number of subjects enrolled
    Slovakia: 41
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 145
    Worldwide total number of subjects
    763
    EEA total number of subjects
    479
    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)
    353
    From 65 to 84 years
    410
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase 3, randomized, double-blind, placebo-controlled study was conducted in patients with moderate to severe COPD at 120 study centers. Patients were randomized in a 5:3 ratio overall (1:1 over 24 weeks and 3:1 over 48 weeks), stratified by duration, smoking status and background medication use, to receive either ensifentrine or placebo.

    Pre-assignment
    Screening details
    		 Patients were screened for eligibility before entering a 28-day run in period to ensure a stable COPD treatment regimen and to collect baseline information on symptoms and rescue medication use.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ensifentrine
    Arm description
    		 3 milligram (mg) twice daily via standard jet nebulizer.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ensifentrine
    Investigational medicinal product code
    RPL554
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Ensifentrine 3 mg inhaled by jet nebulizer twice daily (morning and evening) for 24 weeks or 48 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Twice daily via standard jet nebulizer.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Ensifentrine placebo inhaled by jet nebulizer twice daily (morning and evening) for 24 weeks or 48 weeks.

    Number of subjects in period 1
    		Ensifentrine Placebo
    Started
    479
    284
    Received Treatment
    477
    283
    Completed
    400
    245
    Not completed
    79
    39
         COPD exacerbation withdrawal criteria
    7
    5
         Consent withdrawn by subject
    32
    14
         Adverse event, non-fatal
    10
    1
         Death
    4
    5
         Unspecified
    7
    3
         Investigator discretion
    3
    -
         Lost to follow-up
    5
    3
         Coronavirus disease 2019 (COVID-19)
    8
    6
         Lack of efficacy
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ensifentrine
    Reporting group description
    		 3 milligram (mg) twice daily via standard jet nebulizer.

    Reporting group title
    Placebo
    Reporting group description
    		 Twice daily via standard jet nebulizer.

    Reporting group values
    		 Ensifentrine Placebo Total
    Number of subjects
    		 479 284 763
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.1 ± 7.12 64.9 ± 7.73 -
    Gender categorical
    Units: Subjects
        Female
    		 204 117 321
        Male
    		 275 167 442
    Race
    Units: Subjects
        Asian
    		 13 11 24
        Black or African American
    		 16 9 25
        White
    		 437 251 688
        Other
    		 0 1 1
        Not Reported
    		 13 12 25
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 15 6 21
        Not Hispanic or Latino
    		 464 278 742

    End points

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    End points reporting groups
    Reporting group title
    Ensifentrine
    Reporting group description
    		 3 milligram (mg) twice daily via standard jet nebulizer.

    Reporting group title
    Placebo
    Reporting group description
    		 Twice daily via standard jet nebulizer.

    Primary: Least Square (LS) Mean Change From Baseline in Average Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) at Week 12

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    End point title
    		 Least Square (LS) Mean Change From Baseline in Average Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) at Week 12
    End point description
    Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Average FEV1 AUC0-12h was defined as AUC over 12 hours of the FEV1, divided by 12 hours. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on Day 1. Spirometry assessments were performed in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines. The modified Intent-to-Treat (mITT) population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment. 1 patient was missing a baseline FEV1 assessment.
    End point type
    Primary
    End point timeframe
    Baseline (pre-dose on Day 1) and Week 12
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    477
    282
    Units: liters
        least squares mean (standard error)
    0.0611 ± 0.01825
    -0.0256 ± 0.0195
    Statistical analysis title
    		 Treatment difference in average FEV1 AUC0-12h
    Comparison groups
    Ensifentrine v Placebo
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.0868
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0551
         upper limit
    		 0.1185
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0162
    Notes
    [1] - The analysis of covariance (ANCOVA) model was used to model the change from baseline FEV1 to average FEV1 AUC0-12h with treatment, region, background medication strata and smoking strata as fixed effects and baseline FEV1 as covariate.

    Secondary: LS Mean Change From Baseline FEV1 to Peak FEV1 at Day 1 and Weeks 6, 12 and 24

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    End point title
    		 LS Mean Change From Baseline FEV1 to Peak FEV1 at Day 1 and Weeks 6, 12 and 24
    End point description
    Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Peak FEV1 is the maximum value in the 4 hours after dosing. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on Day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines. The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    477
    282
    Units: liters
    least squares mean (standard error)
        Day 1 (Post-dose)
    0.2274 ± 0.0130
    0.0755 ± 0.0138
        Week 6
    0.2038 ± 0.0193
    0.0677 ± 0.0207
        Week 12
    0.2042 ± 0.0201
    0.0570 ± 0.0217
        Week 24
    0.1623 ± 0.0217
    0.0462 ± 0.0234
    No statistical analyses for this end point

    Secondary: LS Mean Change From Baseline to the Mean Weekly Evaluating-Respiratory Symptoms (E-RS) Total Score at Weeks 6, 12 and 24

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    End point title
    		 LS Mean Change From Baseline to the Mean Weekly Evaluating-Respiratory Symptoms (E-RS) Total Score at Weeks 6, 12 and 24
    End point description
    The E-RS scale consists of 11 questions, with 3 sub-domains of: breathlessness, cough and sputum, and chest symptoms. The E-RS sub-domain score was calculated as the sum from the relevant questions. The E-RS total score was derived as the sum of the raw scores of the 11 items ranging from 0 to 40. Higher scores indicates severe respiratory symptoms. The E-RS was collected daily by electronic diary (e-diary). Baseline is the mean over the 7 days prior to the first intake of study medication, using only days where data was recorded. The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    475
    281
    Units: units on a scale
    least squares mean (standard error)
        Week 6
    -1.944 ± 0.3581
    -1.157 ± 0.3831
        Week 12
    -2.498 ± 0.3897
    -1.127 ± 0.4176
        Week 24
    -2.249 ± 0.4247
    -1.298 ± 0.4573
    No statistical analyses for this end point

    Secondary: LS Mean Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Weeks 6, 12 and 24

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    End point title
    		 LS Mean Change From Baseline in the St. George's Respiratory Questionnaire (SGRQ) Total Score at Weeks 6, 12 and 24
    End point description
    The SGRQ questionnaire consists of 17 questions, split into 2 parts. Part 1 consisted of the first 8 questions and was related to the symptoms subdomain. The remaining 9 questions were in Part 2, which were related to the activity and impacts subdomains. The total score was calculated by dividing the summed weights by the maximum possible weight for all items in the questionnaire and expressing the result as a percentage. Score ranging from 0 to 100 and higher scores indicated a worse outcome. Baseline is the score calculated on Day 1 prior to 4 hour post-dose spirometry. The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    474
    281
    Units: units on a scale
    least squares mean (standard error)
        Week 6
    -6.184 ± 0.9838
    -3.965 ± 1.0511
        Week 12
    -5.665 ± 1.0163
    -2.652 ± 1.0859
        Week 24
    -6.167 ± 1.1405
    -3.868 ± 1.2178
    No statistical analyses for this end point

    Secondary: LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 6, 12 and 24

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    End point title
    		 LS Mean Change From Baseline FEV1 to Morning Trough FEV1 at Weeks 6, 12 and 24
    End point description
    Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Morning trough FEV1 was the last value collected prior to the morning dose. Baseline FEV1 is the mean of the two measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines. The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    477
    282
    Units: liters
    least squares mean (standard error)
        Week 6
    0.0112 ± 0.0181
    -0.0259 ± 0.0193
        Week 12
    0.0076 ± 0.0190
    -0.0272 ± 0.0204
        Week 24
    -0.0236 ± 0.0205
    -0.0369 ± 0.0219
    No statistical analyses for this end point

    Secondary: LS Mean Change From Baseline in Average FEV1 Area Under the Curve Over 4 Hours (AUC0-4h) at Day 1 and Weeks 6, 12 and 24

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    End point title
    		 LS Mean Change From Baseline in Average FEV1 Area Under the Curve Over 4 Hours (AUC0-4h) at Day 1 and Weeks 6, 12 and 24
    End point description
    Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Average FEV1 AUC0-4h was defined as area under the curve over 4 hours of the FEV1, divided by 4 hours. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on Day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines. The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    477
    282
    Units: liters
    least squares mean (standard error)
        Day 1 (Post-dose)
    0.1495 ± 0.0108
    0.0099 ± 0.0115
        Week 6
    0.1259 ± 0.0184
    -0.0044 ± 0.0196
        Week 12
    0.1243 ± 0.0191
    -0.0149 ± 0.0203
        Week 24
    0.0875 ± 0.0206
    -0.0139 ± 0.0220
    No statistical analyses for this end point

    Secondary: Percentage of SGRQ Responders at Weeks 6, 12 and 24

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    End point title
    		 Percentage of SGRQ Responders at Weeks 6, 12 and 24
    End point description
    The SGRQ questionnaire consists of 17 questions, split into 2 parts. Part 1 consisted of the first 8 questions and was related to the symptoms subdomain. The remaining 9 questions were in Part 2, which were related to the activity and impacts subdomains. The total score was calculated by dividing the summed weights by the maximum possible weight for all items in the questionnaire and expressing the result as a percentage. Responder was a patient with an improvement from baseline in SGRQ total score of 4 or more. Percentage of SGRQ responders are reported. The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Weeks 6, 12 and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    474
    281
    Units: percentage of patients
    number (not applicable)
        Week 6
    50.8
    40.6
        Week 12
    52.5
    37.0
        Week 24
    58.2
    45.9
    No statistical analyses for this end point

    Secondary: LS Mean Change From Baseline to the Mean Weekly Rescue Medication Use at Weeks 6, 12 and 24

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    End point title
    		 LS Mean Change From Baseline to the Mean Weekly Rescue Medication Use at Weeks 6, 12 and 24
    End point description
    Use of rescue medication (albuterol/salbutamol) per week was calculated as the LS mean use daily over 7 days. Daily rescue medication use was collected in an e-diary throughout the study. Baseline is the mean over the 7 days prior to the first intake of study medication, calculated as the sum of puffs taken, divided by number of days data has been recorded. The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose on Day 1) and Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    475
    281
    Units: rescue medication puffs per week
    least squares mean (standard error)
        Week 6
    -0.442 ± 0.1065
    -0.306 ± 0.1139
        Week 12
    -0.469 ± 0.1155
    -0.182 ± 0.1234
        Week 24
    -0.506 ± 0.1448
    -0.052 ± 0.1554
    No statistical analyses for this end point

    Secondary: LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 6, 12 and 24

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    End point title
    		 LS Mean Transition Dyspnea Index (TDI) Questionnaire Total Score at Weeks 6, 12 and 24
    End point description
    The TDI is a questionnaire that focused on 3 sub-domains: functional impairment, magnitude of task and magnitude of effort. Sub-domain score was calculated as the sum from the related questions. Total score was calculated as the sum of the sub-domain scores. The TDI measures the change in dyspnea severity from the baseline as measured by the baseline dyspnea index. It was rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement). Higher scores indicate better outcome. Change from baseline was assessed with the Baseline Dyspnea Index. The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Weeks 6, 12 and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    471
    277
    Units: units on a scale
    least squares mean (standard error)
        Week 6
    1.3 ± 0.19
    0.6 ± 0.21
        Week 12
    1.6 ± 0.21
    0.4 ± 0.23
        Week 24
    1.9 ± 0.24
    0.8 ± 0.27
    No statistical analyses for this end point

    Secondary: LS Mean Change From Baseline FEV1 to Evening Trough FEV1 at Week 12

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    End point title
    		 LS Mean Change From Baseline FEV1 to Evening Trough FEV1 at Week 12
    End point description
    Forced spirometry maneuvers including the FEV1 were used to assess pulmonary function. Evening trough FEV1 was the value collected at 12 hours post-morning dose and prior to the evening dose. Baseline FEV1 is the mean of the 2 measurements taken before study medication on the day of first dosing, that is, <=40 minutes pre-dose on day 1. Spirometry assessments were performed in accordance with ATS/ERS guidelines. The mITT population set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose on Day 1) and Week 12
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    477
    282
    Units: liters
        least squares mean (standard error)
    -0.0117 ± 0.0203
    -0.0697 ± 0.0214
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events were collected from first dose of study treatment up to 10 days after final study visit at Week 24, approximately 25 weeks, and for 48-week subset, up to 10 days after final study visit at Week 48, approximately 49 weeks.
    Adverse event reporting additional description
    The safety analysis set included all patients in the randomized set who received at least 1 dose (or partial dose) of study medication, and patients were classified according to treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Up to Week 24: Ensifentrine
    Reporting group description
    		 3 mg twice daily via standard jet nebulizer.

    Reporting group title
    Up to Week 24: Placebo
    Reporting group description
    		 Twice daily via standard jet nebulizer.

    Reporting group title
    From Week 24 to Week 48: Ensifentrine
    Reporting group description
    		 3 mg twice daily via standard jet nebulizer (patients that had at least 1 dose after Week 24 visit).

    Reporting group title
    From Week 24 to Week 48: Placebo
    Reporting group description
    		 Twice daily via standard jet nebulizer (patients that had at least 1 dose after Week 24 visit).

    Serious adverse events
    		 Up to Week 24: Ensifentrine Up to Week 24: Placebo From Week 24 to Week 48: Ensifentrine From Week 24 to Week 48: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 477 (6.71%)
    19 / 283 (6.71%)
    11 / 228 (4.82%)
    5 / 70 (7.14%)
         number of deaths (all causes)
    2
    4
    2
    1
         number of deaths resulting from adverse events
    2
    4
    2
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma metastatic
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    1 / 228 (0.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer stage I
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    1 / 228 (0.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 477 (0.21%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    1 / 228 (0.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    7 / 477 (1.47%)
    6 / 283 (2.12%)
    2 / 228 (0.88%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    1 / 228 (0.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal injury
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    1 / 228 (0.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    1 / 228 (0.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral microangiopathy
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    1 / 228 (0.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary dyskinesia
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 477 (0.42%)
    2 / 283 (0.71%)
    1 / 228 (0.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    3 / 477 (0.63%)
    1 / 283 (0.35%)
    1 / 228 (0.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis bacterial
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 477 (0.63%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumonia chlamydial
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 477 (0.21%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Urosepsis
         subjects affected / exposed
    0 / 477 (0.00%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Up to Week 24: Ensifentrine Up to Week 24: Placebo From Week 24 to Week 48: Ensifentrine From Week 24 to Week 48: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    90 / 477 (18.87%)
    58 / 283 (20.49%)
    16 / 228 (7.02%)
    17 / 70 (24.29%)
    Investigations
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Essential hypertension
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    11 / 477 (2.31%)
    4 / 283 (1.41%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    12
    4
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    5 / 477 (1.05%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    5
    3
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    3 / 477 (0.63%)
    4 / 283 (1.41%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Headache
         subjects affected / exposed
    16 / 477 (3.35%)
    12 / 283 (4.24%)
    4 / 228 (1.75%)
    2 / 70 (2.86%)
         occurrences all number
    16
    13
    4
    2
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    1 / 228 (0.44%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    1
    Chest pain
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Food poisoning
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Toothache
         subjects affected / exposed
    6 / 477 (1.26%)
    2 / 283 (0.71%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    6
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 477 (0.63%)
    4 / 283 (1.41%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Pulmonary mass
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Throat irritation
         subjects affected / exposed
    1 / 477 (0.21%)
    3 / 283 (1.06%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 477 (1.05%)
    3 / 283 (1.06%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    5
    3
    0
    0
    Back pain
         subjects affected / exposed
    10 / 477 (2.10%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    10
    1
    0
    0
    Haemarthrosis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Spinal pain
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    COVID-19
         subjects affected / exposed
    16 / 477 (3.35%)
    9 / 283 (3.18%)
    2 / 228 (0.88%)
    2 / 70 (2.86%)
         occurrences all number
    16
    9
    2
    2
    Cellulitis
         subjects affected / exposed
    0 / 477 (0.00%)
    3 / 283 (1.06%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    1 / 228 (0.44%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    1
    1
    Helicobacter infection
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    13 / 477 (2.73%)
    16 / 283 (5.65%)
    6 / 228 (2.63%)
    0 / 70 (0.00%)
         occurrences all number
    16
    18
    6
    0
    Oral fungal infection
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Pulpitis dental
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 477 (1.26%)
    5 / 283 (1.77%)
    4 / 228 (1.75%)
    0 / 70 (0.00%)
         occurrences all number
    6
    5
    4
    0
    Urinary tract infection
         subjects affected / exposed
    5 / 477 (1.05%)
    1 / 283 (0.35%)
    0 / 228 (0.00%)
    0 / 70 (0.00%)
         occurrences all number
    5
    1
    0
    0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 477 (0.00%)
    0 / 283 (0.00%)
    0 / 228 (0.00%)
    1 / 70 (1.43%)
         occurrences all number
    0
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jun 2020
    The protocol was amended to address minor administrative items, clarifications, and substantial changes to add an electrocardiogram exclusion criterion, spirometry at Week 24, optional rather than mandatory COVID-19 testing, and adding a section on "Treatment After the End of Study".
    26 Jun 2020
    The protocol was amended to remove the requirement for pregnancy testing in all women and to only perform pregnancy testing on women of childbearing potential.
    17 Jul 2020
    The protocol was amended to reorder the secondary endpoint testing hierarchy, to remove an evening dosing requirement at early termination visits with 12-hour spirometry, to revise ‘Events Meeting the Adverse Events Definition’, to clarify COVID-19 testing as optional, to correct a minor document formatting issue, and to clarify the protocol version and amendment numbers.
    30 Apr 2021
    The protocol was amended to allow some patients with stable use of inhaled corticosteroids, reorder the secondary endpoint testing hierarchy and add additional endpoints, to update the handling of missing data in the statistical analysis, to incorporate contents of protocol clarification letters dated 29 September 2020 and 05 November 2020, to revise exclusion criteria relating to hepatitis B and C, and to revise and clarify prohibited medication requirements regarding chronic use of antibiotics and beta-blockers, and to update and clarify requirements for stable use of maintenance therapy in inclusion criteria.
    18 Feb 2022
    This amendment was a minor clarification to the protocol to allow flexibility to enroll approximately 50% of patients on stable background therapy, rather than to cap enrollment of patients on background therapy precisely at 50%. This clarification to the protocol had no impact on the safety of trial patients, as patients on background therapy were already being enrolled into the trial. Additionally, allowing slightly more than 50% of patients on background bronchodilator therapy had no significant impact on the robustness of the trial data or the scientific value of the clinical trial, as the protocol requirement that patients withhold background bronchodilators for a 24 to 48 hour washout period prior to all spirometry visits ensured the planned powering assumptions for the study would not be impacted. Medical Monitor contact information was updated according to administrative letter dated 29 November 2021.

    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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    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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