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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 in Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease.

    Summary
    EudraCT number
    		 2020-002069-32
    Trial protocol
    		 SK   BE   DK   HU   BG  
    Global end of trial date
    06 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2023
    First version publication date
    23 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RPL554-CO-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04542057
    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
    06 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 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 Organizations 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
    22 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
    Belgium: 5
    Country: Number of subjects enrolled
    Bulgaria: 131
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Estonia: 20
    Country: Number of subjects enrolled
    Hungary: 52
    Country: Number of subjects enrolled
    Poland: 58
    Country: Number of subjects enrolled
    Slovakia: 18
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    United States: 455
    Worldwide total number of subjects
    790
    EEA total number of subjects
    322
    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)
    348
    From 65 to 84 years
    442
    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 130 study centers. Patients were randomized in a 5:3 ratio, stratified by smoking status and background medication use, manner to receive either ensifentrine or placebo. A total of 790 patients were randomized in this study.

    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.

    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 solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Ensifentrine placebo inhaled by jet nebulizer twice daily (morning and evening) for 24 weeks.

    Number of subjects in period 1
    		Ensifentrine Placebo
    Started
    499
    291
    Received Treatment
    498
    291
    Completed
    393
    218
    Not completed
    106
    73
         COPD exacerbation withdrawal criteria
    5
    6
         Consent withdrawn by subject
    52
    30
         Adverse event, non-fatal
    15
    6
         Death
    3
    1
         Study terminated by sponsor
    1
    -
         Unspecified
    2
    2
         COVID-19 adverse event
    6
    4
         Investigator discretion
    2
    1
         Lost to follow-up
    8
    11
         Coronavirus disease 2019 (COVID-19)
    10
    7
         Lack of efficacy
    2
    5

    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
    		 499 291 790
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.0 ± 7.38 65.3 ± 7.30 -
    Gender categorical
    Units: Subjects
        Female
    		 254 153 407
        Male
    		 245 138 383
    Race
    Units: Subjects
        American Indian or Alaska native
    		 1 0 1
        Asian
    		 1 1 2
        Black or African American
    		 24 11 35
        White
    		 472 276 748
        Other
    		 1 3 4
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 26 14 40
        Not Hispanic or Latino
    		 473 277 750

    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.
    End point type
    Primary
    End point timeframe
    Baseline (40 minutes before first administration on Day 1) and Week 12
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    498
    291
    Units: liters
        least squares mean (standard error)
    0.0480 ± 0.00941
    -0.0462 ± 0.01236
    Statistical analysis title
    		 Treatment difference in average FEV1 AUC0-12h
    Comparison groups
    Placebo v Ensifentrine
    Number of subjects included in analysis
    789
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.0941
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0647
         upper limit
    		 0.1236
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01501
    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 (40 minutes before first administration on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    498
    291
    Units: liters
    least squares mean (standard error)
        Day 1 (Post-dose)
    0.2369 ± 0.00601
    0.0801 ± 0.00784
        Week 6
    0.2158 ± 0.00969
    0.0636 ± 0.01276
        Week 12
    0.1945 ± 0.01012
    0.0482 ± 0.01349
        Week 24
    0.1957 ± 0.01099
    0.0434 ± 0.01475
    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 (average of 7 days before first administration on Day 1) and Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    492
    291
    Units: units on a scale
    least squares mean (standard error)
        Week 6
    -1.938 ± 0.2086
    -0.614 ± 0.2763
        Week 12
    -2.051 ± 0.2245
    -1.161 ± 0.2963
        Week 24
    -2.146 ± 0.2557
    -1.529 ± 0.3365
    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 4h 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 (40 minutes before first administration on Day 1) and Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    489
    286
    Units: units on a scale
    least squares mean (standard error)
        Week 6
    -3.602 ± 0.5902
    -1.890 ± 0.7692
        Week 12
    -4.019 ± 0.6171
    -2.942 ± 0.8168
        Week 24
    -4.532 ± 0.6840
    -4.054 ± 0.9084
    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 (40 minutes before first administration on Day 1) and Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    498
    291
    Units: liters
    least squares mean (standard error)
        Week 6
    0.0177 ± 0.00899
    -0.0261 ± 0.01181
        Week 12
    0.0057 ± 0.00957
    -0.0435 ± 0.01266
        Week 24
    -0.0066 ± 0.01006
    -0.0318 ± 0.01323
    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 (40 minutes before first administration on Day 1), post-dose on Day 1, Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    498
    291
    Units: liters
    least squares mean (standard error)
        Day 1 (Post-dose)
    0.1556 ± 0.00527
    0.0063 ± 0.00686
        Week 6
    0.1357 ± 0.00932
    -0.0082 ± 0.01209
        Week 12
    0.1148 ± 0.00943
    -0.0209 ± 0.01260
        Week 24
    0.1148 ± 0.01036
    -0.0248 ± 0.01381
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Patients With SGRQ Responders at Weeks 6, 12 and 24
    End point description
    Responder was a patient with an improvement from baseline in SGRQ total score of 4 or more. Percentage of patients with 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
    489
    286
    Units: percentage of patients
    number (not applicable)
        Week 6
    44.0
    39.5
        Week 12
    45.2
    43.0
        Week 24
    45.4
    50.3
    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 (average of 7 days before first administration on Day 1) and Weeks 6, 12, and 24
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    492
    291
    Units: number of rescue medication puffs
    least squares mean (standard error)
        Week 6
    -0.530 ± 0.0883
    -0.191 ± 0.1165
        Week 12
    -0.573 ± 0.0745
    -0.288 ± 0.0976
        Week 24
    -0.485 ± 0.0871
    -0.346 ± 0.1143
    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. 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
    484
    286
    Units: units on a scale
    least squares mean (standard error)
        Week 6
    1.6 ± 0.12
    0.9 ± 0.16
        Week 12
    1.8 ± 0.13
    1.2 ± 0.18
        Week 24
    2.2 ± 0.15
    1.3 ± 0.20
    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 (40 minutes before first administration on Day 1) and Week 12
    End point values
    		 Ensifentrine Placebo
    Number of subjects analysed
    498
    291
    Units: liters
        least squares mean (standard error)
    -0.0246 ± 0.01079
    -0.0783 ± 0.01358
    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 the first dose of study treatment up to 10 days after the final study visit at Week 24, approximately 25 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
    Ensifentrine
    Reporting group description
    		 3 mg twice daily via standard jet nebulizer.

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

    Serious adverse events
    		 Ensifentrine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 498 (5.62%)
    17 / 291 (5.84%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    4
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer stage II
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal neoplasm
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
    Additional description: These adverse events were secondary to: adverse events of COVID-19 pneumonia, acute diastolic congestive heart failure, and toxicity to various agents.
         subjects affected / exposed
    3 / 498 (0.60%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    10 / 498 (2.01%)
    5 / 291 (1.72%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 498 (0.40%)
    2 / 291 (0.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colonic abscess
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 498 (0.40%)
    4 / 291 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 498 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 498 (0.20%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Ensifentrine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 498 (13.65%)
    46 / 291 (15.81%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 498 (1.00%)
    1 / 291 (0.34%)
         occurrences all number
    5
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 498 (0.20%)
    4 / 291 (1.37%)
         occurrences all number
    1
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 498 (2.01%)
    7 / 291 (2.41%)
         occurrences all number
    10
    8
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 498 (0.20%)
    3 / 291 (1.03%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    8 / 498 (1.61%)
    2 / 291 (0.69%)
         occurrences all number
    8
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 498 (0.40%)
    3 / 291 (1.03%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    3 / 498 (0.60%)
    4 / 291 (1.37%)
         occurrences all number
    3
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 498 (1.61%)
    5 / 291 (1.72%)
         occurrences all number
    8
    5
    Infections and infestations
    COVID-19
         subjects affected / exposed
    16 / 498 (3.21%)
    10 / 291 (3.44%)
         occurrences all number
    16
    10
    Nasopharyngitis
         subjects affected / exposed
    9 / 498 (1.81%)
    3 / 291 (1.03%)
         occurrences all number
    10
    3
    Sinusitis
         subjects affected / exposed
    5 / 498 (1.00%)
    0 / 291 (0.00%)
         occurrences all number
    5
    0
    Urinary tract infection
         subjects affected / exposed
    7 / 498 (1.41%)
    5 / 291 (1.72%)
         occurrences all number
    7
    5
    Tooth Abcess
         subjects affected / exposed
    0 / 498 (0.00%)
    4 / 291 (1.37%)
         occurrences all number
    0
    4

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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 criteria, 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 make minor clarifications to the pharmacokinetic section, 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.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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