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    Clinical Trial Results:
    A multicentre, randomised, double-blind, placebo-controlled phase 2 trial to evaluate efficacy and safety of lenabasum in cystic fibrosis

    Summary
    EudraCT number
    		 2017-003723-29
    Trial protocol
    		 GB   DE   HU   SE   FR   PT   SK   AT   BE   ES   BG   NL   CZ   GR   PL   IT   RO  
    Global end of trial date
    17 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jan 2022
    First version publication date
    20 Jan 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    JBT101-CF-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03451045
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Corbus Pharmaceuticals Inc.
    Sponsor organisation address
    500 River Ridge Drive, Norwood, United States, MA 02062
    Public contact
    Corbus General Information, Corbus Pharmaceuticals Inc., +1 617-963-0100, info@corbuspharma.com
    Scientific contact
    Corbus General Information, Corbus Pharmaceuticals Inc., +1 617-963-0100, info@corbuspharma.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
    10 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of lenabasum 20 mg twice per day (BID) compared to placebo in the treatment of cystic fibrosis (CF) by assessing the rate of pulmonary exacerbations (PEx) using this study's primary definition of new PEx (the physician diagnosis of PEx, treatment with new oral, intravenous, or inhaled antibiotic(s) starting >28 days after completion of the last course of antibiotics for a prior PEx, and met at least 4 of 12 Fuch’s criteria).
    Protection of trial subjects
    Oversight of subject safety in this trial was provided by a data monitoring committee (DMC) subcommittee of the Cystic Fibrosis Foundation Therapeutics Data Safety Monitoring Board, an independent group of CF experts that was to advise the Sponsor. The primary responsibilities of the DMC were to: 1) periodically review and evaluate the accumulated study data for participant safety, study conduct and progress, and, when appropriate, efficacy; and 2) make recommendations to the Sponsor concerning the continuation, modification, or termination of the trial.
    Background therapy
    		 Each patient was maintained on all his/her baseline medications for CF from screening through Visit 9, unless the investigator or treating physician judged a change in therapy was needed to provide best medical care for the patient.
    Evidence for comparator
    		 This was a placebo-controlled trial. All patients in the trial maintained their previous CF medication in addition to randomised study medication.
    Actual start date of recruitment
    14 Feb 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 151
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Serbia: 6
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Slovakia: 8
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hungary: 35
    Country: Number of subjects enrolled
    Italy: 18
    Worldwide total number of subjects
    447
    EEA total number of subjects
    211
    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)
    85
    Adults (18-64 years)
    361
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited between 08 May 2018 and 08 November 2019 (211 in Europe and 236 outside Europe).

    Pre-assignment
    Screening details
    		 A total of 541 patients were screened and of these 447 were randomised, including 425 patients treated and 22 randomised but not treated.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Lenabasum and placebo capsules had similar physical appearance and were packaged, labelled and handled so that patients and site staff were not able to distinguish treatments.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Lenabasum 20 mg
    Arm description
    		 Randomised treatment arm, in which patients were treated with the higher dose of lenabasum.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenabasum 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg Lenabasum, taken orally twice daily (total dose: 40 mg lenabasum per day)

    Arm title
    		 Lenabasum 5 mg
    Arm description
    		 Randomised treatment arm, in which patients were treated with the lower dose of lenabasum.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenabasum 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg lenabasum , taken orally twice daily (total dose: 10 mg lenabasum per day)

    Arm title
    		 Placebo
    Arm description
    		 Randomised treatment arm, in which patients were treated with placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching lenabasum capsules administered twice daily.

    Arm title
    		 Lenabasum 20 mg age <18
    Arm description
    		 Patients aged <18 years in the lenabasum 20 mg treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenabasum 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg lenabasum, taken orally twice daily (total dose: 40 mg lenabasum per day)

    Arm title
    		 Lenabasum 5 mg age <18
    Arm description
    		 Patients aged <18 years in the lenabasum 5 mg treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenabasum 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg Lenabasum, taken orally twice daily (total dose: 10 mg lenabasum per day)

    Arm title
    		 Placebo <18
    Arm description
    		 Patients aged <18 years in the placebo treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching lenabasum capsules administered twice daily.

    Arm title
    		 Lenabasum 20 mg age >=18
    Arm description
    		 Patients aged >=18 years in the lenabasum 20 mg treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenabasum 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg lenabasum , taken orally twice daily (total dose: 40 mg lenabasum per day)

    Arm title
    		 Lenabasum 5 mg age >=18
    Arm description
    		 Patients aged >=18 years in the lenabasum 5 mg treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenabasum 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg Lenabasum, taken orally twice daily (total dose: 10 mg lenabasum per day)

    Arm title
    		 Placebo >=18
    Arm description
    		 Patients aged >=18 years in the placebo treatment group
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching lenabasum capsules administered twice daily.

    Number of subjects in period 1
    		Lenabasum 20 mg Lenabasum 5 mg Placebo Lenabasum 20 mg age <18 Lenabasum 5 mg age <18 Placebo <18 Lenabasum 20 mg age >=18 Lenabasum 5 mg age >=18 Placebo >=18
    Started
    165
    89
    171
    32
    13
    40
    133
    76
    131
    Completed
    148
    85
    154
    29
    13
    36
    119
    72
    118
    Not completed
    17
    4
    17
    3
    0
    4
    14
    4
    13
         Consent withdrawn by subject
    4
    -
    5
    2
    -
    2
    2
    -
    3
         Physician decision
    1
    1
    1
    -
    -
    1
    1
    1
    -
         Adverse event, non-fatal
    7
    1
    3
    -
    -
    1
    7
    1
    2
         Not specified
    -
    -
    3
    -
    -
    -
    -
    -
    3
         Pregnancy
    -
    -
    2
    -
    -
    -
    -
    -
    2
         Non-compliance with study drug
    -
    -
    -
    1
    -
    -
    -
    -
    -
         Noncompliance with study drug
    -
    -
    -
    -
    -
    -
    1
    -
    1
         Lack of efficacy
    3
    2
    2
    -
    -
    -
    3
    2
    2
         Noncompliance
    2
    -
    1
    -
    -
    -
    -
    -
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups [1]
    Reporting group title
    Lenabasum 20 mg
    Reporting group description
    		 Randomised treatment arm, in which patients were treated with the higher dose of lenabasum.

    Reporting group title
    Lenabasum 5 mg
    Reporting group description
    		 Randomised treatment arm, in which patients were treated with the lower dose of lenabasum.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomised treatment arm, in which patients were treated with placebo.

    Reporting group title
    Lenabasum 20 mg age <18
    Reporting group description
    		 Patients aged <18 years in the lenabasum 20 mg treatment group

    Reporting group title
    Lenabasum 5 mg age <18
    Reporting group description
    		 Patients aged <18 years in the lenabasum 5 mg treatment group

    Reporting group title
    Placebo <18
    Reporting group description
    		 Patients aged <18 years in the placebo treatment group

    Reporting group title
    Lenabasum 20 mg age >=18
    Reporting group description
    		 Patients aged >=18 years in the lenabasum 20 mg treatment group

    Reporting group title
    Lenabasum 5 mg age >=18
    Reporting group description
    		 Patients aged >=18 years in the lenabasum 5 mg treatment group

    Reporting group title
    Placebo >=18
    Reporting group description
    		 Patients aged >=18 years in the placebo treatment group

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The numbers of patients in the baseline period includes a total of 425 randomised and treated patients. Additional groups appearing for the baseline period were subgroups of this population according to age <18 or >= 18 years. Also, patients enrolled but not treated were not included.
    Reporting group values
    		 Lenabasum 20 mg Lenabasum 5 mg Placebo Lenabasum 20 mg age <18 Lenabasum 5 mg age <18 Placebo <18 Lenabasum 20 mg age >=18 Lenabasum 5 mg age >=18 Placebo >=18 Total
    Number of subjects
    		 165 89 171 32 13 40 133 76 131
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age at baseline (start of treatment period).
    Units: years
        arithmetic mean (standard deviation)
    		 26.2 ( 9.08 ) 28.9 ( 11.24 ) 26.6 ( 10.81 ) 14.5 ( 1.37 ) 15.0 ( 1.96 ) 15.1 ( 1.63 ) 29.1 ( 7.79 ) 31.3 ( 10.42 ) 30.1 ( 9.94 ) -
    Gender categorical
    Units: Subjects
        Female
    		 91 44 93 17 4 16 74 40 77 228
        Male
    		 74 45 78 15 9 24 59 36 54 197
    FEV1
    Forced expiratory volume in 1 second (FEV1), categorical: <70% predicted or >=70% predicted at baseline.
    Units: Subjects
        <70% predicted
    		 120 62 121 16 6 18 104 56 103 303
        >=70% predicted
    		 45 27 50 16 7 22 29 20 28 122
    Pulmonary exacerbations (PEx)
    Number of previous PEx requiring antibiotics in the year before study entry
    Units: Subjects
        None
    		 2 0 0 0 0 0 2 0 0 2
        One
    		 76 44 78 20 9 23 56 35 55 198
        Two
    		 57 30 68 8 1 14 49 29 54 155
        Three
    		 30 15 24 4 3 2 26 12 22 69
        Four
    		 0 0 1 0 0 1 0 0 0 1
    FEV1
    FEV1 (L), at baseline.
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 2.0947 ( 0.73374 ) 2.2004 ( 0.76964 ) 2.1659 ( 0.78117 ) 2.2749 ( 0.68323 ) 2.4378 ( 0.65759 ) 2.4551 ( 0.76960 ) 2.0513 ( 0.74128 ) 2.1598 ( 0.78383 ) 2.0776 ( 0.76598 ) -
    Subject analysis sets

    Subject analysis set title
    Modified ITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intention-to-treat (mITT) population included all randomised subjects who received at least 1 dose of study drug, categorised by planned treatment. Note: the mITT population was identical to the population of all treated patients.

    Subject analysis sets values
    		 Modified ITT population
    Number of subjects
    425
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age at baseline (start of treatment period).
    Units: years
        arithmetic mean (standard deviation)
    26.9 ( 25.0 )
    Gender categorical
    Units: Subjects
        Female
    228
        Male
    197
    FEV1
    Forced expiratory volume in 1 second (FEV1), categorical: <70% predicted or >=70% predicted at baseline.
    Units: Subjects
        <70% predicted
    303
        >=70% predicted
    122
    Pulmonary exacerbations (PEx)
    Number of previous PEx requiring antibiotics in the year before study entry
    Units: Subjects
        None
    2
        One
    198
        Two
    155
        Three
    69
        Four
    1
    FEV1
    FEV1 (L), at baseline.
    Units: litre(s)
        arithmetic mean (standard deviation)
    2.1455 ( 1.9880 )

    End points

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    End points reporting groups
    Reporting group title
    Lenabasum 20 mg
    Reporting group description
    		 Randomised treatment arm, in which patients were treated with the higher dose of lenabasum.

    Reporting group title
    Lenabasum 5 mg
    Reporting group description
    		 Randomised treatment arm, in which patients were treated with the lower dose of lenabasum.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomised treatment arm, in which patients were treated with placebo.

    Reporting group title
    Lenabasum 20 mg age <18
    Reporting group description
    		 Patients aged <18 years in the lenabasum 20 mg treatment group

    Reporting group title
    Lenabasum 5 mg age <18
    Reporting group description
    		 Patients aged <18 years in the lenabasum 5 mg treatment group

    Reporting group title
    Placebo <18
    Reporting group description
    		 Patients aged <18 years in the placebo treatment group

    Reporting group title
    Lenabasum 20 mg age >=18
    Reporting group description
    		 Patients aged >=18 years in the lenabasum 20 mg treatment group

    Reporting group title
    Lenabasum 5 mg age >=18
    Reporting group description
    		 Patients aged >=18 years in the lenabasum 5 mg treatment group

    Reporting group title
    Placebo >=18
    Reporting group description
    		 Patients aged >=18 years in the placebo treatment group

    Subject analysis set title
    Modified ITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified intention-to-treat (mITT) population included all randomised subjects who received at least 1 dose of study drug, categorised by planned treatment. Note: the mITT population was identical to the population of all treated patients.

    Primary: Rate of new pulmonary exacerbations - primary definition

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    End point title
    		 Rate of new pulmonary exacerbations - primary definition [1]
    End point description
    The proportion of subjects with at least 1 PEx event at end of treatment, based on the primary definition of PEx (physician diagnosis of PEx, treatment with new oral, intravenous, or inhaled antibiotic(s) starting >28 days after completion of the last course of antibiotics for a prior PEx, and meeting at least 4 of 12 Fuch’s criteria).
    End point type
    Primary
    End point timeframe
    Event rate at the end of treatment
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The groups not included represent subgroups of the overall population including only patients aged less than 18 years or aged greater than or equal to 18 years.
    End point values
    		 Lenabasum 20 mg Lenabasum 5 mg Placebo
    Number of subjects analysed
    165
    89
    171
    Units: Subjects
    89
    50
    94
    Statistical analysis title
    		 PEx rate: Lenabasum 20 mg vs placebo
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Placebo v Lenabasum 20 mg
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.6178 [3]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    1.0624
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8375
         upper limit
    		 1.3478
    Notes
    [2] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CF transmembrane conductance regulator (CFTR) targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [3] - Lenabasum 20 mg vs placebo
    Statistical analysis title
    		 PEx rate: Lenabasum 5 mg vs placebo
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Lenabasum 5 mg v Placebo
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.427 [5]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.887
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6597
         upper limit
    		 1.1924
    Notes
    [4] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [5] - Lenabasum 5 mg vs placebo

    Primary: Rate of new pulmonary exacerbations in patients age >=18 - primary definition

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    End point title
    		 Rate of new pulmonary exacerbations in patients age >=18 - primary definition [6]
    End point description
    The proportion of subjects aged >=18 years with at least 1 PEx event at end of treatment, based on the primary definition of PEx (physician diagnosis of PEx, treatment with new oral, intravenous, or inhaled antibiotic(s) starting >28 days after completion of the last course of antibiotics for a prior PEx, and meeting at least 4 of 12 Fuch’s criteria).
    End point type
    Primary
    End point timeframe
    Event rate at the end of treatment
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This represents a subgroup of the overall population including only patients aged greater than or equal to 18 years.
    End point values
    		 Lenabasum 20 mg age >=18 Lenabasum 5 mg age >=18 Placebo >=18
    Number of subjects analysed
    133
    76
    131
    Units: Subjects aged >=18 years
    72
    34
    82
    Statistical analysis title
    		 PEx rate: Lenabasum 20 mg vs placebo age >=18
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups in patients aged >=18 years. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Lenabasum 20 mg age >=18 v Placebo >=18
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.9296 [8]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.9884
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7639
         upper limit
    		 1.2791
    Notes
    [7] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [8] - Lenabasum 20 mg vs placebo in patients aged >=18 years
    Statistical analysis title
    		 PEx rate: Lenabasum 5 mg vs placebo ag...
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups in patients aged >=18 years. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Placebo >=18 v Lenabasum 5 mg age >=18
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.2757 [10]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.8404
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6147
         upper limit
    		 1.1489
    Notes
    [9] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [10] - Lenabasum 5 mg vs placebo in patients aged >=18 years

    Secondary: Rate of PEx - secondary definition

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    End point title
    		 Rate of PEx - secondary definition [11]
    End point description
    The proportion of subjects with at least 1 PEx event, based on the secondary definition of PEx (physician diagnosis of PEx, treatment with new oral, intravenous, or inhaled antibiotic(s) starting >28 days after completion of the last course of antibiotics for a prior PEx).
    End point type
    Secondary
    End point timeframe
    Event rate at the end of treatment
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The groups not included represent subgroups of the overall population including only patients aged less than 18 years or aged greater than or equal to 18 years.
    End point values
    		 Lenabasum 20 mg Lenabasum 5 mg Placebo
    Number of subjects analysed
    165
    89
    171
    Units: Subjects
    99
    56
    107
    Statistical analysis title
    		 PEx rate: Lenabasum 20 mg vs placebo
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Lenabasum 20 mg v Placebo
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.7145 [13]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    1.0419
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8364
         upper limit
    		 1.2978
    Notes
    [12] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [13] - Lenabasum 20 mg vs placebo
    Statistical analysis title
    		 PEx rate: Lenabasum 5 mg vs placebo
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Lenabasum 5 mg v Placebo
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.3797 [15]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.8851
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.674
         upper limit
    		 1.1622
    Notes
    [14] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [15] - Lenabasum 5 mg vs placebo

    Secondary: Rate of new pulmonary exacerbations in patients age <18 - primary definition

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    End point title
    		 Rate of new pulmonary exacerbations in patients age <18 - primary definition [16]
    End point description
    The proportion of subjects aged <18 years with at least 1 PEx event at end of treatment, based on the primary definition of PEx (physician diagnosis of PEx, treatment with new oral, intravenous, or inhaled antibiotic(s) starting >28 days after completion of the last course of antibiotics for a prior PEx, and meeting at least 4 of 12 Fuch’s criteria).
    End point type
    Secondary
    End point timeframe
    Event rate at the end of treatment
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This represents a subgroup of the overall population including only patients aged less than 18 years.
    End point values
    		 Lenabasum 20 mg age <18 Lenabasum 5 mg age <18 Placebo <18
    Number of subjects analysed
    32
    13
    40
    Units: Subjects aged <18 years
    17
    5
    12
    Statistical analysis title
    		 PEx rate: Lenabasum 20 mg vs placebo
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups in patients aged <18 years. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Lenabasum 20 mg age <18 v Placebo <18
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.17 [18]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    1.5496
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.829
         upper limit
    		 2.8965
    Notes
    [17] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [18] - Lenabasum 20 mg vs placebo in patients aged <18 years
    Statistical analysis title
    		 PEx rate: Lenabasum 5 mg vs placebo age <18
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups in patients aged <18 years. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Lenabasum 5 mg age <18 v Placebo <18
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.8789 [20]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    1.072
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.438
         upper limit
    		 2.6236
    Notes
    [19] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [20] - Lenabasum 5 mg vs placebo in patients aged <18 years

    Secondary: Rate of PEx - secondary definition – age <18 years

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    End point title
    		 Rate of PEx - secondary definition – age <18 years [21]
    End point description
    The proportion of subjects age <18 years with at least 1 PEx event, based on the secondary definition of PEx (physician diagnosis of PEx, treatment with new oral, intravenous, or inhaled antibiotic(s) starting >28 days after completion of the last course of antibiotics for a prior PEx).
    End point type
    Secondary
    End point timeframe
    Event rate at the end of treatment
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This represents a subgroup of the overall population including only patients aged less than 18 years.
    End point values
    		 Lenabasum 20 mg age <18 Lenabasum 5 mg age <18 Placebo <18
    Number of subjects analysed
    32
    13
    40
    Units: Subjects aged <18 years
    21
    7
    15
    Statistical analysis title
    		 PEx rate: Lenabasum 20 mg vs placebo – age <18
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Lenabasum 20 mg age <18 v Placebo <18
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.172 [23]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    1.4377
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8539
         upper limit
    		 2.4209
    Notes
    [22] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [23] - Lenabasum 20 mg vs placebo
    Statistical analysis title
    		 PEx rate: Lenabasum 5 mg vs placebo – age >=18
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Placebo <18 v Lenabasum 5 mg age <18
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.8897 [25]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.9463
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4334
         upper limit
    		 2.0661
    Notes
    [24] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [25] - Lenabasum 5 mg vs placebo

    Secondary: Rate of PEx - secondary definition – age >= 18

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    End point title
    		 Rate of PEx - secondary definition – age >= 18 [26]
    End point description
    The proportion of subjects age >=18 years with at least 1 PEx event, based on the secondary definition of PEx (physician diagnosis of PEx, treatment with new oral, intravenous, or inhaled antibiotic(s) starting >28 days after completion of the last course of antibiotics for a prior PEx).
    End point type
    Secondary
    End point timeframe
    Event rate at the end of treatment
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This represents a subgroup of the overall population including only patients aged greater than or equal to 18 years.
    End point values
    		 Lenabasum 20 mg age >=18 Lenabasum 5 mg age >=18 Placebo >=18
    Number of subjects analysed
    133
    76
    131
    Units: Subjects aged >= 18 years
    78
    49
    92
    Statistical analysis title
    		 PEx rate: Lenabasum 20 mg vs placebo – age >=18
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Lenabasum 20 mg age >=18 v Placebo >=18
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.7062 [28]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.9548
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7505
         upper limit
    		 1.2146
    Notes
    [27] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [28] - Lenabasum 20 mg vs placebo
    Statistical analysis title
    		 PEx rate: Lenabasum 5 mg vs placebo – age >=18
    Statistical analysis description
    The event rate of new PEx was compared between the lenabasum and placebo groups. The overall type I error rate was controlled for primary and secondary efficacy outcomes with a fixed sequence independent hierarchical assessment of efficacy.
    Comparison groups
    Placebo >=18 v Lenabasum 5 mg age >=18
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.2926 [30]
    Method
    		 Poisson regression model
    Parameter type
    		 rate ratio
    Point estimate
    0.8568
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6425
         upper limit
    		 1.1426
    Notes
    [29] - Estimated using a Poisson regression model with effects of treatment and log(subject treatment exposure duration) as offset and scale = deviance options, adjusting for FEV1 % predicted (<70 versus >=70 predicted) at baseline, number of previous PEx requiring IV antibiotics in the previous year, baseline CFTR-targeting medications use (Yes, No), and region (United States versus Non-United States). P-values are for the comparison of lenabasum with placebo.
    [30] - Lenabasum 5 mg vs placebo

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to end of treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Lenabasum 20 mg
    Reporting group description
    		 Randomised treatment arm, in which patients were treated with the higher dose of lenabasum.

    Reporting group title
    Lenabasum 5 mg
    Reporting group description
    		 Randomised treatment arm, in which patients were treated with the lower dose of lenabasum.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomised treatment arm, in which patients were treated with placebo.

    Serious adverse events
    		 Lenabasum 20 mg Lenabasum 5 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    50 / 165 (30.30%)
    25 / 89 (28.09%)
    50 / 171 (29.24%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular torsion
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 165 (1.82%)
    1 / 89 (1.12%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    42 / 165 (25.45%)
    22 / 89 (24.72%)
    41 / 171 (23.98%)
         occurrences causally related to treatment / all
    3 / 61
    2 / 29
    1 / 53
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 89 (1.12%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Human rhinovirus test positive
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Non-compaction cardiomyopathy
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 89 (1.12%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    3 / 165 (1.82%)
    1 / 89 (1.12%)
    3 / 171 (1.75%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 89 (1.12%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 89 (1.12%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal disease carrier
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 165 (0.61%)
    0 / 89 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 165 (0.00%)
    0 / 89 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 165 (0.00%)
    1 / 89 (1.12%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lenabasum 20 mg Lenabasum 5 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    148 / 165 (89.70%)
    79 / 89 (88.76%)
    148 / 171 (86.55%)
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    8 / 165 (4.85%)
    6 / 89 (6.74%)
    7 / 171 (4.09%)
         occurrences all number
    9
    7
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 165 (7.88%)
    6 / 89 (6.74%)
    6 / 171 (3.51%)
         occurrences all number
    17
    12
    8
    Headache
         subjects affected / exposed
    24 / 165 (14.55%)
    11 / 89 (12.36%)
    16 / 171 (9.36%)
         occurrences all number
    32
    13
    22
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 165 (12.73%)
    10 / 89 (11.24%)
    16 / 171 (9.36%)
         occurrences all number
    25
    11
    16
    Pyrexia
         subjects affected / exposed
    16 / 165 (9.70%)
    7 / 89 (7.87%)
    12 / 171 (7.02%)
         occurrences all number
    31
    10
    16
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 165 (6.06%)
    5 / 89 (5.62%)
    9 / 171 (5.26%)
         occurrences all number
    11
    6
    10
    Constipation
         subjects affected / exposed
    10 / 165 (6.06%)
    2 / 89 (2.25%)
    5 / 171 (2.92%)
         occurrences all number
    10
    2
    5
    Diarrhoea
         subjects affected / exposed
    10 / 165 (6.06%)
    10 / 89 (11.24%)
    10 / 171 (5.85%)
         occurrences all number
    11
    22
    14
    Nausea
         subjects affected / exposed
    11 / 165 (6.67%)
    6 / 89 (6.74%)
    8 / 171 (4.68%)
         occurrences all number
    13
    7
    11
    Vomiting
         subjects affected / exposed
    10 / 165 (6.06%)
    3 / 89 (3.37%)
    10 / 171 (5.85%)
         occurrences all number
    11
    4
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 165 (18.79%)
    22 / 89 (24.72%)
    29 / 171 (16.96%)
         occurrences all number
    44
    33
    45
    Dyspnoea
         subjects affected / exposed
    8 / 165 (4.85%)
    6 / 89 (6.74%)
    8 / 171 (4.68%)
         occurrences all number
    9
    6
    9
    Haemoptysis
         subjects affected / exposed
    19 / 165 (11.52%)
    12 / 89 (13.48%)
    17 / 171 (9.94%)
         occurrences all number
    27
    15
    25
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    97 / 165 (58.79%)
    50 / 89 (56.18%)
    97 / 171 (56.73%)
         occurrences all number
    196
    93
    180
    Oropharyngeal pain
         subjects affected / exposed
    5 / 165 (3.03%)
    3 / 89 (3.37%)
    9 / 171 (5.26%)
         occurrences all number
    6
    3
    10
    Rales
         subjects affected / exposed
    11 / 165 (6.67%)
    4 / 89 (4.49%)
    12 / 171 (7.02%)
         occurrences all number
    15
    4
    15
    Sputum increased
         subjects affected / exposed
    14 / 165 (8.48%)
    11 / 89 (12.36%)
    20 / 171 (11.70%)
         occurrences all number
    19
    17
    25
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 165 (1.21%)
    7 / 89 (7.87%)
    3 / 171 (1.75%)
         occurrences all number
    5
    7
    4
    Nasopharyngitis
         subjects affected / exposed
    18 / 165 (10.91%)
    7 / 89 (7.87%)
    16 / 171 (9.36%)
         occurrences all number
    24
    8
    19
    Sinusitis
         subjects affected / exposed
    7 / 165 (4.24%)
    10 / 89 (11.24%)
    8 / 171 (4.68%)
         occurrences all number
    9
    11
    8
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 165 (7.27%)
    5 / 89 (5.62%)
    17 / 171 (9.94%)
         occurrences all number
    13
    6
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2017
    Reason for change: requested by FDA Key changes: Endpoints - Order of endpoints changed so that pulmonary exacerbation (PEx) rate was made primary endpoint (instead of secondary endpoint), and time to first exacerbation was demoted to a secondary endpoint. Moreover, for primary endpoint of PEx, the event had to meet 4/12 symptoms from Fuch’s criteria, in presence of antibiotic usage for respiratory signs and symptoms. Sample size - Sample size changed from 315 randomized subjects to 415 randomized subjects, because of change in primary endpoint. Treatment discontinuation - Clarified that treatment discontinuation not the same as withdrawal from the study, and further details around data collection and reporting added for treatment discontinuations. Screening: clarified that rescreening was permitted.
    14 Jun 2018
    Reason for change: clarifications by sponsor; request of some health authorities Key changes: Potential risk - convulsions or seizures added. Subjects with a history of any seizure within the last 2 years were excluded to mitigate a potential risk of seizures identified in animal studies. Premature study termination or suspension: Modified study stop/suspension criteria from 2 life-threatening clinical events deemed probably/definitely related to study drug to 1 related event. Safety reporting - Added the Sponsor’s responsibilities for reporting SUSARs per local country regulatory requirements. DMC - Clarified DMC responsibilities and members.
    09 Oct 2019
    Reason for change: clarifications and additional objective added by sponsor Key changes: Endpoints and objectives - Addition of a second tertiary efficacy objective and corresponding endpoints: To evaluate recovery from PEx in lenabasum 20 mg BID, lenabasum 5 mg BID, and placebo. Follow-up - Addition of language to indicate subjects would be asked to participate in a 2-year safety follow-up study. Subjects who agreed to participate in the follow-up study would be consented under a separate protocol. Primary endpoint - Clarification of Definition of Pulmonary Exacerbation: addition of phrase “Physician diagnosis of pulmonary exacerbation” to the primary definition. Responder definition - Addition of definition of Early Rapid Responder: Early rapid responders will be defined in several ways including but not limited to achieving a certain degree of improvement in FEV1, improvement in CRISS score, and improvement of other related measurements within a certain period of time.

    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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