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    Clinical Trial Results:
    Multicenter, International, Double-blind, Two-Arm, Randomized, Placebo-controlled Phase II Trial of Pirfenidone in Patients with Unclassifiable Progressive Fibrosing ILD

    Summary
    EudraCT number
    		 2016-002744-17
    Trial protocol
    		 ES   DK   CZ   DE   PL   PT   GR   BE   GB   IT  
    Global end of trial date
    10 Jan 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Jan 2021
    First version publication date
    03 Dec 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MA39189
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03099187
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124., Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the effect of pirfenidone versus (vs.) placebo on lung function parameters.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 May 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 38
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Greece: 13
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Portugal: 18
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United Kingdom: 40
    Worldwide total number of subjects
    253
    EEA total number of subjects
    179
    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)
    85
    From 65 to 84 years
    165
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 253 subjects were randomized at 65 study centers) in Australia, Europe, the Middle East, and North America. Subjects who were withdrawn from the trial were not replaced.

    Pre-assignment
    Screening details
    		 Subjects were requested to taper and/or discontinue all prohibited medications in the 28 days prior to the start of screening during the washout period.

    Period 1
    Period 1 title
    Double-Blind Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pirfenidone
    Arm description
    		 Subjects received pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pirfenidone
    Investigational medicinal product code
    Other name
    Esbriet
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pirfenidone was administered at a daily dose of 2403 mg orally in the form of three 267 mg capsules (801 mg) three times daily with food.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Pirfenidone matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pirfenisone matching placebo was administered orally in the form of hard capsules three times daily.

    Number of subjects in period 1
    		Pirfenidone Placebo
    Started
    127
    126
    Completed
    94
    110
    Not completed
    33
    16
         Adverse event, serious fatal
    1
    3
         Randomization error
    -
    2
         Physician decision
    2
    1
         Consent withdrawn by subject
    9
    4
         Disease progression
    -
    1
         Adverse event, non-fatal
    19
    1
         Lung transplantation
    -
    1
         Non-compliance with study drug
    -
    2
         Non-compliance with Protocol procedure
    1
    1
         Lack of efficacy
    1
    -
    Period 2
    Period 2 title
    12-month Safety Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Open-Label Treatment (Pirfenidone)
    Arm description
    		 After subjects completed the double-blind treatment period and the follow-up visit at Week 28, they were offered the option to receive open-label pirfenidone within the trial protocol in a safety follow-up period of up to 12 months. A final follow-up visit was performed at the end of the safety period, 28 days after the last open-label dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pirfenidone
    Investigational medicinal product code
    Other name
    Esbriet
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pirfenidone was administered at a daily dose of 2403 mg orally in the form of three 267 mg capsules (801 mg) three times daily with food.

    Arm title
    		 Open-Label Treatment (Placebo)
    Arm description
    		 After subjects completed the double-blind treatment period and the follow-up visit at Week 28, they were offered the option to receive open-label pirfenidone within the trial protocol in a safety follow-up period of up to 12 months. A final follow-up visit was performed at the end of the safety period, 28 days after the last open-label dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pirfenidone
    Investigational medicinal product code
    Other name
    Esbriet
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pirfenidone was administered at a daily dose of 2403 mg orally in the form of three 267 mg capsules (801 mg) three times daily with food.

    Number of subjects in period 2
    		Open-Label Treatment (Pirfenidone) Open-Label Treatment (Placebo)
    Started
    94
    110
    Completed
    75
    84
    Not completed
    19
    26
         Adverse event, serious fatal
    7
    9
         Consent withdrawn by subject
    3
    2
         Due to hospitalization
    -
    1
         Adverse event, non-fatal
    5
    12
         Symptomatic deterioration
    1
    1
         Lung transplantation
    2
    1
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pirfenidone
    Reporting group description
    		 Subjects received pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.

    Reporting group values
    		 Pirfenidone Placebo Total
    Number of subjects
    		 127 126 253
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 43 42 85
        From 65-84 years
    		 82 83 165
        85 years and over
    		 2 1 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 68.0 ± 10.1 67.7 ± 9.2 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 57 57 114
        Male
    		 70 69 139
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 7 9 16
        Not Hispanic or Latino
    		 115 112 227
        Not reported
    		 5 5 10
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaskan Native
    		 1 0 1
        Asian
    		 5 0 5
        Black or African American
    		 1 2 3
        Other
    		 0 1 1
        White
    		 120 123 243

    End points

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    End points reporting groups
    Reporting group title
    Pirfenidone
    Reporting group description
    		 Subjects received pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.
    Reporting group title
    Open-Label Treatment (Pirfenidone)
    Reporting group description
    		 After subjects completed the double-blind treatment period and the follow-up visit at Week 28, they were offered the option to receive open-label pirfenidone within the trial protocol in a safety follow-up period of up to 12 months. A final follow-up visit was performed at the end of the safety period, 28 days after the last open-label dose.

    Reporting group title
    Open-Label Treatment (Placebo)
    Reporting group description
    		 After subjects completed the double-blind treatment period and the follow-up visit at Week 28, they were offered the option to receive open-label pirfenidone within the trial protocol in a safety follow-up period of up to 12 months. A final follow-up visit was performed at the end of the safety period, 28 days after the last open-label dose.

    Subject analysis set title
    Intent-toTreat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population was defined as all randomized subjects. The ITT population was the primary analysis population for all efficacy analyses.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.

    Subject analysis set title
    Safety Follow-Up Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    For the 12-month safety follow-up period, the safety follow-up population was defined as all subjects who received at least one dose of pirfenidone after the end of randomized treatment plus 28 days. Safety analyses for the 12-month follow-up period were performed from the date of the first pirfenidone drug intake during the safety follow-up period up to the study completion/discontinuation visit.

    Primary: Rate of Decline in Forced Vital Capacity (FVC) Over the 24-week Double-blind Treatment Period

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    End point title
    		 Rate of Decline in Forced Vital Capacity (FVC) Over the 24-week Double-blind Treatment Period
    End point description
    Rate of decline in FVC was measured in mL by daily handheld spirometer. The analyses were repeated due to an additional independent review of the home spirometry data.
    End point type
    Primary
    End point timeframe
    Up to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    124 [1]
    123 [2]
    Units: milliliter (mL)
    arithmetic mean (confidence interval 95%)
        Primary Analysis in 2019
    -17.9 (-311.7 to 275.9)
    116.6 (-451.9 to 685.2)
        Final Analysis in 2020
    -90.3 (-157.0 to -23.7)
    125.6 (-458.4 to 709.6)
    Notes
    [1] - 116 subject data analyzed in 2020.
    [2] - 116 subject data analyzed in 2020.
    Statistical analysis title
    		 Primary Analysis in 2019
    Statistical analysis description
    Mean FVC decline comparison between treatment groups using a Student's t-test with a two-sided significance level of 0.05
    Comparison groups
    Placebo v Pirfenidone
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6777 [3]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Difference in Group Means
    Point estimate
    -134.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -772.4
         upper limit
    		 503.3
    Notes
    [3] - p-value is not adjusted for multiplicity and is provided for descriptive purpose only
    Statistical analysis title
    		 Final analysis in 2020
    Statistical analysis description
    Mean FVC decline comparison between treatment groups using a Student's t-test with a two-sided significance level of 0.05
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4682 [4]
    Method
    		 Student's t-test
    Parameter type
    		 Difference in Group Means
    Point estimate
    -216
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -803.6
         upper limit
    		 317.7
    Notes
    [4] - p-value was not adjusted for multiplicity and is provided for descriptive purpose only

    Secondary: Change in Percent Predicted FVC

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    End point title
    		 Change in Percent Predicted FVC
    End point description
    FVC was measured in liter (L) by spirometry. The analyses were repeated due to additional data cleaning activities that were not conducted during the primary analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127 [5]
    126 [6]
    Units: Percent predicted (%)
    arithmetic mean (standard deviation)
        Baseline (Day 1)
    73.95 ± 18.815
    73.95 ± 19.974
        Week 4
    74.04 ± 19.009
    74.55 ± 21.223
        Week 8
    73.98 ± 19.324
    73.50 ± 20.168
        Week 12
    73.96 ± 19.493
    73.91 ± 20.856
        Week 16
    74.56 ± 20.299
    72.65 ± 22.479
        Week 20
    73.94 ± 21.000
    71.99 ± 21.673
        Week 24
    72.95 ± 20.819
    73.55 ± 22.383
    Notes
    [5] - Number of subjects analysed was different at each time point; only collected data were analysed.
    [6] - Number of subjects analysed was different at each time point; only collected data were analysed.
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0383
    Method
    		 rank ANCOVA
    Confidence interval
    Statistical analysis title
    		 Final analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0239
    Method
    		 rank ANCOVA
    Confidence interval

    Secondary: Change in FVC

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    End point title
    		 Change in FVC
    End point description
    FVC was measured in liter (L) by spirometry. The analyses were repeated due to additional data cleaning activities that were not conducted during the primary analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127 [7]
    126 [8]
    Units: Litre (L)
    arithmetic mean (standard deviation)
        Baseline
    2.36 ± 0.793
    2.38 ± 0.747
        Week 4
    2.37 ± 0.818
    2.37 ± 0.786
        Week 8
    2.37 ± 0.822
    2.36 ± 0.816
        Week 12
    2.37 ± 0.820
    2.35 ± 0.773
        Week 16
    2.41 ± 0.860
    2.31 ± 0.782
        Week 20
    2.40 ± 0.866
    2.30 ± 0.796
        Week 24
    2.37 ± 0.863
    2.34 ± 0.773
    Notes
    [7] - Number of subjects analysed was different at each time point; only collected data were analysed.
    [8] - Number of subjects analysed was different at each time point; only collected data were analysed.
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018 [9]
    Method
    		 Student's t-test
    Parameter type
    		 Overall Mean Difference
    Point estimate
    95.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 35.9
         upper limit
    		 154.6
    Notes
    [9] - p-value was not adjusted for multiplicity and is provided for descriptive purpose only.
    Statistical analysis title
    		 Final analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0096 [10]
    Method
    		 Student's t-test
    Parameter type
    		 Overall Mean Difference
    Point estimate
    84.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.7
         upper limit
    		 147.8
    Notes
    [10] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only

    Secondary: Categorical Change in FVC of >5%

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    End point title
    		 Categorical Change in FVC of >5%
    End point description
    Categorical change in FVC was measured both by daily spirometry as well as by spirometry during clinical visits. Only the site spirometry data were used as the daily spirometry data were not normally distributed. The analyses were repeated due to additional data cleaning activities that were not conducted during the primary analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    126
    Units: Number of Subjects
        Primary Analysis in 2019
    47
    74
        Updated Analysis in 2020
    47
    73
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.69
    Notes
    [11] - p-values was not adjusted for multiplicity and was provided for descriptive purpose only
    Statistical analysis title
    		 Final analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0009 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.71
    Notes
    [12] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only

    Secondary: Categorical Change in FVC of >10%

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    End point title
    		 Categorical Change in FVC of >10%
    End point description
    Categorical change in FVC was measured both by daily spirometry as well as by spirometry during clinical visits. Only the site spirometry data were used as the daily spirometry data were not normally distributed. The analyses were repeated due to additional data cleaning activities that were not conducted during the primary analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    126
    Units: Number of Subjects
        Primary Analysis in 2019
    18
    34
        Updated Analysis in 2020
    18
    33
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0114 [13]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.84
    Notes
    [13] - p-values was not adjusted for multiplicity and was provided for descriptive purpose only
    Statistical analysis title
    		 Final analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0168 [14]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.88
    Notes
    [14] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only

    Secondary: Change in Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLco)

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    End point title
    		 Change in Percent Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLco)
    End point description
    The DLco is a pulmonary function test that measures the capacity for the lung to carry out gas exchange between the inhaled breath and the pulmonary capillary blood vessels and the DLco %-predicted represents the DLco expressed as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127 [15]
    125 [16]
    Units: Percent Predicted
    arithmetic mean (standard deviation)
        Baseline (Day 1)
    46.19 ± 12.403
    49.57 ± 13.931
        Change from Baseline at Week 12 (Primary Analysis)
    -0.52 ± 6.193
    -0.56 ± 8.807
        Change from Baseline at Week 24 (Primary Analysis)
    -0.65 ± 7.113
    -2.47 ± 8.833
        Change from Baseline at Week 12 (Final Analysis)
    -0.52 ± 6.193
    -0.89 ± 9.407
        Change from Baseline at Week 24 (Final Analysis)
    -0.65 ± 7.113
    -2.48 ± 8.893
    Notes
    [15] - Number of subjects analysed was different at each time point; only collected data were analysed.
    [16] - Number of subjects analysed was different at each time point; only collected data were analysed.
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0874 [17]
    Method
    		 rank ANCOVA
    Confidence interval
    Notes
    [17] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only
    Statistical analysis title
    		 Final Analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1191 [18]
    Method
    		 rank ANCOVA
    Confidence interval
    Notes
    [18] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only

    Secondary: Change in 6-minute Walk Distance (6MWD)

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    End point title
    		 Change in 6-minute Walk Distance (6MWD)
    End point description
    Comparison of 6-minute walk distance before beginning and after completing study therapy.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127 [19]
    126 [20]
    Units: meter (m)
    arithmetic mean (standard deviation)
        Baseline
    391.6 ± 114.93
    394.0 ± 108.09
        Change from Baseline at Week 12
    -14.8 ± 66.23
    -7.7 ± 57.60
        Change from Baseline at Week 24
    -2.0 ± 68.11
    -26.7 ± 79.32
    Notes
    [19] - Number of subjects analysed was different at each time point; only collected data were analysed.
    [20] - Number of subjects analysed was different at each time point; only collected data were analysed.
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0395 [21]
    Method
    		 rank ANCOVA
    Confidence interval
    Notes
    [21] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only
    Statistical analysis title
    		 Final Analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0299 [22]
    Method
    		 rank ANCOVA
    Confidence interval
    Notes
    [22] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only

    Secondary: Change in University of California, San Diego-Shortness of Breath Questionnaire Score

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    End point title
    		 Change in University of California, San Diego-Shortness of Breath Questionnaire Score
    End point description
    University of California, San Diego Shortness of Breath Questionnaire (SOBQ) consists of 24-item on a scale of 0 to 5 with 0=not at all and 5=maximal or unable to do because of breathlessness. The total scores were calculated by summation of the 24 items scores and transformed into 0-100, with 0= poor quality of life , and 100= excellent quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    113 [23]
    114 [24]
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Baseline
    44.17 ± 25.204
    48.89 ± 23.441
        Change from Baseline at Week 12
    1.47 ± 19.707
    2.24 ± 18.617
        Change from Baseline at Week 24
    5.21 ± 18.701
    5.30 ± 22.078
    Notes
    [23] - Number of subjects analysed was different at each time point; only collected data were analysed.
    [24] - Number of subjects analysed was different at each time point; only collected data were analysed.
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7788
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann Median Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 5
    Statistical analysis title
    		 Final Analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8289 [25]
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann Median Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 5
    Notes
    [25] - Analysis of Covariance Changes from baseline to week 24 or early discontinuation visit are compared between the treatment arms using a rank ANCOVA with change from baseline as outcome variable and standardized rank baseline value as covariate

    Secondary: Change in Score in Leicester Cough Questionnaire Score

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    End point title
    		 Change in Score in Leicester Cough Questionnaire Score
    End point description
    The Leicester Cough Questionnaire is a subject-reported questionnaire evaluating the impact of cough on quality of life. The questionnaire comprises 19 items. Each item assesses symptoms, or the impact of symptoms, over the last 2 weeks on a seven-point Likert scale. Scores in three domains (physical, psychological and social) were calculated as a mean for each domain (range 1 to 7). A total score (range 3 to 21) was also calculated by adding the domain scores together. Higher scores indicate better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127 [26]
    125 [27]
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Baseline
    16.13 ± 3.711
    15.15 ± 3.928
        Change from Baseline at Week 12 (Primary Analysis)
    0.35 ± 2.903
    -0.23 ± 3.654
        Change from Baseline at Week 24 (Primary Analysis
    0.36 ± 2.889
    0.04 ± 3.702
        Change from Baseline at Week 12 (Final Analysis)
    0.35 ± 2.903
    -0.23 ± 3.654
        Change from Baseline at Week 24 (Final Analysis)
    0.35 ± 2.884
    0.04 ± 3.702
    Notes
    [26] - Number of subjects analysed was different at each time point; only collected data were analysed.
    [27] - Number of subjects analysed was different at each time point; only collected data were analysed.
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1872 [28]
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann Median difference
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 1.04
    Notes
    [28] - p-value was not adjusted for multiplicity and was provided for descriptive purpose only
    Statistical analysis title
    		 Final Analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2019 [29]
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann Median Difference
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 1.02
    Notes
    [29] - Analysis of Covariance Changes from baseline to week 24 or early discontinuation visit are compared between the treatment arms using a rank ANCOVA with change from baseline as outcome variable and standardized rank baseline value as covariate.

    Secondary: Change in Cough Visual Analog Scale (VAS) Score

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    End point title
    		 Change in Cough Visual Analog Scale (VAS) Score
    End point description
    Cough VAS are 100-mm linear scales on which subjects indicate the severity of their cough; 0 mm represents no cough and 100 mm the worst cough ever.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127 [30]
    125 [31]
    Units: millimeter (mm)
    arithmetic mean (standard deviation)
        Baseline
    35.60 ± 27.497
    37.18 ± 26.270
        Change from Baseline at Week 12
    -4.33 ± 20.017
    3.32 ± 26.429
        Change from Baseline at Week 24
    -2.52 ± 26.720
    0.78 ± 30.121
    Notes
    [30] - Number of subjects analysed was different at each time point; only collected data were analysed.
    [31] - Number of subjects analysed was different at each time point; only collected data were analysed.
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2995
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann Median Difference
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10
         upper limit
    		 4
    Statistical analysis title
    		 Final Analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3372 [32]
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann Median Difference
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10
         upper limit
    		 4
    Notes
    [32] - Analysis of Covariance Changes from baseline to week 24 or early discontinuation visit are compared between the treatment arms using a rank ANCOVA with change from baseline as outcome variable and standardized rank baseline value as covariate.

    Secondary: Change in Total and Sub-scores of the Saint George's Respiratory Questionnaire (SGRQ)

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    End point title
    		 Change in Total and Sub-scores of the Saint George's Respiratory Questionnaire (SGRQ)
    End point description
    The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in subjects with diseases of airways obstruction. Three component scores are: Symptoms (respiratory symptoms and severity); Activity (activities that cause or are limited by breathlessness); Impacts (social functioning and psychological disturbances due to airway disease). Each component sub-scores are calculated from the summed weights for the positive responses to questions. Total score summaries the impact of disease on overall health status. Scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status. It is calculated by summing all positive responses in the questionnaire and expressing the result as a percentage of the total weight for the questionnaire.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127 [33]
    126 [34]
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Symptoms sub-score - Baseline
    49.28 ± 21.687
    53.10 ± 21.450
        Symptoms sub-score - Week 12
    -2.60 ± 19.173
    0.86 ± 16.212
        Symptoms sub-score - Week 24
    -1.69 ± 19.186
    -0.66 ± 15.407
        Activities sub-score - Baseline
    63.93 ± 20.388
    66.96 ± 18.615
        Activities sub-score - Week 12
    1.17 ± 13.376
    1.13 ± 13.704
        Activities sub-score - Week 24
    1.25 ± 14.629
    2.22 ± 13.110
        Impacts sub-score - Baseline
    37.12 ± 20.484
    41.47 ± 20.520
        Impacts sub-score - Week 12
    0.29 ± 16.826
    0.33 ± 13.888
        Impacts sub-score - Week 24
    -0.18 ± 13.884
    1.07 ± 17.539
        Total score - Baseline
    47.37 ± 18.465
    51.46 ± 17.699
        Total score - Week 12
    -0.17 ± 13.633
    0.53 ± 11.724
        Total score - Week 24
    0.05 ± 12.549
    0.85 ± 13.383
    Notes
    [33] - Number of subjects analysed was different at each time point; only collected data were analysed.
    [34] - Number of subjects analysed was different at each time point; only collected data were analysed.
    Statistical analysis title
    		 Primary Analysis in 2019
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.163
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann Median Difference
    Point estimate
    -1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.06
         upper limit
    		 1.38
    Statistical analysis title
    		 Final Analysis in 2020
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1851 [35]
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann Median Difference
    Point estimate
    -1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 1.55
    Notes
    [35] - Analysis of Covariance Changes from baseline to week 24 or early discontinuation visit are compared between the treatment arms using a rank ANCOVA with change from baseline as outcome variable and standardized rank baseline value as covariate.

    Secondary: Number of Subjects with Non-elective Hospitalization, Both Respiratory and all Cause

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    End point title
    		 Number of Subjects with Non-elective Hospitalization, Both Respiratory and all Cause
    End point description
    Subjects with non-elective hospitalization are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    126
    Units: Number of Subjects
        All-cause hospitalization
    16
    13
        Respiratory-related hospitalization
    5
    5
    Statistical analysis title
    		 All-cause non-elective hospitalization.
    Statistical analysis description
    Primary Analysis in 2019. Log-rank tests based on the time to the first event are to compare the two treatment arms.
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5922
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 2.49
    Statistical analysis title
    		 Respiratory non-elective hospitalization.
    Statistical analysis description
    Primary Analysis in 2019. Log-rank tests based on the time to the first event are to compare the two treatment arms.
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 2.83
    Statistical analysis title
    		 All-cause non-elective hospitalization.
    Statistical analysis description
    Final Analysis in 2020. Log-rank tests based on the time to the first event are to compare the two treatment arms.
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4613
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 2.73
    Statistical analysis title
    		 Respiratory non-elective hospitalization.
    Statistical analysis description
    Final Analysis in 2020. Log-rank tests based on the time to the first event are to compare the two treatment arms.
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9523
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 3.59

    Secondary: Percentage of Subjects with Investigator-reported Acute Exacerbations

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    End point title
    		 Percentage of Subjects with Investigator-reported Acute Exacerbations
    End point description
    Percentage of subjects with acute exacerbation are reported.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    126
    Units: Percentage of Subjects
        number (not applicable)
    3.9
    5.6
    No statistical analyses for this end point

    Secondary: Time to First Investigator-reported Acute Exacerbations

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    End point title
    		 Time to First Investigator-reported Acute Exacerbations
    End point description
    Time to first investigator reported acute exacerbations from start of treatment are reported. 9999=not estimable; The end point could not be analysed due to the limited number of events.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    126
    Units: Weeks
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Superiority
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7871
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 2.78

    Secondary: Progression-free Survival (PFS) defined as the time to the first occurrence of a >10% absolute decline in percent predicted FVC, a >50 m decline of 6MWD

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    End point title
    		 Progression-free Survival (PFS) defined as the time to the first occurrence of a >10% absolute decline in percent predicted FVC, a >50 m decline of 6MWD
    End point description
    PFS is defined as the time to the first occurrence of a >10% absolute decline in percent predicted FVC, a >50 m decline of 6MWD, or death. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    126
    Units: Week
        median (confidence interval 95%)
    25.14 (24.14 to 9999)
    24.71 (24.14 to 9999)
    Statistical analysis title
    		 Primary Analysis in 2019
    Statistical analysis description
    Log-rank tests based on the time to the first event are to compare the two treatment arms.
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.366
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.24
    Statistical analysis title
    		 Final Analysis in 2020
    Statistical analysis description
    Log-rank tests based on the time to the first event are to compare the two treatment arms.
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4173
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.26

    Secondary: PFS defined as the time to the first occurrence of a >10% relative decline in percent predicted FVC, non-elective respiratory hospitalization, or death

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    End point title
    		 PFS defined as the time to the first occurrence of a >10% relative decline in percent predicted FVC, non-elective respiratory hospitalization, or death
    End point description
    PFS is defined as the time to the first occurrence of a >10% absolute decline in percent predicted FVC, non-elective respiratory hospitalization, or death. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    126
    Units: Week
        median (confidence interval 95%)
    9999 (24.86 to 9999)
    9999 (24.14 to 9999)
    Statistical analysis title
    		 Primary Analysis in 2019
    Statistical analysis description
    Log-rank tests based on the time to the first event are to compare the two treatment arms.
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2726
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.2
    Statistical analysis title
    		 Final Analysis in 2020
    Statistical analysis description
    Log-rank tests based on the time to the first event are to compare the two treatment arms.
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3386
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.24

    Secondary: Time to Death From any Cause

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    End point title
    		 Time to Death From any Cause
    End point description
    Time to first documented death from start of treatment is reported. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127 [36]
    126 [37]
    Units: Week
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [36] - The end point could not be analysed due to the limited number of events.
    [37] - The end point could not be analysed due to the limited number of events
    Statistical analysis title
    		 Superiority
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9969
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 16.08

    Secondary: Time to Death from Respiratory Diseases

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    End point title
    		 Time to Death from Respiratory Diseases
    End point description
    Time to first documented death due to respiratory diseases from start of treatment will be reported. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127 [38]
    126 [39]
    Units: Week
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [38] - The end point could not be analysed due to the limited number of events
    [39] - The end point could not be analysed due to the limited number of events
    Statistical analysis title
    		 Superiority
    Statistical analysis description
    Log-rank tests based on the time to the first event are to compare the two treatment arms.
    Comparison groups
    Pirfenidone v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3231
    Method
    		 Logrank
    Confidence interval

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 28
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    124 [40]
    Units: Subjects
    120
    101
    Notes
    [40] - Two subjects did not receive treatment.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Dose Reductions and Treatment Interruptions during the Double-Blind Period

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    End point title
    		 Number of Subjects With Dose Reductions and Treatment Interruptions during the Double-Blind Period
    End point description
    Number of subjects with dose reduction and treatment interruptions are reported. The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
    End point type
    Secondary
    End point timeframe
    From administration of the first dose of study drug to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    124
    Units: Number of Subjects
        Subjects with at least one dose modification
    51
    34
        Subjects with at least one dose interruption
    40
    12
    No statistical analyses for this end point

    Secondary: Number of Subjects With Dose Reductions and Treatment Interruptions during the 12-month Safety Follow-up

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    End point title
    		 Number of Subjects With Dose Reductions and Treatment Interruptions during the 12-month Safety Follow-up
    End point description
    Number of subjects with dose reduction and treatment interruptions are reported. The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
    End point type
    Secondary
    End point timeframe
    From the Follow-up Visit at Week 28 through the follow-up period of 12 Months
    End point values
    		 Open-Label Treatment (Pirfenidone) Open-Label Treatment (Placebo)
    Number of subjects analysed
    94
    110
    Units: Number of Subjects
    number (not applicable)
        Subjects with at least one dose modification
    41
    60
        Subjects with at least one dose interruption
    24
    34
    No statistical analyses for this end point

    Secondary: Number of Subjects Withdrawn from Trial Treatment or Trial Discontinuations during the Double-Blind Period

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    End point title
    		 Number of Subjects Withdrawn from Trial Treatment or Trial Discontinuations during the Double-Blind Period
    End point description
    Number of subjects withdrawn from trial treatment or trial discontinuations are reported. The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Week 24
    End point values
    		 Pirfenidone Placebo
    Number of subjects analysed
    127
    124 [41]
    Units: Number of Subjects
    25
    12
    Notes
    [41] - Two subjects did not receive treatment.
    No statistical analyses for this end point

    Secondary: Number of Subjects Withdrawn from Trial Treatment or Trial Discontinuations during the 12-month Safety Follow-up

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    End point title
    		 Number of Subjects Withdrawn from Trial Treatment or Trial Discontinuations during the 12-month Safety Follow-up
    End point description
    Number of subjects withdrawn from trial treatment or trial discontinuations are reported. The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
    End point type
    Secondary
    End point timeframe
    From the Follow-up Visit at Week 28 through the follow-up period of 12 Months
    End point values
    		 Open-Label Treatment (Pirfenidone) Open-Label Treatment (Placebo)
    Number of subjects analysed
    94
    110
    Units: Number of Subjects
        number (not applicable)
    19
    26
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) to Week 28 in the double-blind period From the Follow-up Visit at Week 28 through the follow-up period of 12 Months in the open-label treatment period
    Adverse event reporting additional description
    The safety population was defined as all subjects with at least one intake of pirfenidone or placebo, i.e., at least one record in the drug-log of the double-blind period with a non-zero dose. Subjects in the safety population were assigned to a treatment arm according to the actual treatment they received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Pirfenidone
    Reporting group description
    		 Participants received pirfenidone 267 mg capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo capsule three times a day from Day 1 to 7 followed by 2 capsules three times a day from Day 8 to 14 then 3 capsules three times a day from Day 15 up to Week 24.

    Reporting group title
    Open-Label Treatment (Pirfenidone)
    Reporting group description
    		 After subjects completed the double-blind treatment period and the follow-up visit at Week 28, they were offered the option to receive open-label pirfenidone within the trial protocol in a safety follow-up period of up to 12 months. A final follow-up visit was performed at the end of the safety period, 28 days after the last open-label dose.

    Reporting group title
    Open-Label Treatment (Placebo)
    Reporting group description
    		 After subjects completed the double-blind treatment period and the follow-up visit at Week 28, they were offered the option to receive open-label pirfenidone within the trial protocol in a safety follow-up period of up to 12 months. A final follow-up visit was performed at the end of the safety period, 28 days after the last open-label dose.

    Serious adverse events
    		 Pirfenidone Placebo Open-Label Treatment (Pirfenidone) Open-Label Treatment (Placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 127 (14.17%)
    20 / 124 (16.13%)
    26 / 94 (27.66%)
    27 / 110 (24.55%)
         number of deaths (all causes)
    4
    7
    7
    9
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Lung transplant rejection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 124 (1.61%)
    2 / 94 (2.13%)
    3 / 110 (2.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    2 / 94 (2.13%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
    0 / 94 (0.00%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    Respiratory disorder
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    3 / 110 (2.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    2 / 94 (2.13%)
    3 / 110 (2.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    2 / 94 (2.13%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    2 / 94 (2.13%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    3 / 94 (3.19%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    2 / 94 (2.13%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
    0 / 94 (0.00%)
    2 / 110 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
    1 / 94 (1.06%)
    4 / 110 (3.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 124 (2.42%)
    2 / 94 (2.13%)
    6 / 110 (5.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Respiratory tract infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    2 / 94 (2.13%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia viral
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxocariasis
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella zoster pneumonia
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    1 / 110 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pirfenidone Placebo Open-Label Treatment (Pirfenidone) Open-Label Treatment (Placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    107 / 127 (84.25%)
    81 / 124 (65.32%)
    64 / 94 (68.09%)
    86 / 110 (78.18%)
    Investigations
    Weight decreased
         subjects affected / exposed
    11 / 127 (8.66%)
    6 / 124 (4.84%)
    2 / 94 (2.13%)
    7 / 110 (6.36%)
         occurrences all number
    11
    6
    2
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 127 (8.66%)
    13 / 124 (10.48%)
    4 / 94 (4.26%)
    8 / 110 (7.27%)
         occurrences all number
    13
    14
    4
    8
    Headache
         subjects affected / exposed
    13 / 127 (10.24%)
    4 / 124 (3.23%)
    3 / 94 (3.19%)
    12 / 110 (10.91%)
         occurrences all number
    19
    5
    3
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 127 (16.54%)
    19 / 124 (15.32%)
    5 / 94 (5.32%)
    12 / 110 (10.91%)
         occurrences all number
    22
    20
    5
    14
    Pyrexia
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    8 / 110 (7.27%)
         occurrences all number
    0
    0
    1
    9
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    7 / 127 (5.51%)
    4 / 124 (3.23%)
    6 / 94 (6.38%)
    3 / 110 (2.73%)
         occurrences all number
    7
    4
    6
    5
    Diarrhoea
         subjects affected / exposed
    23 / 127 (18.11%)
    23 / 124 (18.55%)
    9 / 94 (9.57%)
    15 / 110 (13.64%)
         occurrences all number
    27
    24
    16
    15
    Dyspepsia
         subjects affected / exposed
    17 / 127 (13.39%)
    7 / 124 (5.65%)
    5 / 94 (5.32%)
    8 / 110 (7.27%)
         occurrences all number
    21
    7
    5
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    10 / 127 (7.87%)
    6 / 124 (4.84%)
    7 / 94 (7.45%)
    7 / 110 (6.36%)
         occurrences all number
    10
    7
    8
    7
    Nausea
         subjects affected / exposed
    40 / 127 (31.50%)
    9 / 124 (7.26%)
    15 / 94 (15.96%)
    30 / 110 (27.27%)
         occurrences all number
    49
    10
    18
    39
    Vomiting
         subjects affected / exposed
    14 / 127 (11.02%)
    6 / 124 (4.84%)
    4 / 94 (4.26%)
    18 / 110 (16.36%)
         occurrences all number
    17
    7
    6
    25
    Abdominal pain
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    2 / 94 (2.13%)
    8 / 110 (7.27%)
         occurrences all number
    0
    0
    2
    8
    Abdominal pain upper
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    1 / 94 (1.06%)
    10 / 110 (9.09%)
         occurrences all number
    0
    0
    1
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 127 (14.96%)
    16 / 124 (12.90%)
    10 / 94 (10.64%)
    9 / 110 (8.18%)
         occurrences all number
    21
    17
    12
    9
    Dyspnoea
         subjects affected / exposed
    14 / 127 (11.02%)
    22 / 124 (17.74%)
    9 / 94 (9.57%)
    8 / 110 (7.27%)
         occurrences all number
    16
    25
    10
    8
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    8 / 127 (6.30%)
    0 / 124 (0.00%)
    2 / 94 (2.13%)
    9 / 110 (8.18%)
         occurrences all number
    9
    0
    2
    12
    Rash
         subjects affected / exposed
    9 / 127 (7.09%)
    7 / 124 (5.65%)
    8 / 94 (8.51%)
    16 / 110 (14.55%)
         occurrences all number
    12
    8
    10
    19
    Psychiatric disorders
    Depression
         subjects affected / exposed
    7 / 127 (5.51%)
    0 / 124 (0.00%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    7
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 127 (6.30%)
    3 / 124 (2.42%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    8
    3
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 127 (7.87%)
    3 / 124 (2.42%)
    0 / 94 (0.00%)
    0 / 110 (0.00%)
         occurrences all number
    11
    3
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    8 / 127 (6.30%)
    13 / 124 (10.48%)
    9 / 94 (9.57%)
    14 / 110 (12.73%)
         occurrences all number
    10
    16
    12
    15
    Nasopharyngitis
         subjects affected / exposed
    7 / 127 (5.51%)
    6 / 124 (4.84%)
    10 / 94 (10.64%)
    11 / 110 (10.00%)
         occurrences all number
    8
    9
    11
    11
    Respiratory tract infection
         subjects affected / exposed
    11 / 127 (8.66%)
    5 / 124 (4.03%)
    8 / 94 (8.51%)
    4 / 110 (3.64%)
         occurrences all number
    11
    7
    9
    5
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 127 (9.45%)
    9 / 124 (7.26%)
    7 / 94 (7.45%)
    3 / 110 (2.73%)
         occurrences all number
    15
    10
    9
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 124 (0.00%)
    7 / 94 (7.45%)
    3 / 110 (2.73%)
         occurrences all number
    0
    0
    9
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    18 / 127 (14.17%)
    11 / 124 (8.87%)
    7 / 94 (7.45%)
    13 / 110 (11.82%)
         occurrences all number
    22
    11
    8
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2017
    1) Version included additional safety monitoring during the 12-month safety follow-up period, in accordance with the pirfenidone Investigator’s Brochure (RO0220912) and the Summary of Product Characteristics (Esbriet). Increased safety monitoring included additional liver function and pregnancy tests initially at monthly visits during the first 6 months and approximately every 3 months, thereafter. Urine pregnancy tests would continue to be performed on a monthly basis. Relevant sections of the protocol including the Schedule of Assessments have been amended. 2) Guidance text for sections on inclusion and exclusion criteria was amended in order to provide more clear guidance as to when subjects must fulfil the eligibility criteria in order to participate in the trial since results for screening assessments may not all be available at the time of screening. 3) Inclusion criterion no. 11 was amended in order to correct the error in the classification of the acceptable methods of contraception. 4) Section on ‘Trial Rationale and Benefit-Risk Assessment’ was amended to provide further clarification that trial subjects are allowed to be treated with mycophenolate (MMF) regardless of which treatment arm they were randomized onto during the 24-week double-blind period and throughout the study.
    03 Mar 2017
    5) Section on ‘Pirfenidone and Placebo’ was amended in order to correct that no markings were made on the capsules. The list of printing ink ingredients was deleted. 6) Section on ‘Method of Treatment Assignment and Unblinding’ was amended in order to delete the sentence providing Investigators with the option of unblinding subjects for any other reason but safety. Unblinding could only occur for safety reasons. 6) Section on ‘Electrocardiograms’ was amended in order to revise the template text requiring for ECGs to be obtained prior to other trial procedures and not prior to treatment administration. This template text did not apply to this trial as there were no cardiac safety concerns with pirfenidone treatment or any justification for requiring ECGs to be obtained prior to any other study procedures. 7) The ‘Cough Visual Analogue Scale’ was amended in order to replace the previous scale with the actual scale and guidance text that would be provided to the subjects.
    28 Jun 2018
    Protocol was amended mainly in order to provide additional guidance on trial specific procedures. Changes to the protocol including the rationale for each change: 1) Synopsis (Target Population) and Protocol Section 4.1 (Patients) of the protocol were amended in order to provide guidance on conditions for allowing the rescreening of subjects. 2) Section 4.5.5 (FVC) was amended to provide guidance on when to use a short-acting bronchodilator prior to on-site spirometry for subjects who are routinely treated with such medication. 3) Sections 4.5.9 (Electrocardiograms) and 5.1.1.8 (Management of Increases in QT Interval) were amended to provide more clear guidance for ECGs and the management of increases in QT interval. 4) Section 4.5.10 (Patient-Reported Outcomes) was amended as the timing for the completion of the Patient-Reported Outcomes was independent of the administration time of the trial treatment. 5) Section 4.6.1 (Patient Discontinuation) was amended to include lung transplantation during the trial as a reason for subject discontinuation. 6) Schedule of Assessments was amended to reflect the changes made to the body of the protocol and also to provide further trial-specific guidance.

    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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