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    Clinical Trial Results:
    A Phase IIb, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Sildenafil Added to Pirfenidone in Subjects With Advanced Idiopathic Pulmonary Fibrosis and Risk of Group 3 Pulmonary Hypertension

    Summary
    EudraCT number
    2015-005131-40
    Trial protocol
    ES   NL   BE   DE   GR   HU   CZ   IT  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Sep 2020
    First version publication date
    03 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MA29957
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02951429
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    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
    Medical Communications, Hoffmann-La Roche, +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
    Interim
    Date of interim/final analysis
    11 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This Phase IIb, randomized, placebo-controlled, multicenter, international study will evaluate the efficacy, safety, and tolerability of sildenafil or placebo added to pirfenidone (Esbriet) treatment in subjects with advanced IPF and intermediate or high probability of Group 3 pulmonary hypertension (PH) who are on a stable dose of pirfenidone with demonstrated tolerability. Subjects were randomized to receive 1 year of treatment with either oral sildenafil or matching placebo while continuing to take pirfenidone.
    Protection of trial subjects
    This study was conducted in accordance with the protocol and with the following: ● Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines ● Applicable ICH Good Clinical Practice (GCP) Guidelines ● Applicable laws and regulations
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Jan 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    11 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Egypt: 15
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Greece: 18
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Israel: 21
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Turkey: 26
    Worldwide total number of subjects
    177
    EEA total number of subjects
    100
    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)
    49
    From 65 to 84 years
    128
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Written informed consent for participation in the study was obtained before performing any study-specific screening tests or evaluations.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pirfenidone+Sildenafil
    Arm description
    Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    RO0280296
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sildenafil will be given as 20 mg, TID.

    Investigational medicinal product name
    Pirfenidone
    Investigational medicinal product code
    Other name
    Esbriet, RO0220912
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses.

    Arm title
    Pirfenidone+Placebo
    Arm description
    Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched with sildenafil.

    Investigational medicinal product name
    Pirfenidone
    Investigational medicinal product code
    Other name
    Esbriet, RO0220912
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Pirfenidone will be given in the range of 1602 to 2403 milligram per day (mg/day), as 3 divided doses.

    Number of subjects in period 1
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Started
    88
    89
    Completed
    16
    6
    Not completed
    72
    83
         Adverse event, serious fatal
    28
    36
         Consent withdrawn by subject
    7
    11
         Adverse event, non-fatal
    3
    7
         Progressive Disease
    1
    1
         Unknown
    1
    3
         Lung Transplantation
    9
    6
         Lost to follow-up
    -
    1
         Participant ongoing in the study
    23
    17
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pirfenidone+Sildenafil
    Reporting group description
    Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.

    Reporting group title
    Pirfenidone+Placebo
    Reporting group description
    Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.

    Reporting group values
    Pirfenidone+Sildenafil Pirfenidone+Placebo Total
    Number of subjects
    88 89 177
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    27 22 49
        From 65-84 years
    61 67 128
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    68.2 ± 7.7 68.9 ± 7.1 -
    Sex: Female, Male
    Units: Participants
        Female
    19 24 43
        Male
    69 65 134
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    1 0 1
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Black or African American
    0 1 1
        White
    85 88 173
        More than one race
    0 0 0
        Unknown or Not Reported
    1 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    2 3 5
        Not Hispanic or Latino
    78 79 157
        Unknown or Not Reported
    8 7 15

    End points

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    End points reporting groups
    Reporting group title
    Pirfenidone+Sildenafil
    Reporting group description
    Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.

    Reporting group title
    Pirfenidone+Placebo
    Reporting group description
    Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.

    Primary: Percentage of Subjects With Disease Progression, as Determined by Relevant Decline in 6 Minute Walk Distance (6MWD) of At Least (>=) 15 Percent (%) From Baseline, Respiratory-Related Non-Elective Hospitalization, or Death From Any Cause

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    End point title
    Percentage of Subjects With Disease Progression, as Determined by Relevant Decline in 6 Minute Walk Distance (6MWD) of At Least (>=) 15 Percent (%) From Baseline, Respiratory-Related Non-Elective Hospitalization, or Death From Any Cause
    End point description
    Disease Progression defined as relative decline in 6MWD from baseline (defined as >25% from baseline or 15–25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality. Population: Subjects with data available at week 52.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Percentage
        number (not applicable)
    72.7
    69.7
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6527
    Method
    Clopper-Pearson
    Parameter type
    Difference (95% CI)
    Point estimate
    3.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.3
         upper limit
    17.97

    Secondary: Time to First Occurrence of Disease Progression

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    End point title
    Time to First Occurrence of Disease Progression
    End point description
    Disease Progression defined as relative decline in 6MWD from baseline (defined as >25% from baseline or 15–25% from baseline associated with worsening oxygen saturation, worsening Borg score, or increased oxygen requirements), respiratory-related non-elective hospitalizations, or all-cause mortality. Population: Subjects with data available at week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Weeks
        median (confidence interval 95%)
    26.00 (20.57 to 38.14)
    25.43 (13.00 to 37.71)
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7568
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    1.34

    Secondary: Time to Multiple Occurrence Event

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    End point title
    Time to Multiple Occurrence Event
    End point description
    Population: Subjects with data available at week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Weeks
        median (confidence interval 95%)
    20.57 (13.14 to 26.43)
    13.29 (12.71 to 23.29)
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.376
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    1.15

    Secondary: Percentage of Subjects With Decline From Baseline in 6MWD of >= 15%

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    End point title
    Percentage of Subjects With Decline From Baseline in 6MWD of >= 15%
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Percentage
        number (not applicable)
    53.4
    50.6
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7046
    Method
    Clopper-Pearson
    Parameter type
    Difference (95% CI)
    Point estimate
    2.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.13
         upper limit
    17.84

    Secondary: Time to First Occurrence of Relevant ≥15% Decline from Baseline in 6MWD

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    End point title
    Time to First Occurrence of Relevant ≥15% Decline from Baseline in 6MWD
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Weeks
        median (confidence interval 95%)
    39.00 (27.86 to 52.14)
    38.71 (25.14 to 52.57)
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.755
    Method
    Clopper-Pearson
    Parameter type
    Difference (95% CI)
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    1.41

    Secondary: Time to Respiratory-Related Non-Elective Hospitalization

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    End point title
    Time to Respiratory-Related Non-Elective Hospitalization
    End point description
    9999 = non-calculable Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Weeks
        median (confidence interval 95%)
    54.29 (36.29 to 9999)
    9999 (42.14 to 9999)
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9174
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.61

    Secondary: Time to All-Cause Non-Elective Hospitalization

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    End point title
    Time to All-Cause Non-Elective Hospitalization
    End point description
    9999 = non calculable. KM-curves ends at 52 weeks and the upper CI is higher than 52 weeks and thus based on the data cannot be presented. Population: Subjects with data available at week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Weeks
        median (confidence interval 95%)
    45.57 (28.00 to 9999)
    49.86 (32.00 to 9999)
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7748
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.62

    Secondary: Time to Death From Any Cause

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    End point title
    Time to Death From Any Cause
    End point description
    9999 = non-calculable Population: Subjects with data available at week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Weeks
        median (confidence interval 95%)
    9999 (54.43 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4258
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    1.5

    Secondary: Percentage of Participants With Lung Transplantation

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    End point title
    Percentage of Participants With Lung Transplantation
    End point description
    Population: Subjects with data available at week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Percentage
        number (not applicable)
    10.2
    6.7
    No statistical analyses for this end point

    Secondary: Time to Respiratory-Related Death

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    End point title
    Time to Respiratory-Related Death
    End point description
    9999 = non-calculable Population: Subjects with data available at week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Weeks
        median (confidence interval 95%)
    9999 (54.43 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3161
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.31
         upper limit
    1.46

    Secondary: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity

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    End point title
    Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Peak Tricuspid Regurgitation Velocity
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    38
    29
    Units: m/s
        arithmetic mean (standard deviation)
    -0.014 ± 0.6326
    0.103 ± 0.6699
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs)

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    End point title
    Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Pulmonary Artery Pressure (PAPs)
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    41
    30
    Units: mmHg
        arithmetic mean (standard deviation)
    2.0 ± 15.65
    3.6 ± 22.38
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE)

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    End point title
    Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Tricuspid Annular Plane Systolic Excursion (TAPSE)
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    30
    27
    Units: cm
        arithmetic mean (standard deviation)
    -0.204 ± 0.4170
    -0.146 ± 0.4453
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter

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    End point title
    Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Right Ventricle Basal Diameter
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    29
    24
    Units: cm
        arithmetic mean (standard deviation)
    0.462 ± 1.2305
    0.095 ± 1.2875
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter

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    End point title
    Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Inferior Vena Cava Diameter
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    24
    22
    Units: cm
        arithmetic mean (standard deviation)
    -0.05 ± 0.595
    -0.09 ± 0.540
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF)

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    End point title
    Change From Baseline to Week 52 in Transthoracic Echocardiography (ECHO) Parameter: Left Ventricular Ejection Fraction (LVEF)
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    43
    30
    Units: Percentage
        arithmetic mean (standard deviation)
    1.22 ± 9.166
    -0.85 ± 5.767
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO)

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    End point title
    Change From Baseline to Week 52 in Carbon Monoxide Diffusing Capacity/ Pulmonary Diffusing Capacity (DLCO)
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    43
    29
    Units: Percentage predicted
        arithmetic mean (standard deviation)
    -2.918 ± 6.2296
    -2.440 ± 8.2820
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 52 in Forced Vital Capacity (FVC)

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    End point title
    Change From Baseline to Week 52 in Forced Vital Capacity (FVC)
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    45
    33
    Units: Percentage predicted
        arithmetic mean (standard deviation)
    -2.761 ± 7.8044
    -1.161 ± 11.1158
    No statistical analyses for this end point

    Secondary: Percentage of Subjects by World Health Organization (WHO) Functional Class at Week 52

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    End point title
    Percentage of Subjects by World Health Organization (WHO) Functional Class at Week 52
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    49
    36
    Units: Percentage
    number (not applicable)
        Class II
    19.3
    13.5
        Class III
    33.0
    24.7
        Class IV
    3.4
    1.1
        Missing
    0
    1.1
    No statistical analyses for this end point

    Secondary: Change from Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52

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    End point title
    Change from Baseline in N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) Level (pg/mL) at Week 52
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    44
    28
    Units: pg/mL)
        arithmetic mean (standard deviation)
    110.1 ± 612.98
    605.9 ± 1273.19
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5646
    Method
    Linear Mixed Effects Model
    Parameter type
    Estimate
    Point estimate
    -206.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -920.03
         upper limit
    506.85

    Secondary: St. George's Respiratory Questionnaire (SGRQ) Changes from Baseline at Week 52

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    End point title
    St. George's Respiratory Questionnaire (SGRQ) Changes from Baseline at Week 52
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    41
    31
    Units: Points on scale
    arithmetic mean (standard deviation)
        Total score
    6.149 ± 12.3407
    11.437 ± 12.5187
        Symptoms component score
    2.498 ± 19.6074
    8.261 ± 19.5558
        Activities component score
    3.997 ± 15.4341
    10.871 ± 14.5246
        Impacts component score
    8.417 ± 15.0040
    12.118 ± 15.3487
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5255
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    -3.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.98
         upper limit
    2.36

    Secondary: University of California, San Diego–Shortness of Breath Questionnaire (UCSD-SOBQ) Changes from Baseline at Week 52

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    End point title
    University of California, San Diego–Shortness of Breath Questionnaire (UCSD-SOBQ) Changes from Baseline at Week 52
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    35
    25
    Units: Points on scale
        arithmetic mean (standard deviation)
    12.5 ± 20.93
    18.8 ± 19.68
    Statistical analysis title
    Superiority
    Comparison groups
    Pirfenidone+Sildenafil v Pirfenidone+Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4263
    Method
    ANCOVA
    Parameter type
    Median difference (final values)
    Point estimate
    -6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18
         upper limit
    6

    Secondary: Change from Baseline in Distance Walked, 6MWT at Week 52

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    End point title
    Change from Baseline in Distance Walked, 6MWT at Week 52
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    42
    30
    Units: meters
        arithmetic mean (standard deviation)
    -52.9 ± 121.07
    -40.8 ± 91.26
    No statistical analyses for this end point

    Secondary: Change from Baseline in Oxygen Requirements, 6MWT at Week 52

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    End point title
    Change from Baseline in Oxygen Requirements, 6MWT at Week 52
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    42
    30
    Units: Liters
        arithmetic mean (standard deviation)
    0.6 ± 1.27
    0.6 ± 1.43
    No statistical analyses for this end point

    Secondary: Change from Baseline in other 6MWT Parameters at Week 52

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    End point title
    Change from Baseline in other 6MWT Parameters at Week 52
    End point description
    Population: Subjects with data available at week 52 to calculate a change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    42
    30
    Units: Percentage
    arithmetic mean (standard deviation)
        SpO2 before the test (at rest)
    -0.5 ± 4.63
    -0.8 ± 3.77
        SpO2 lowest during the test
    -3.4 ± 8.93
    0.3 ± 5.27
        SpO2 after the test
    0.5 ± 9.97
    -2.3 ± 6.67
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adverse Events

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    End point title
    Percentage of Subjects with Adverse Events
    End point description
    Population: Subjects with data available at week 52. AEs that started or worsened on or after first intake of randomized treatment until last positive dose + 28 days.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    88
    89
    Units: Percentage
        number (not applicable)
    98.9
    93.3
    No statistical analyses for this end point

    Secondary: Borg scale Result at the End of the Test at Week 52

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    End point title
    Borg scale Result at the End of the Test at Week 52
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Pirfenidone+Sildenafil Pirfenidone+Placebo
    Number of subjects analysed
    42
    30
    Units: Points on Scale
        arithmetic mean (standard deviation)
    0.9 ± 3.00
    0.7 ± 3.24
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to primary data cut-off (up to 2 years 7 months). The safety data includes DBP and SFU up to 11-Nov-2019.
    Adverse event reporting additional description
    Total # of Deaths (all causes n= 64) represent deaths occurring during Double blind treatment period+4 week FU+additional safety follow up to the database snapshot of 11-Nov-2019.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Pirfenidone+Placebo
    Reporting group description
    Participants received pirfenidone along with placebo matched to sildenafil, orally, three times a day for 52 weeks.

    Reporting group title
    Pirfenidone+Sildenafil
    Reporting group description
    Participants received pirfenidone along with sildenafil, orally, three times a day for 52 weeks.

    Serious adverse events
    Pirfenidone+Placebo Pirfenidone+Sildenafil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 89 (61.80%)
    54 / 88 (61.36%)
         number of deaths (all causes)
    36
    28
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Cryoglobulinaemia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Lung transplant
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 88 (3.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Inflammation
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 88 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Chronic respiratory failure
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 89 (5.62%)
    7 / 88 (7.95%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 9
         deaths causally related to treatment / all
    0 / 3
    1 / 1
    Hypoxia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    21 / 89 (23.60%)
    19 / 88 (21.59%)
         occurrences causally related to treatment / all
    1 / 31
    0 / 23
         deaths causally related to treatment / all
    0 / 8
    0 / 3
    Interstitial lung disease
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    2 / 89 (2.25%)
    4 / 88 (4.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary hypertension
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    3 / 89 (3.37%)
    5 / 88 (5.68%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Injury, poisoning and procedural complications
    Postoperative respiratory failure
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    4 / 89 (4.49%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 89 (0.00%)
    2 / 88 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 88 (3.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Eye disorders
    Blindness transient
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary bladder polyp
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 89 (1.12%)
    4 / 88 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    4 / 89 (4.49%)
    7 / 88 (7.95%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pneumonia bacterial
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 89 (1.12%)
    2 / 88 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Pirfenidone+Placebo Pirfenidone+Sildenafil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 89 (65.17%)
    53 / 88 (60.23%)
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 89 (3.37%)
    5 / 88 (5.68%)
         occurrences all number
    3
    5
    Vascular disorders
    Hypotension
         subjects affected / exposed
    9 / 89 (10.11%)
    6 / 88 (6.82%)
         occurrences all number
    10
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 89 (2.25%)
    5 / 88 (5.68%)
         occurrences all number
    2
    5
    Headache
         subjects affected / exposed
    2 / 89 (2.25%)
    6 / 88 (6.82%)
         occurrences all number
    3
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 89 (6.74%)
    8 / 88 (9.09%)
         occurrences all number
    6
    8
    Oedema peripheral
         subjects affected / exposed
    5 / 89 (5.62%)
    3 / 88 (3.41%)
         occurrences all number
    5
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 89 (2.25%)
    11 / 88 (12.50%)
         occurrences all number
    2
    15
    Vomiting
         subjects affected / exposed
    3 / 89 (3.37%)
    5 / 88 (5.68%)
         occurrences all number
    3
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 89 (10.11%)
    7 / 88 (7.95%)
         occurrences all number
    9
    9
    Dyspnoea
         subjects affected / exposed
    17 / 89 (19.10%)
    22 / 88 (25.00%)
         occurrences all number
    18
    23
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    7 / 89 (7.87%)
    8 / 88 (9.09%)
         occurrences all number
    10
    8
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    5 / 89 (5.62%)
    3 / 88 (3.41%)
         occurrences all number
    6
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 89 (10.11%)
    6 / 88 (6.82%)
         occurrences all number
    15
    6
    Influenza
         subjects affected / exposed
    5 / 89 (5.62%)
    2 / 88 (2.27%)
         occurrences all number
    6
    2
    Respiratory tract infection
         subjects affected / exposed
    4 / 89 (4.49%)
    9 / 88 (10.23%)
         occurrences all number
    6
    11
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 89 (2.25%)
    8 / 88 (9.09%)
         occurrences all number
    4
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 89 (10.11%)
    6 / 88 (6.82%)
         occurrences all number
    9
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2017
    Protocol MA29957 has been amended to reflect the feedback received after the start of the study from the Steering Committee, sites or ethic committees.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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