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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of FG-3019 in Patients with Idiopathic Pulmonary Fibrosis

    Summary
    EudraCT number
    		 2014-005658-20
    Trial protocol
    		 BG  
    Global end of trial date
    16 Nov 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Aug 2020
    First version publication date
    11 Apr 2020
    Other versions
    		 v1
    Version creation reason
    • Changes to summary attachments
    Needed finalised XML results

    Trial information

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    Trial identification
    Sponsor protocol code
    FGCL-3019-067
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01890265
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    FibroGen, Inc.
    Sponsor organisation address
    409 Illinois Street, San Francisco, United States, CA 94158
    Public contact
    Clinical Trial Information Desk, FibroGen, Inc., 067study@fibrogen.com
    Scientific contact
    Clinical Trial Information Desk, FibroGen, Inc., 067study@fibrogen.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
    16 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety, tolerability, and efficacy of pamrevlumab in subjects with idiopathic pulmonary fibrosis (IPF).
    Protection of trial subjects
    This trial was designed and monitored in accordance with procedures that comply with the United States Food and Drug Administration regulations, the ethical principles of Good Clinical Practice as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 9
    Country: Number of subjects enrolled
    United States: 64
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    India: 12
    Country: Number of subjects enrolled
    New Zealand: 10
    Worldwide total number of subjects
    103
    EEA total number of subjects
    4
    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)
    29
    From 65 to 84 years
    74
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase 2 study was conducted at 44 study centers in 7 countries from July 2013 to November 2017. Adult subjects with a history of IPF ≤5 years duration and a forced vital capacity (FVC) predicted value ≥55% at screening were randomized in the main study to receive pamrevlumab or placebo by intravenous (IV) infusion every 3 weeks (Q3W).

    Pre-assignment
    Screening details
    		 The main study consisted of a screening period of up to 6 weeks, a 48-week randomized treatment period and a follow-up period of 4 weeks. Subjects who completed the main study and met the eligibility criteria were offered participation in an extended open-label treatment period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Subjects, investigators and study staff were blinded to treatment assignments and did not have access to the randomization codes. The high-resolution computed tomography (HRCT) readers were blinded to treatment assignments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pamrevlumab 30 mg/kg Q3W
    Arm description
    		 Subjects were randomized to receive pamrevlumab 30 mg/kg by IV infusion Q3W.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pamrevlumab
    Investigational medicinal product code
    FG-3019
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an IV infusion of pamrevlumab 30 mg/kg Q3W. Pamrevlumab is a fully human immunoglobulin G1 kappa monoclonal antibody and was administered in normal saline. The pamrevlumab solution formulation contained sodium chloride, L-histidine hydrochloride (HCl), L-histidine and polysorbate 20.

    Arm title
    		 Placebo Q3W
    Arm description
    		 Subjects were randomized to receive placebo matching pamrevlumab by IV infusion Q3W.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received placebo matching pamrevlumab by IV infusion Q3W. Placebo was a sterile, aqueous solution for dilution into 0.9% serum chloride injection prior to IV infusion. The solution formulation contained sodium chloride, L-histidine HCl, L-histidine and polysorbate 20.

    Number of subjects in period 1
    		Pamrevlumab 30 mg/kg Q3W Placebo Q3W
    Started
    50
    53
    Completed
    40
    40
    Not completed
    10
    13
         Consent withdrawn by subject
    -
    2
         Adverse event, non-fatal
    2
    1
         Progressive disease
    6
    6
         Other (Death)
    2
    3
         Other (Unspecified reason)
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pamrevlumab 30 mg/kg Q3W
    Reporting group description
    		 Subjects were randomized to receive pamrevlumab 30 mg/kg by IV infusion Q3W.

    Reporting group title
    Placebo Q3W
    Reporting group description
    		 Subjects were randomized to receive placebo matching pamrevlumab by IV infusion Q3W.

    Reporting group values
    		 Pamrevlumab 30 mg/kg Q3W Placebo Q3W Total
    Number of subjects
    		 50 53
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.3 ( 7.05 ) 68.4 ( 7.20 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 10 27
        Male
    		 33 43 76
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 1 1 2
        Not Hispanic or Latino
    		 49 52 101
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 5 3 8
        Black or African American
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 41 44 85
        Other
    		 4 5 9

    End points

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    End points reporting groups
    Reporting group title
    Pamrevlumab 30 mg/kg Q3W
    Reporting group description
    		 Subjects were randomized to receive pamrevlumab 30 mg/kg by IV infusion Q3W.

    Reporting group title
    Placebo Q3W
    Reporting group description
    		 Subjects were randomized to receive placebo matching pamrevlumab by IV infusion Q3W.

    Primary: Change from Baseline to Week 48 in FVC (Percent of Predicted FVC Value [% predicted])

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    End point title
    		 Change from Baseline to Week 48 in FVC (Percent of Predicted FVC Value [% predicted])
    End point description
    FVC in liters was measured during the spirometry assessments at screening and during the randomized treatment period at Day 1 and every 12 weeks. The FVC (% predicted) was calculated using an algorithm for the corresponding gender-race-age group (Hankinson et al, Am J Resp Crit Care Med. 1999; 159:179-87). The least squares (LS) mean change from baseline to Week 48 (end of the randomized treatment period) in FVC (% predicted) is presented for the intention-to-treat (ITT) population which included randomized subjects who met all protocol eligibility criteria. Baseline was defined as the mean of the last screening visit and the Day 1 visit values. Analysis of treatment difference in change from baseline to Week 48 used a random coefficient regression model which included treatment arm, visit, treatment by visit interaction, and baseline as fixed effects and linear slope as random effect, based on the missing at random assumption. Observed data from all visits were included in the model.
    End point type
    Primary
    End point timeframe
    Baseline (screening and Day 1) up to Week 48 of randomized treatment period.
    End point values
    		 Pamrevlumab 30 mg/kg Q3W Placebo Q3W
    Number of subjects analysed
    50
    51
    Units: % predicted FVC
        least squares mean (confidence interval 95%)
    -2.85 (-4.41 to -1.29)
    -7.17 (-10.83 to -3.52)
    Statistical analysis title
    		 Absolute treatment difference
    Statistical analysis description
    The absolute LS mean treatment difference (pamrevlumab - placebo) for change from baseline to Week 48 in FVC (% predicted) is presented.
    Comparison groups
    Pamrevlumab 30 mg/kg Q3W v Placebo Q3W
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0331 [1]
    Method
    		 Random coefficient regression
    Parameter type
    		 LS mean difference
    Point estimate
    4.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 8.3
    Notes
    [1] - The analysis of the change from baseline to Week 48 in FVC (% predicted) was based on the random coefficient regression model based on observed cases.

    Secondary: Mean Change from Baseline to Week 24 and Week 48 in the HRCT Quantitative Lung Fibrosis (QLF) Score

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    End point title
    		 Mean Change from Baseline to Week 24 and Week 48 in the HRCT Quantitative Lung Fibrosis (QLF) Score
    End point description
    The extent of pulmonary fibrosis was measured by HRCT scans of the chest at screening and at Weeks 24 and 48, to determine the HRCT QLF score. Each lung was divided into 5 lobes and a computer algorithm calculated the percent of fibrotic reticulation in each lung lobe. The fibrosis score of the whole lung was defined as the average of the 5 lung lobes. The mean changes from baseline to Week 24 and Week 48 in the HRCT QLF score are presented for subjects in the ITT population and who also had a baseline fibrosis evaluation. Baseline was defined as the screening evaluation. Missing data were imputed using the multiple imputation (MI) method to handle missing values.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 24 and Week 48.
    End point values
    		 Pamrevlumab 30 mg/kg Q3W Placebo Q3W
    Number of subjects analysed
    47
    49
    Units: Percent of fibrosis
    least squares mean (standard error)
        Week 24
    0.9 ( 0.52 )
    2.6 ( 0.58 )
        Week 48
    2.8 ( 1.02 )
    5.9 ( 1.45 )
    Statistical analysis title
    		 Week 24: Absolute treatment difference
    Statistical analysis description
    The absolute LS mean treatment difference (pamrevlumab - placebo) for change from baseline to Week 24 in QLF score is presented.
    Comparison groups
    Pamrevlumab 30 mg/kg Q3W v Placebo Q3W
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0236
    Method
    		 ANCOVA with MI
    Parameter type
    		 LS mean difference
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 -0.2
    Statistical analysis title
    		 Week 48: Absolute treatment difference
    Statistical analysis description
    The absolute LS mean treatment difference (pamrevlumab - placebo) for change from baseline to Week 48 in QLF score is presented.
    Comparison groups
    Pamrevlumab 30 mg/kg Q3W v Placebo Q3W
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0729
    Method
    		 ANCOVA with MI
    Parameter type
    		 LS mean difference
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 0.3

    Secondary: Percentage of Subjects with IPF Progression Events up to Week 48

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    End point title
    		 Percentage of Subjects with IPF Progression Events up to Week 48
    End point description
    IPF progression events included death from any cause or absolute decline in FVC (% predicted) value of ≥10%, confirmed by repeat spirometry. Classification of FVC (% predicted) declined ≥10% was based on observed and imputed data. Missing data in FVC (% predicted) were imputed using the predicted values from the random coefficient module with treatment, visit, visit-by-treatment interaction, and baseline FVC (% predicted) as fixed effects and linear slope as random effect. The percentage of subjects with progression events at Week 48 is presented for the ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline (screening and Day 1) up to Week 48.
    End point values
    		 Pamrevlumab 30 mg/kg Q3W Placebo Q3W
    Number of subjects analysed
    50
    51
    Units: percentage of subjects
        number (not applicable)
    10.0
    31.4
    Statistical analysis title
    		 Absolute treatment difference
    Statistical analysis description
    The absolute treatment difference (pamrevlumab - placebo) for percentage of subjects with IPF progression at Week 48 is presented.
    Comparison groups
    Pamrevlumab 30 mg/kg Q3W v Placebo Q3W
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0133
    Method
    		 Regression, Logistic
    Parameter type
    		 Absolute difference
    Point estimate
    -21.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.6
         upper limit
    		 -6.2

    Secondary: Mean Change from Baseline to Week 24 and Week 48 in the Health-Related Quality of Life (HRQoL) Saint George's Respiratory Questionnaire (SGRQ) Domain and Total Scores

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    End point title
    		 Mean Change from Baseline to Week 24 and Week 48 in the Health-Related Quality of Life (HRQoL) Saint George's Respiratory Questionnaire (SGRQ) Domain and Total Scores
    End point description
    HRQoL was assessed by the SGRQ to measure health impairment, and includes 17 questions in 3 domains: Symptoms, Activity and Impacts. The domain and total scores range from 0 to 100, with 0 indicating the best and 100 indicating the worst possible health status. The LS mean changes from baseline to Week 24 and Week 48 for each domain score and for the total score are presented for subjects in the ITT population and who also had baseline and at least 1 follow-up value. Missing data at post-baseline visits were imputed as the predicted values from the random coefficient model which included treatment, visit, visit-by-treatment interaction and baseline SGRQ score as fixed effects and linear slope of visit as random effect.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 24 and Week 48.
    End point values
    		 Pamrevlumab 30 mg/kg Q3W Placebo Q3W
    Number of subjects analysed
    47
    46
    Units: Score
    least squares mean (standard error)
        Week 24 Symptoms Score
    -0.66 ( 1.963 )
    -1.44 ( 1.984 )
        Week 24 Activity Score
    -0.41 ( 1.847 )
    0.63 ( 1.867 )
        Week 24 Impacts Score
    -1.08 ( 1.835 )
    -0.51 ( 1.855 )
        Week 24 Total Score
    -0.75 ( 1.544 )
    -0.61 ( 1.561 )
        Week 48 Symptoms Score
    -3.38 ( 2.345 )
    1.89 ( 2.370 )
        Week 48 Activity Score
    -4.42 ( 2.464 )
    1.72 ( 2.490 )
        Week 48 Impacts Score
    -1.76 ( 2.682 )
    3.03 ( 2.711 )
        Week 48 Total Score
    -2.83 ( 2.255 )
    2.54 ( 2.279 )
    No statistical analyses for this end point

    Other pre-specified: Mean Change from Baseline to Week 48 in FVC

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    End point title
    		 Mean Change from Baseline to Week 48 in FVC
    End point description
    The LS mean change from baseline to Week 48 in the FVC was estimated using the random coefficient linear regression model which included treatment, visit, visit-by-treatment interaction, baseline FVC, age, sex and height as fixed effects and linear slope as random effect. Data is presented for the ITT population. Observed data from all visits were included in the model.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day 1) to Week 48.
    End point values
    		 Pamrevlumab 30 mg/kg Q3W Placebo Q3W
    Number of subjects analysed
    50
    51
    Units: Liters
        least squares mean (standard error)
    -0.129 ( 0.0271 )
    -0.308 ( 0.0743 )
    Statistical analysis title
    		 Absolute treatment difference
    Statistical analysis description
    The absolute LS mean treatment difference (pamrevlumab - placebo) for change from baseline to Week 48 in FVC (liters) is presented.
    Comparison groups
    Pamrevlumab 30 mg/kg Q3W v Placebo Q3W
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0249 [2]
    Method
    		 Random coefficient regression
    Parameter type
    		 LS mean difference
    Point estimate
    0.178
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.023
         upper limit
    		 0.334
    Notes
    [2] - The analysis of the change from baseline to Week 48 in FVC (liters) was based on the random coefficient regression model based on observed cases.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs are reported for the randomized treatment period, collected from Day 1 to the end of the follow-up period (approximately 13 months).
    Adverse event reporting additional description
    The safety population included randomized subjects who received any amount of study treatment. TEAEs were defined as new or worsening AEs that occurred after the start of first infusion of the study treatment and within 28 days of last infusion, or before the first pamrevlumab infusion in the extended treatment period, whichever occurred first.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Pamrevlumab 30 mg/kg Q3W
    Reporting group description
    		 Subjects were randomized to receive pamrevlumab 30 mg/kg by IV infusion Q3W.

    Reporting group title
    Placebo Q3W
    Reporting group description
    		 Subjects were randomized to receive placebo matching pamrevlumab by IV infusion Q3W.

    Serious adverse events
    		 Pamrevlumab 30 mg/kg Q3W Placebo Q3W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 50 (24.00%)
    8 / 53 (15.09%)
         number of deaths (all causes)
    3
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         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
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Angina pectoris
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         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
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 53 (7.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Antisynthetase syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         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
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pamrevlumab 30 mg/kg Q3W Placebo Q3W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 50 (84.00%)
    41 / 53 (77.36%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 53 (7.55%)
         occurrences all number
    15
    21
    Hypertension
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 53 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 50 (20.00%)
    4 / 53 (7.55%)
         occurrences all number
    21
    4
    Oedema peripheral
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 53 (3.77%)
         occurrences all number
    5
    2
    Chest pain
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 53 (1.89%)
         occurrences all number
    4
    1
    Chest discomfort
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 53 (1.89%)
         occurrences all number
    3
    1
    Pain
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 53 (0.00%)
         occurrences all number
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 50 (28.00%)
    23 / 53 (43.40%)
         occurrences all number
    22
    25
    Dyspnoea
         subjects affected / exposed
    13 / 50 (26.00%)
    11 / 53 (20.75%)
         occurrences all number
    13
    12
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    10 / 50 (20.00%)
    7 / 53 (13.21%)
         occurrences all number
    15
    8
    Nasopharyngitis
         subjects affected / exposed
    9 / 50 (18.00%)
    5 / 53 (9.43%)
         occurrences all number
    12
    7
    Upper-airway cough syndrome
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 53 (3.77%)
         occurrences all number
    6
    2
    Throat irritation
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 53 (7.55%)
         occurrences all number
    1
    4
    Pulmonary hypertension
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 53 (1.89%)
         occurrences all number
    3
    1
    Sinus congestion
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 53 (1.89%)
         occurrences all number
    3
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 53 (9.43%)
         occurrences all number
    4
    5
    Insomnia
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 53 (1.89%)
         occurrences all number
    4
    2
    Investigations
    Heart sounds abnormal
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Oxygen consumption increased
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 50 (4.00%)
    3 / 53 (5.66%)
         occurrences all number
    2
    3
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 50 (8.00%)
    6 / 53 (11.32%)
         occurrences all number
    14
    7
    Dizziness
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 53 (0.00%)
         occurrences all number
    6
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 50 (14.00%)
    7 / 53 (13.21%)
         occurrences all number
    17
    8
    Diarrhoea
         subjects affected / exposed
    8 / 50 (16.00%)
    4 / 53 (7.55%)
         occurrences all number
    21
    4
    Constipation
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 53 (7.55%)
         occurrences all number
    2
    4
    Abdominal pain upper
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 53 (0.00%)
         occurrences all number
    4
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 53 (9.43%)
         occurrences all number
    5
    5
    Back pain
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 53 (3.77%)
         occurrences all number
    6
    3
    Musculoskeletal pain
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 53 (3.77%)
         occurrences all number
    4
    2
    Myalgia
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 53 (1.89%)
         occurrences all number
    3
    1
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    15 / 50 (30.00%)
    10 / 53 (18.87%)
         occurrences all number
    19
    11
    Sinusitis
         subjects affected / exposed
    8 / 50 (16.00%)
    8 / 53 (15.09%)
         occurrences all number
    9
    9
    Urinary tract infection
         subjects affected / exposed
    10 / 50 (20.00%)
    4 / 53 (7.55%)
         occurrences all number
    13
    5
    Bronchitis
         subjects affected / exposed
    2 / 50 (4.00%)
    6 / 53 (11.32%)
         occurrences all number
    3
    7
    Viral infection
         subjects affected / exposed
    0 / 50 (0.00%)
    5 / 53 (9.43%)
         occurrences all number
    0
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 53 (3.77%)
         occurrences all number
    3
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2014
    - Increased target enrollment and stratified subjects by prior therapy (nintedanib and/or pirfenidone). - Amended procedures for replacing subjects to account for early dropouts. - Revised enrollment criteria for extended treatment period from <3% absolute decrease in FVC (%predicted) after 48 weeks to no decrease or an increase in FVC (% predicted) after 48 weeks. - Revised assessments so diffusing capacity of the lung for carbon monoxide was performed at screening only. - Removed evaluation of dyspnoea; evaluations for prothrombin time and partial prothromboplastin time and reduced frequency of laboratory tests. - Removed exclusion criteria for subjects with an international normalized ratio of >1.5. - Permitted enrollment of subjects with a cancer diagnosis >3 years prior to screening and of subjects with a history of in situ cancer. - Added an optional whole blood sample collection on Day 1 for DNA analysis.
    09 Mar 2015
    - Increased number of sites to 76 to maximize enrollment. - Clarified extended treatment period procedures. - Clairfication regarding prior therapy with pirfenidone and/or nintedanib, and for subjects who had previously received perfenidone and/or nintedanib and experienced a decrease of >10% in FVC (% predicted). - Clarified that subjects could not receive sildenafil for IPF but could for a different indication. - Expanded the rationale for the placebo arm. - Clarified mandatory discontinuation criteria, and specification of minimum washout period for prohibited drugs as 5 half-lives prior to Day 1 dosing. - Clarified study termination description that pamrevlumab would not be provided if the planned analysis showed it was not effective for IPF treatment. - Clarification that FVC criterion for disease progression should be on pre-bronchodilator values. - Clarification that SAEs related to disease progression, lung transplantation and worsening of baseline conditions requiring elective surgery were to be reported as SAEs. - Added HRCT to study procedure descriptions, and added statement that serial spirometry would be performed as part of pulmonary function tests.
    28 May 2015
    - Follow-up period extended from 7 weeks to 10 weeks. - Required use of double-barrier contraception methods during the study and for 3 months after the last dose of study drug for women of childbearing potential and male partners of women of childbearing potential.

    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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