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    Clinical Trial Results:
    Zephyrus II: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Pamrevlumab in Subjects with Idiopathic Pulmonary Fibrosis (IPF)

    Summary
    EudraCT number
    2020-000697-22
    Trial protocol
    FR   HU   NL   ES   CZ   DE   DK   IE   PL   IT  
    Global end of trial date
    04 Sep 2023

    Results information
    Results version number
    v2(current)
    This version publication date
    25 Aug 2024
    First version publication date
    27 Jul 2024
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    FGCL-3019-095
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04419558
    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., zephyrus@fibrogen.com
    Scientific contact
    Clinical Trial Information Desk, FibroGen, Inc., zephyrus@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
    04 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to evaluate the efficacy and safety of Pamrevlumab infusion (30 milligrams [mg]/kilogram [kg] intravenous [IV]) as compared to placebo in participants with Idiopathic Pulmonary Fibrosis (IPF).
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Council for Harmonisation (ICH) Harmonized Tripartite Guideline.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Sep 2020
    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
    Argentina: 5
    Country: Number of subjects enrolled
    Brazil: 24
    Country: Number of subjects enrolled
    China: 20
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Georgia: 6
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 33
    Country: Number of subjects enrolled
    Korea, Republic of: 77
    Country: Number of subjects enrolled
    Lebanon: 16
    Country: Number of subjects enrolled
    Mexico: 24
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Peru: 38
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Ukraine: 9
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    372
    EEA total number of subjects
    112
    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)
    87
    From 65 to 84 years
    281
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study included a Double-blind (DB) Period and an Open-label Extension (OLE) Period.

    Period 1
    Period 1 title
    DB Period (48 Weeks)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pamrevlumab
    Arm description
    Participants received pamrevlumab 30 mg/kg, administered by IV infusion, every 3 weeks, for a total of up to 17 infusions over 48 weeks in the DB period.
    Arm type
    Experimental

    Investigational medicinal product name
    Pamrevlumab
    Investigational medicinal product code
    FG-3019
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pamrevlumab was administered per dose and schedule specified in the arm description.

    Arm title
    Placebo
    Arm description
    Participants received pamrevlumab-matching placebo, administered by IV infusion every 3 weeks for a total of up to 17 infusions over 48 weeks in the DB period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    FG-3019
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pamrevlumab-matching placebo was administered per schedule specified in the arm description.

    Number of subjects in period 1
    Pamrevlumab Placebo
    Started
    184
    188
    Received at least 1 dose of study drug
    183
    188
    Completed
    47
    56
    Not completed
    137
    132
         Adverse event, serious fatal
    14
    11
         Participant Decision
    4
    3
         Consent withdrawn by subject
    11
    7
         Lung Transplant
    1
    -
         Adverse event, non-fatal
    6
    6
         Study terminated by sponsor
    99
    101
         Investigator Decision
    -
    1
         Lost to follow-up
    1
    3
         Disease Progression
    1
    -
    Period 2
    Period 2 title
    OLE Period (48 Weeks)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Pamrevlumab/Pamrevlumab
    Arm description
    Participants who completed the treatment in DB period and entered in the OLE period, continued to receive pamrevlumab 30 mg/kg administered by IV infusion, every 3 weeks for up to 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Pamrevlumab
    Investigational medicinal product code
    FG-3019
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pamrevlumab was administered per dose and schedule specified in the arm description.

    Arm title
    Placebo/Pamrevlumab
    Arm description
    Participants who completed the treatment in DB period and entered in the OLE period, received pamrevlumab 30 mg/kg administered by IV infusion, every 3 weeks for up to 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Pamrevlumab
    Investigational medicinal product code
    FG-3019
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pamrevlumab was administered per dose and schedule specified in the arm description.

    Number of subjects in period 2 [1]
    Pamrevlumab/Pamrevlumab Placebo/Pamrevlumab
    Started
    41
    45
    Completed
    0
    0
    Not completed
    41
    45
         Adverse event, serious fatal
    4
    6
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    3
    1
         Study terminated by sponsor
    34
    37
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: All participants who completed DB Period did not enter into the OLE Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pamrevlumab
    Reporting group description
    Participants received pamrevlumab 30 mg/kg, administered by IV infusion, every 3 weeks, for a total of up to 17 infusions over 48 weeks in the DB period.

    Reporting group title
    Placebo
    Reporting group description
    Participants received pamrevlumab-matching placebo, administered by IV infusion every 3 weeks for a total of up to 17 infusions over 48 weeks in the DB period.

    Reporting group values
    Pamrevlumab Placebo Total
    Number of subjects
    184 188 372
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    70.2 ( 7.8 ) 70.1 ( 8.2 ) -
    Sex: Female, Male
    Units: participants
        Female
    45 44 89
        Male
    139 144 283
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 2 2
        Asian
    42 55 97
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    2 1 3
        White
    111 114 225
        More than one race
    0 0 0
        Unknown or Not Reported
    29 16 45
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    52 45 97
        Not Hispanic or Latino
    125 141 266
        Unknown or Not Reported
    7 2 9
    Forced Vital Capacity (FVC)
    FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters.
    Units: liters
        arithmetic mean (standard deviation)
    2.4811 ( 0.6477 ) 2.5097 ( 0.6573 ) -

    End points

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    End points reporting groups
    Reporting group title
    Pamrevlumab
    Reporting group description
    Participants received pamrevlumab 30 mg/kg, administered by IV infusion, every 3 weeks, for a total of up to 17 infusions over 48 weeks in the DB period.

    Reporting group title
    Placebo
    Reporting group description
    Participants received pamrevlumab-matching placebo, administered by IV infusion every 3 weeks for a total of up to 17 infusions over 48 weeks in the DB period.
    Reporting group title
    Pamrevlumab/Pamrevlumab
    Reporting group description
    Participants who completed the treatment in DB period and entered in the OLE period, continued to receive pamrevlumab 30 mg/kg administered by IV infusion, every 3 weeks for up to 48 weeks.

    Reporting group title
    Placebo/Pamrevlumab
    Reporting group description
    Participants who completed the treatment in DB period and entered in the OLE period, received pamrevlumab 30 mg/kg administered by IV infusion, every 3 weeks for up to 48 weeks.

    Primary: DB Period: Change From Baseline in FVC at Week 48

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    End point title
    DB Period: Change From Baseline in FVC at Week 48
    End point description
    FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Least square (LS) mean and standard error (SE) were analyzed using mixed model repeated measures (MMRM). The ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 48
    End point values
    Pamrevlumab Placebo
    Number of subjects analysed
    70
    76
    Units: liters
        least squares mean (standard error)
    -0.30 ( 0.057 )
    -0.33 ( 0.059 )
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Pamrevlumab v Placebo
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6579
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.12
         upper limit
    0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.077

    Secondary: DB Period: Time to Disease Progression

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    End point title
    DB Period: Time to Disease Progression
    End point description
    Time to disease progression was defined as time from randomization to either the first occurrence of an absolute FVC percent predicted (FVCpp) decline of ≥10% from baseline or death, whichever occurred first. 'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks. The ITT population included all randomized participants. Here, '9.99' and '99999' represents 'NA' that is; 'Data could not be calculated due to smaller number of participants with an event'.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Pamrevlumab Placebo
    Number of subjects analysed
    184
    188
    Units: weeks
        median (confidence interval 95%)
    59.0 (9.99 to 99999)
    99999 (49.4 to 99999)
    No statistical analyses for this end point

    Secondary: DB Period: Change from Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48

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    End point title
    DB Period: Change from Baseline in Quantitative Lung Fibrosis (QLF) Volume at Week 48
    End point description
    The QLF volume is calculated as QLF=total lung capacity volume (TLC) * % of quantitative lung fibrosis for fibrosis of the whole lung. LS mean and SE were analyzed using MMRM. The ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    Pamrevlumab Placebo
    Number of subjects analysed
    71
    76
    Units: milliliters
        least squares mean (standard error)
    255.14 ( 72.028 )
    269.15 ( 60.898 )
    No statistical analyses for this end point

    Secondary: DB Period: Time to First Occurrence of Any Component of the Clinical Composite Endpoint, Whichever Occurred First

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    End point title
    DB Period: Time to First Occurrence of Any Component of the Clinical Composite Endpoint, Whichever Occurred First
    End point description
    The components of the clinical composite endpoints included acute idiopathic pulmonary fibrosis (IPF) exacerbation, respiratory hospitalization, or death. 'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks. The ITT population included all randomized participants. Here, '99999' represents 'NA' that is; 'Data could not be calculated due to smaller number of participants with an event'.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Pamrevlumab Placebo
    Number of subjects analysed
    184
    188
    Units: weeks
        median (confidence interval 95%)
    99999 (59.0 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: DB Period: Time to First Acute IPF Exacerbation

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    End point title
    DB Period: Time to First Acute IPF Exacerbation
    End point description
    'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks. The ITT population included all randomized participants. Here, '99999' represents 'NA' that is; 'Data could not be calculated due to smaller number of participants with an event'.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Pamrevlumab Placebo
    Number of subjects analysed
    184
    188
    Units: weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: DB Period: Time to All-Cause Mortality

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    End point title
    DB Period: Time to All-Cause Mortality
    End point description
    'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks. The ITT population included all randomized participants. Here, '9.99' and '99999' represents 'NA' that is; 'Data could not be calculated due to smaller number of participants with an event'.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Pamrevlumab Placebo
    Number of subjects analysed
    184
    188
    Units: weeks
        median (confidence interval 95%)
    99999 (59.0 to 99999)
    62.9 (9.99 to 99999)
    No statistical analyses for this end point

    Secondary: DB Period: Time to First Respiratory Hospitalization

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    End point title
    DB Period: Time to First Respiratory Hospitalization
    End point description
    'Median Time to Event' is an estimated value, which was calculated based on Kaplan-Meier method. For an endpoint in which less than half of the participants have encountered the events, the 'Median Time to Event' might be longer than the reported timeframe of 48 weeks. The ITT population included all randomized participants. Here, '99999' represents 'NA' that is; 'Data could not be calculated due to smaller number of participants with an event'.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Pamrevlumab Placebo
    Number of subjects analysed
    184
    188
    Units: weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to Week 104
    Adverse event reporting additional description
    As pre-specified, All-cause mortality data were collected and reported for all enrolled participants; and Serious and Non-serious adverse events data were collected and reported for all participants who received any dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    DB Period: Pamrevlumab
    Reporting group description
    Participants received pamrevlumab 30 mg/kg, administered by IV infusion, every 3 weeks, for a total of up to 17 infusions over 48 weeks in the DB period.

    Reporting group title
    OLE Period: Pamrevlumab
    Reporting group description
    Participants who completed the treatment in DB period and entered in the OLE period, received pamrevlumab 30 mg/kg administered by IV infusion, every 3 weeks for up to 48 weeks.

    Reporting group title
    DB Period: Placebo
    Reporting group description
    Participants received pamrevlumab-matching placebo, administered by IV infusion every 3 weeks for a total of up to 17 infusions over 48 weeks in the DB period.

    Serious adverse events
    DB Period: Pamrevlumab OLE Period: Pamrevlumab DB Period: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 183 (20.77%)
    20 / 86 (23.26%)
    37 / 188 (19.68%)
         number of deaths (all causes)
    16
    12
    15
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    9 / 183 (4.92%)
    12 / 86 (13.95%)
    10 / 188 (5.32%)
         occurrences causally related to treatment / all
    4 / 9
    1 / 12
    1 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 86 (1.16%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    4 / 183 (2.19%)
    2 / 86 (2.33%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 86 (2.33%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Pelvic fracture
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin injury
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar stroke
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    2 / 188 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Scleritis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal abscess
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 183 (4.92%)
    0 / 86 (0.00%)
    10 / 188 (5.32%)
         occurrences causally related to treatment / all
    3 / 9
    0 / 0
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 86 (1.16%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 86 (1.16%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 86 (0.00%)
    0 / 188 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 183 (0.00%)
    0 / 86 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    DB Period: Pamrevlumab OLE Period: Pamrevlumab DB Period: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 183 (45.36%)
    21 / 86 (24.42%)
    74 / 188 (39.36%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 183 (6.01%)
    4 / 86 (4.65%)
    7 / 188 (3.72%)
         occurrences all number
    14
    4
    8
    Fatigue
         subjects affected / exposed
    11 / 183 (6.01%)
    0 / 86 (0.00%)
    5 / 188 (2.66%)
         occurrences all number
    15
    0
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 183 (7.65%)
    4 / 86 (4.65%)
    15 / 188 (7.98%)
         occurrences all number
    22
    5
    23
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 183 (14.21%)
    5 / 86 (5.81%)
    24 / 188 (12.77%)
         occurrences all number
    38
    6
    27
    Dyspnoea
         subjects affected / exposed
    16 / 183 (8.74%)
    5 / 86 (5.81%)
    12 / 188 (6.38%)
         occurrences all number
    18
    7
    16
    Infections and infestations
    COVID-19
         subjects affected / exposed
    20 / 183 (10.93%)
    8 / 86 (9.30%)
    16 / 188 (8.51%)
         occurrences all number
    21
    8
    16
    Nasopharyngitis
         subjects affected / exposed
    13 / 183 (7.10%)
    4 / 86 (4.65%)
    14 / 188 (7.45%)
         occurrences all number
    15
    5
    15
    Bronchitis
         subjects affected / exposed
    9 / 183 (4.92%)
    0 / 86 (0.00%)
    12 / 188 (6.38%)
         occurrences all number
    10
    0
    14

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2021
    It included following changes: - Timeframe for efficacy assessments of secondary study endpoints were updated from Week 52 to Week 48. - Clarification was added that for calculation of Global Alignment and Proportion (GAP) Score, the Best-Test Review (BTR) assessment provided by the spirometry vendor Over-Reader of the screening value is to be used. - A final safety follow-up phone call 60 day post last dose was added. - Participant eligibility criteria updated: o Updated Inclusion criterion to add clarity about requirements of a High-resolution computed tomography (HRCT) scan done within 3 months of screening, to meet screening scan requirements. o Updated FVCpp eligibility criteria to be more inclusive, without compromising the target participant population. o Updated diffusing capacity of the lungs for carbon monoxide (DLCO) eligibility criteria and window to be more inclusive, without compromising the target participant population. o Revised per Clinical Trial Facilitation Group (CTFG) recommendation. o To ensure exclusion of participants who may have a history of allergic or anaphylactic reaction to any component of the excipient. o New criteria added to provide more specific guidance for the exclusionary intercurrent conditions and medications/vaccines. - Clarified to ensure that Investigators may unblind single participant in emergency situations without the need for Sponsor approval. - Clarified that if a participant has a life-threatening infusion-associated AE, study drug treatment must be permanently discontinued. - Added guidance on recommended timing between COVID-19 vaccination and study drug administration. - Incorporated Guidance from the Food and Drug Administration (FDA)/European Medicines Agency (EMA) in response to the COVID-19 pandemic and resulting need for flexibility with respect to study assessments and visit schedule. - Added on-study Physical Exams (PEs) and electrocardiograms (ECGs).
    09 Jan 2023
    It included following changes: - The primary efficacy endpoint was updated from time to disease progression to change in FVC. - The secondary endpoints were updated to reflect shift in the primary efficacy endpoint and several secondary endpoints were also moved to exploratory endpoints; additionally, a composite efficacy endpoint was added. - The exploratory endpoints were updated to include several of the previous secondary endpoints. - Clarified required procedures/assessments at early termination visits. - Added language describing infusion duration and post-infusion observation periods in the OLE. - Clarified requirements for medications and supplies for home health care. - Added preliminary non-clinical study results. - Added language regarding pregnancy testing. - Added pharmacokinetic (PK), Human Anti-Human Antibody (HAHA), HAHA-NA, Connective Tissue Growth Factor, and tryptase scheduled blood draws at the time of any suspected hypersensitivity/anaphylactic reactions. - Added additional time-points as follows in the main period of the study: CTGF at Weeks 24 and 36, and HAHA and HAHA-NA at Week 36 and Week 48/last dose/early termination (ET). - Clarified the order of Patient-Reported Outcome questionnaire administration. - Added objectives in the OLE period. - Added additional safety assessments – vitals and immunogenicity. - Clarified main period procedures and AEs. - Added OLE home health care requirements.

    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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    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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