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    Clinical Trial Results:
    A Randomized, Double-blind, Dose-ranging, Placebo-controlled Phase 2a Evaluation of The Safety, Tolerability And Pharmacokinetics of PLN-74809 in Participants With Idiopathic Pulmonary Fibrosis (IPF) (INTEGRIS-IPF)

    Summary
    EudraCT number
    2019-002709-23
    Trial protocol
    GB   DE   NL   BE   IT  
    Global end of trial date
    15 Feb 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    08 May 2024
    First version publication date
    08 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PLN-74809-IPF-202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04396756
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pliant Therapeutics Inc.
    Sponsor organisation address
    331 Oyster Point Boulevard, South San Francisco, United States, CA 94080
    Public contact
    Gregory P. Cosgrove, MD, Pliant Therapeutics Inc., +1 650-481-6770, GCosgrove@pliantrx.com
    Scientific contact
    Gregory P. Cosgrove, MD, Pliant Therapeutics Inc., +1 650-481-6770, GCosgrove@pliantrx.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
    15 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is the assessment of the safety and tolerability of PLN-74809.
    Protection of trial subjects
    The Investigator documented approval from the Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as appropriate, for the study protocol, any amendments, informed consent forms (ICFs) and any revised ICFs, participant recruitment documents (eg, advertisements, video and/or video script), and any other study documentation provided to participants.
    Background therapy
    Participants who were receiving treatment for IPF with nintedanib or pirfenidone were allowed, provided these drugs had been given at a stable dose for at least 3 months before the Screening Visit and were expected to remain unchanged during the study.
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Feb 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
    New Zealand: 4
    Country: Number of subjects enrolled
    United States: 89
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Canada: 5
    Worldwide total number of subjects
    120
    EEA total number of subjects
    14
    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)
    16
    From 65 to 84 years
    102
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were screened at 37 sites in 7 countries (Australia, Belgium, Canada, Italy, the Netherlands, New Zealand, and the United States) between Feb 2020 and Feb 2023. This study was divided into 4 parts, each part comprised a screening period of up to 28 days, a double-blind treatment period, and a 2-week post-treatment follow-up period.

    Pre-assignment
    Screening details
    Out of 168 participants who were screened, 10 participants were re-screened, 49 participants failed screening and 119 participants were enrolled and assigned to one of four treatment arms. One participant received both placebo and PLN-74809 320 mg due to incorrect study drug dispensation.

    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
    Part A: PLN-74809 40 mg
    Arm description
    PLN-74809 (Part A): Consists of an up to 28-day screening period, a 4-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 40mg or a matching placebo with 100ml water after fasting.
    Arm type
    Experimental

    Investigational medicinal product name
    PLN-74809
    Investigational medicinal product code
    Other name
    Bexotegrast
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    PLN-74809 administered orally.

    Arm title
    Part B: PLN-74809 40 mg
    Arm description
    PLN-74809 (Part B): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 40mg or a matching placebo with 240ml water after fasting.
    Arm type
    Experimental

    Investigational medicinal product name
    PLN-74809
    Investigational medicinal product code
    Other name
    Bexotegrast
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PLN-74809 tablet administered orally.

    Arm title
    Part C: PLN-74809 80 mg
    Arm description
    PLN-74809 (Part C): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 80mg or a matching placebo with 240ml water after fasting.
    Arm type
    Experimental

    Investigational medicinal product name
    PLN-74809
    Investigational medicinal product code
    Other name
    Bexotegrast
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PLN-74809 tablet(s) administered orally.

    Arm title
    Part C: PLN-74809 160 mg
    Arm description
    PLN-74809 (Part C): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 160mg or a matching placebo with 240ml water after fasting.
    Arm type
    Experimental

    Investigational medicinal product name
    PLN-74809
    Investigational medicinal product code
    Other name
    Bexotegrast
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PLN-74809 tablets administered orally.

    Arm title
    Part D: PLN-74809 320 mg
    Arm description
    PLN-74809 (Part D): Consists of an up to 28-day screening period, at least 24-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 320 mg or a matching placebo with 240ml water after fasting.
    Arm type
    Experimental

    Investigational medicinal product name
    Part D: PLN-74809 320 mg
    Investigational medicinal product code
    Other name
    Bexotegrast
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PLN-74809 tablet administered orally

    Arm title
    Placebo
    Arm description
    Participants took a matching placebo with water after fasting.
    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
    Matching placebo tablets administered orally.

    Number of subjects in period 1
    Part A: PLN-74809 40 mg Part B: PLN-74809 40 mg Part C: PLN-74809 80 mg Part C: PLN-74809 160 mg Part D: PLN-74809 320 mg Placebo
    Started
    1
    22
    23
    22
    21
    31
    Completed
    1
    21
    23
    20
    15
    25
    Not completed
    0
    1
    0
    2
    6
    6
         Adverse event, serious fatal
    -
    -
    -
    -
    1
    -
         Physician decision
    -
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    -
    -
    -
    2
    3
    3
         Adverse event, non-fatal
    -
    -
    -
    -
    2
    2
         Not specified
    -
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: PLN-74809 40 mg
    Reporting group description
    PLN-74809 (Part A): Consists of an up to 28-day screening period, a 4-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 40mg or a matching placebo with 100ml water after fasting.

    Reporting group title
    Part B: PLN-74809 40 mg
    Reporting group description
    PLN-74809 (Part B): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 40mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Part C: PLN-74809 80 mg
    Reporting group description
    PLN-74809 (Part C): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 80mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Part C: PLN-74809 160 mg
    Reporting group description
    PLN-74809 (Part C): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 160mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Part D: PLN-74809 320 mg
    Reporting group description
    PLN-74809 (Part D): Consists of an up to 28-day screening period, at least 24-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 320 mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Placebo
    Reporting group description
    Participants took a matching placebo with water after fasting.

    Reporting group values
    Part A: PLN-74809 40 mg Part B: PLN-74809 40 mg Part C: PLN-74809 80 mg Part C: PLN-74809 160 mg Part D: PLN-74809 320 mg Placebo Total
    Number of subjects
    1 22 23 22 21 31 120
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64 ( 999 ) 69.2 ( 7.11 ) 74.2 ( 4.70 ) 71.5 ( 6.63 ) 70.6 ( 7.31 ) 72.1 ( 6.20 ) -
    Gender categorical
    Units: Subjects
        Female
    0 4 4 6 1 4 19
        Male
    1 18 19 16 20 27 101

    End points

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    End points reporting groups
    Reporting group title
    Part A: PLN-74809 40 mg
    Reporting group description
    PLN-74809 (Part A): Consists of an up to 28-day screening period, a 4-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 40mg or a matching placebo with 100ml water after fasting.

    Reporting group title
    Part B: PLN-74809 40 mg
    Reporting group description
    PLN-74809 (Part B): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 40mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Part C: PLN-74809 80 mg
    Reporting group description
    PLN-74809 (Part C): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 80mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Part C: PLN-74809 160 mg
    Reporting group description
    PLN-74809 (Part C): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 160mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Part D: PLN-74809 320 mg
    Reporting group description
    PLN-74809 (Part D): Consists of an up to 28-day screening period, at least 24-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 320 mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Placebo
    Reporting group description
    Participants took a matching placebo with water after fasting.

    Primary: Parts A,B,C, and D - Number of Participants With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Parts A,B,C, and D - Number of Participants With Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    An AE was any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug. TEAEs were defined as any AEs with an onset date on or after the study drug start date and no later than 14 days after permanent discontinuation of study drug. Safety Population: All participants who took at least 1 dose of study drug. Values of 9999 indicate that data are not available for the specified time point.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks for Part A, 12 weeks for Part B-C, and up to week 12 and 48 for Part D
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analyses were pre-specified for this endpoint.
    End point values
    Part A: PLN-74809 40 mg Part B: PLN-74809 40 mg Part C: PLN-74809 80 mg Part C: PLN-74809 160 mg Part D: PLN-74809 320 mg Placebo
    Number of subjects analysed
    1
    22
    23
    22
    21
    31 [2]
    Units: Number of Participants
        Up to 4 weeks
    1
    9999
    9999
    9999
    9999
    9999
        Up to 12 weeks
    9999
    16
    15
    14
    17
    21
        Up to 48 weeks
    9999
    9999
    9999
    9999
    20
    7
    Notes
    [2] - N=31 for Placebo (Part B, C, D) "Up to 12 week" data N=8 for Placebo (Part D) "Up to 48 week" data
    No statistical analyses for this end point

    Primary: Parts A,B,C, and D - Number of Participants With Serious TEAEs

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    End point title
    Parts A,B,C, and D - Number of Participants With Serious TEAEs [3]
    End point description
    A serious adverse event (SAE) was defined as an event that, at any dose, results in the following: death, a life-threatening situation; in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect or a medically important event or reaction. Safety Population: All participants who took at least 1 dose of study drug. Value of 9999 indicate that data are not available for the specified time point.
    End point type
    Primary
    End point timeframe
    Up to 4 weeks for Part A, 12 weeks for Part B-C, and up to week 12 and 48 for Part D
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analyses were pre-specified for this endpoint.
    End point values
    Part A: PLN-74809 40 mg Part B: PLN-74809 40 mg Part C: PLN-74809 80 mg Part C: PLN-74809 160 mg Part D: PLN-74809 320 mg Placebo
    Number of subjects analysed
    1
    22
    23
    22
    21
    31 [4]
    Units: Number of Participants
        Up to 4 weeks
    0
    9999
    9999
    9999
    9999
    9999
        Up to 12 weeks
    9999
    1
    0
    2
    1
    3
        Up to 48 weeks
    9999
    9999
    9999
    9999
    2
    1
    Notes
    [4] - N=31 for Placebo (Part B, C, D) "Up to 12 week" data N=8 for Placebo (Part D) "Up to 48 week" data
    No statistical analyses for this end point

    Secondary: Parts A,B, C, and D - PLN-74809 Total Plasma Concentrations

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    End point title
    Parts A,B, C, and D - PLN-74809 Total Plasma Concentrations [5]
    End point description
    PK Analysis Population: All randomized participants who had sufficient PLN-74809 concentration data for PK calculation were included in the PK analyses. Values of "9999.99" indicate mean and standard deviation could not be calculated.
    End point type
    Secondary
    End point timeframe
    Part A: week 4, 1-hour post-dose; Part B-D: week 12, 2 hours post-dose; Part D: week 24, 2 hours post-dose
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: NA
    End point values
    Part A: PLN-74809 40 mg Part B: PLN-74809 40 mg Part C: PLN-74809 80 mg Part C: PLN-74809 160 mg Part D: PLN-74809 320 mg
    Number of subjects analysed
    1
    20
    23
    21
    18 [6]
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 4, 1 hour post-dose
    829 ( 9999.99 )
    9999.99 ( 9999.99 )
    9999.99 ( 9999.99 )
    9999.99 ( 9999.99 )
    9999.99 ( 9999.99 )
        Week 12, 2-hours post-dose
    9999.99 ( 9999.99 )
    921.45 ( 549.103 )
    1731.70 ( 875.776 )
    2733.71 ( 1038.402 )
    3742.78 ( 1383.345 )
        Week 24, 2 hours post-dose
    9999.99 ( 9999.99 )
    9999.99 ( 9999.99 )
    9999.99 ( 9999.99 )
    9999.99 ( 9999.99 )
    4120.63 ( 1866.606 )
    Notes
    [6] - N=16 for Part D (320 mg) - "Week 24, 2 hours post-dose"
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    ACM: Randomization up to 190.1 days +14 days. AEs: First dose date up to 29 days +14 (Part A 40 mg), 83.6 days +14 (Part B 40 mg), 86.0 days +14 (Part C 80 mg), 82.7 days +14 (Part C 160 mg), 190.1 days +14 (Part D 320 mg), and 107.6 days +14 (Placebo).
    Adverse event reporting additional description
    Safety population included all participants who took at least 1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Part A: PLN-74809 40 mg
    Reporting group description
    PLN-74809 (Part A): Consists of an up to 28-day screening period, a 4-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 40mg or a matching placebo with 100ml water after fasting.

    Reporting group title
    Part B: PLN-74809 40 mg
    Reporting group description
    PLN-74809 (Part B): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 40mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Part C: PLN-74809 80 mg
    Reporting group description
    PLN-74809 (Part C): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 80mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Part C: PLN-74809 160 mg
    Reporting group description
    PLN-74809 (Part C): Consists of an up to 28-day screening period, a 12-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 160mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Part D: PLN-74809 320 mg
    Reporting group description
    PLN-74809 (Part D): Consists of an up to 28-day screening period, at least 24-week treatment period, and a 2-week (+/- 3 days) post-treatment follow-up period. Participants took either PLN-74809 320 mg or a matching placebo with 240ml water after fasting.

    Reporting group title
    Placebo
    Reporting group description
    Participants took a matching placebo with water after fasting.

    Serious adverse events
    Part A: PLN-74809 40 mg Part B: PLN-74809 40 mg Part C: PLN-74809 80 mg Part C: PLN-74809 160 mg Part D: PLN-74809 320 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    2 / 22 (9.09%)
    3 / 31 (9.68%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Haemorrhagic arteriovenous malformation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis/Pulmonary fibrosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder dilatation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperlactacidaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part A: PLN-74809 40 mg Part B: PLN-74809 40 mg Part C: PLN-74809 80 mg Part C: PLN-74809 160 mg Part D: PLN-74809 320 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    8 / 22 (36.36%)
    8 / 23 (34.78%)
    10 / 22 (45.45%)
    18 / 22 (81.82%)
    14 / 31 (45.16%)
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    2 / 22 (9.09%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 22 (9.09%)
    2 / 23 (8.70%)
    1 / 22 (4.55%)
    2 / 22 (9.09%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    2
    1
    3
    2
    Oedema peripheral
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 22 (0.00%)
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    1 / 22 (4.55%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    1
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 1 (100.00%)
    2 / 22 (9.09%)
    5 / 23 (21.74%)
    5 / 22 (22.73%)
    7 / 22 (31.82%)
    4 / 31 (12.90%)
         occurrences all number
    1
    2
    5
    8
    11
    5
    Vomiting
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    0 / 22 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Nausea
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 22 (4.55%)
    1 / 23 (4.35%)
    2 / 22 (9.09%)
    0 / 22 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    1
    1
    1
    5
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    1 / 23 (4.35%)
    2 / 22 (9.09%)
    5 / 22 (22.73%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    2
    6
    1
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 22 (4.55%)
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    3 / 22 (13.64%)
    3 / 31 (9.68%)
         occurrences all number
    0
    1
    2
    1
    3
    3
    Idiopathic pulmonary fibrosis/Pulmonary fibrosis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    4 / 22 (18.18%)
    3 / 31 (9.68%)
         occurrences all number
    0
    2
    0
    2
    4
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    2
    3
    0
    Pneumonia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 22 (4.55%)
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    2 / 22 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    1
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    2 / 22 (9.09%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    0
    0
    0
    0
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Mar 2020
    Version 1.1: Part A was no longer described in the protocol. -Part B was introduced as a randomized, double-blind, placebo controlled cohort in which 28 participants with IPF were to be randomized in a 3:1 ratio to receive PLN-74809 40 mg or placebo once daily for 28 days. -Part C was introduced following favorable DSMB review and completion of enrollment in Part B, to proceed with randomized, double-blind, placebo-controlled cohorts introducing doses above 40 mg. -The sample size was changed to capture the increased number of participants to be enrolled in the study.
    30 Nov 2020
    Version 2.0: A description and rationale for the 80 and 160 mg doses studied in Part C was added. -Clarified that participants in Part C were to be allocated in a 3:3:2 ratio (parallel randomization) to receive once daily PLN-74809 80 mg or 160 mg, or placebo. Participants in Part C were enrolled under protocol v2.0 in Australia, Canada, and the United States.
    02 Dec 2020
    Version 2.1: Clarified that participants in Part C were to be allocated in a 3:1 ratio (sequential randomization) to receive once daily PLN-74809 80 mg or placebo (sequential Cohort 1) or 160 mg or placebo (sequential Cohort 2). Participants in Part C were enrolled under protocol v2.1 in Italy, the Netherlands, New Zealand, and the United States. -Inclusion criteria 7, 8, and 9 regarding contraception were revised in alignment with feedback from various competent authorities. Contraception was also updated. -Exclusion criterion 6 (HRCT scan) was clarified and refined based on feedback from competent authorities. - “Diagnosis” was removed from exclusion criterion 7 in relation to severe pulmonary hypertension to simplify PI assessment for eligibility. -Hepatic impairment was removed from exclusion criterion 11 as it was covered by the exclusion of both end-stage liver disease and liver function tests above the specified limits. -Clarified that participation in a previous clinical study should be the linger of either 30 days prior to screening OR 5 half-lives in exclusion criterion 21. -Added standardized guidance for the management of missed or delayed study drug administration in Section 6.3 Selection and Timing of Dose for Each Participant. -Global guidance for procedures that were to be followed should unblinding have occurred was added. -Grapefruit, grapefruit-containing foods and beverages, and St. John’s Wort were added as disallowed medications as they can affect the concentration of PLN- 74809. -Study Procedures was updated to allow a home health care vendor to conduct some of the study visits. -Language describing triplicate ECGs and how they were to be captured and measured was added. -Historical FVC and FEV1 could be used for eligibility assessments. -Clarified that Investigators or the Sponsor could discontinue participants with COVID-19 if their continued study involvement posed a safety risk.
    02 Dec 2020
    02-Dec-2020 continued: - The schedule of assessments was revised for consistency. - The definition of SAEs was clarified to include examples of important medical events, including laboratory abnormalities consistent with drug-induced liver injury, QT prolongation that results in study drug discontinuation, allergic bronchospasm requiring intensive treatment, blood dyscrasias, convulsions, and the development of drug dependency or abuse. - The determination of sample size was clarified to explain that 21 participants per dose level pertained only to those who would receive PLN-74809.
    19 Oct 2021
    Version 3.0: Timepoints specific to Part B and C were removed from the objectives to account for the different duration in Parts B and C and Part D.
    20 Oct 2021
    Version 3.1: A description and rationale for the 320 mg once daily dose for Part D was added following DSMB evaluation of the 80 and 160 mg doses from Part C. -Updated on the progress of Part C to explain that the DSMB had evaluated the 40 mg dose and recommended to continue without modification. -Digoxin (a P-gp substrate) was removed from exclusion criterion 25 following completion of the drug-drug interaction study PLN-74809-110. -Additional data was added to Section 6.6.1 Allowed Medications to describe drug-drug interaction studies between PLN-74809 and fluconazole and digoxin. Additional data was also added to Section 6.6.2 Disallowed Medications to describe the drug-drug interactions studies between PLN-74809 and itraconazole. -The phosphate salt formulation of PLN-74809 used in Part D was described, and storage conditions were revised. -Added language to provide direction as to how AEs and SAEs were to be reported. The process for reporting SAEs was revised to align with pharmacovigilance vendor reporting procedures. -Interim Analysis was updated to include a description of additional interim analyses. -Assessments and visits were added to the schedules of assessments for Parts B, C, and D to align with the revised study design and objectives.

    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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