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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind Study of Pamrevlumab or Placebo in combination with Gemcitabine Plus Nab-paclitaxel or FOLFIRINOX as Neoadjuvant Treatment in Patients with Locally Advanced, Unresectable Pancreatic Cancer

    Summary
    EudraCT number
    		 2019-001925-28
    Trial protocol
    		 AT   ES   DE   GB   FR   BE   IT  
    Global end of trial date
    11 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Oct 2024
    First version publication date
    31 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FGCL-3019-087
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03941093
    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., lapis@fibrogen.com
    Scientific contact
    Clinical Trial Information Desk, FibroGen, Inc., lapis@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
    19 Jul 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jun 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to evaluate the efficacy and safety of neoadjuvant treatment with pamrevlumab in combination with either gemcitabine plus nab-paclitaxel or FOLFIRINOX when compared to treatment with placebo in combination with either gemcitabine plus nab-paclitaxel or FOLFIRINOX in locally advanced, unresectable pancreatic cancer.
    Protection of trial subjects
    This trial was conducted according to the International Conference On Harmonization (ICH) Harmonized Tripartite Guideline in compliance with Good Clinical Practices (GCP), including the archiving of essential documents.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 May 2019
    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
    United States: 99
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 32
    Country: Number of subjects enrolled
    China: 21
    Worldwide total number of subjects
    284
    EEA total number of subjects
    100
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    140
    From 65 to 84 years
    143
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 ratio to one of the 2 study treatment arms: Pamrevlumab with Gemcitabine/Nab-paclitaxel or FOLFIRINOX or Placebo with Gemcitabine/Nab-paclitaxel or FOLFIRINOX.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Arm description
    		 Participants received pamrevlumab in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Pamrevlumab was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via intravenous (IV) infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil.
    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
    Pamrevlumab was administered per schedule specified in the arm description.

    Investigational medicinal product name
    FOLFIRINOX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FOLFIRINOX is a combination of several agents including Oxaliplatin, Folinic Acid, Irinotecan, and Fluorouracil. FOLFIRINOX was administered per schedule specified in the arm description.

    Investigational medicinal product name
    Gemcitabine plus Nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine plus nab-paclitaxel was administered per schedule specified in the arm description.

    Arm title
    		 Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Arm description
    		 Participants received pamrevlumab matched placebo in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Placebo was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil.
    Arm type
    		 Experimental

    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
    Placebo matched to pamrevlumab was administered per schedule specified in the arm description.

    Investigational medicinal product name
    FOLFIRINOX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FOLFIRINOX is a combination of several agents including Oxaliplatin, Folinic Acid, Irinotecan, and Fluorouracil. FOLFIRINOX was administered per schedule specified in the arm description.

    Investigational medicinal product name
    Gemcitabine plus Nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine plus nab-paclitaxel was administered per schedule specified in the arm description.

    Number of subjects in period 1
    		Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Started
    143
    141
    Received At Least 1 Dose of Study Drug
    142
    141
    Completed
    134
    134
    Not completed
    9
    7
         Consent withdrawn by subject
    9
    6
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Reporting group description
    		 Participants received pamrevlumab in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Pamrevlumab was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via intravenous (IV) infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil.

    Reporting group title
    Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Reporting group description
    		 Participants received pamrevlumab matched placebo in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Placebo was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil.

    Reporting group values
    		 Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Total
    Number of subjects
    		 143 141 284
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.5 ( 9.54 ) 64.5 ( 9.60 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 61 72 133
        Male
    		 82 69 151
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 2 2
        Asian
    		 25 35 60
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 5 5 10
        White
    		 96 79 175
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 17 20 37
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 2 12
        Not Hispanic or Latino
    		 122 124 246
        Unknown or Not Reported
    		 11 15 26

    End points

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    End points reporting groups
    Reporting group title
    Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Reporting group description
    		 Participants received pamrevlumab in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Pamrevlumab was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via intravenous (IV) infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil.

    Reporting group title
    Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Reporting group description
    		 Participants received pamrevlumab matched placebo in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Placebo was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil.

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the time from date of randomization to date of death due to any cause. Overall survival was calculated using the Kaplan-Meier method. The intent-to-treat (ITT) population included all randomized participants regardless of whether or not study treatment was received.
    End point type
    Primary
    End point timeframe
    Up to approximately 5 years
    End point values
    		 Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Number of subjects analysed
    143
    141
    Units: months
        median (confidence interval 95%)
    17.25 (15.47 to 18.89)
    17.94 (14.59 to 20.34)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX v Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5487
    Method
    		 Stratified Log Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.41

    Secondary: Progression-free Survival (PFS) as Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

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    End point title
    		 Progression-free Survival (PFS) as Assessed Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
    End point description
    The PFS was defined as time from date of randomization until disease progression or death due to any cause, whichever occurred first. PFS was calculated using the Kaplan-Meier method. Progression was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters (mm). Unequivocal progression of existing non-target lesions and the appearance of one or more new lesions was also considered progression. The ITT population included all randomized participants regardless of whether or not study treatment was received.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5 years
    End point values
    		 Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Number of subjects analysed
    143
    141
    Units: months
        median (confidence interval 95%)
    9.36 (7.75 to 11.79)
    9.40 (7.69 to 10.84)
    No statistical analyses for this end point

    Secondary: Number of Participants With Best Overall Objective Response as Assessed Using RECIST v1.1

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    End point title
    		 Number of Participants With Best Overall Objective Response as Assessed Using RECIST v1.1
    End point description
    Best overall objective response was defined as a complete response (CR) or partial response (PR). CR was defined as disappearance of all target or non-target lesions and normalization of tumor marker level (for non-target lesions), any pathological lymph nodes (whether target or non-target) must have reduced in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The ITT population included all randomized participants regardless of whether or not study treatment was received.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5 years
    End point values
    		 Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Number of subjects analysed
    143
    141
    Units: participants
    43
    64
    No statistical analyses for this end point

    Secondary: Event-free Survival (EFS)

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    End point title
    		 Event-free Survival (EFS)
    End point description
    The EFS endpoint was a composite time-to-event endpoint. The event being analyzed (‘treatment failure’) was defined as the earliest occurrence of: a) failure to achieve disease-free status locally after completion of neoadjuvant treatment and/or after surgery (that is, resection failure or progression that precludes surgery); b) local or distant recurrence, or c) death. The EFS was calculated using the Kaplan-Meier method. The ITT population included all randomized participants regardless of whether or not study treatment was received.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5 years
    End point values
    		 Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Number of subjects analysed
    143
    141
    Units: months
        median (confidence interval 95%)
    5.72 (5.59 to 6.01)
    5.78 (5.62 to 6.37)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 5 years
    Adverse event reporting additional description
    Per planned analysis all-cause mortality data were collected and reported for all randomized participants. Adverse events (serious and other) were collected and reported for all randomized participants who received study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Reporting group description
    		 Participants received pamrevlumab matched placebo in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Placebo was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil.

    Reporting group title
    Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Reporting group description
    		 Participants received pamrevlumab in combination with one chemotherapy treatment regimen (gemcitabine plus nab-paclitaxel or FOLFIRINOX) over a 28-day cycle, for up to 6 cycles. Pamrevlumab was administered on Days 1, 8 and 15 of Treatment Cycle 1 and on Day 1 and 15 of each subsequent treatment cycle via IV infusion. Nab-paclitaxel was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. Gemcitabine was administered on Days 1, 8 and 15 of each 28-day treatment cycle via IV infusion. FOLFIRINOX was a combination of several agents administered on Days 1 and 15 of each 28-day treatment cycle via IV infusion. The specific agents were oxaliplatin, folinic acid, irinotecan, and fluorouracil.

    Serious adverse events
    		 Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    62 / 141 (43.97%)
    75 / 142 (52.82%)
         number of deaths (all causes)
    112
    118
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (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
    Oedema peripheral
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 141 (0.00%)
    3 / 142 (2.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 141 (4.26%)
    5 / 142 (3.52%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 141 (0.71%)
    3 / 142 (2.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (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
    Fall
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fever
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic complication
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 141 (1.42%)
    4 / 142 (2.82%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 141 (0.00%)
    4 / 142 (2.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 141 (2.13%)
    4 / 142 (2.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jejunal perforation
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    2 / 141 (1.42%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 141 (2.84%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    6 / 141 (4.26%)
    3 / 142 (2.11%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 141 (2.13%)
    4 / 142 (2.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic fistula
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (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 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 141 (0.71%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder rupture
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    5 / 141 (3.55%)
    3 / 142 (2.11%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    8 / 141 (5.67%)
    7 / 142 (4.93%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant biliary obstruction
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudocellulitis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 141 (1.42%)
    4 / 142 (2.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Enterocolitis infectious
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    3 / 141 (2.13%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis infective
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 141 (0.00%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    3 / 141 (2.13%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 141 (2.84%)
    5 / 142 (3.52%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 141 (0.71%)
    7 / 142 (4.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue fungal infection
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 141 (0.00%)
    3 / 142 (2.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 141 (0.71%)
    2 / 142 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 141 (0.00%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 141 (0.71%)
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperlipidaemia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 141 (1.42%)
    0 / 142 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 142 (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
    		 Placebo + Gemcitabine/Nab-paclitaxel or FOLFIRINOX Pamrevlumab + Gemcitabine/Nab-paclitaxel or FOLFIRINOX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    140 / 141 (99.29%)
    139 / 142 (97.89%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    13 / 141 (9.22%)
    16 / 142 (11.27%)
         occurrences all number
    15
    17
    Hypertension
         subjects affected / exposed
    8 / 141 (5.67%)
    5 / 142 (3.52%)
         occurrences all number
    8
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    76 / 141 (53.90%)
    84 / 142 (59.15%)
         occurrences all number
    164
    178
    Oedema peripheral
         subjects affected / exposed
    52 / 141 (36.88%)
    44 / 142 (30.99%)
         occurrences all number
    75
    59
    Asthenia
         subjects affected / exposed
    27 / 141 (19.15%)
    27 / 142 (19.01%)
         occurrences all number
    45
    68
    Pyrexia
         subjects affected / exposed
    30 / 141 (21.28%)
    30 / 142 (21.13%)
         occurrences all number
    64
    60
    Chills
         subjects affected / exposed
    11 / 141 (7.80%)
    10 / 142 (7.04%)
         occurrences all number
    17
    15
    Influenza like illness
         subjects affected / exposed
    8 / 141 (5.67%)
    4 / 142 (2.82%)
         occurrences all number
    19
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    18 / 141 (12.77%)
    17 / 142 (11.97%)
         occurrences all number
    31
    28
    Pulmonary embolism
         subjects affected / exposed
    5 / 141 (3.55%)
    8 / 142 (5.63%)
         occurrences all number
    5
    8
    Epistaxis
         subjects affected / exposed
    14 / 141 (9.93%)
    12 / 142 (8.45%)
         occurrences all number
    18
    19
    Cough
         subjects affected / exposed
    21 / 141 (14.89%)
    10 / 142 (7.04%)
         occurrences all number
    25
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    20 / 141 (14.18%)
    16 / 142 (11.27%)
         occurrences all number
    25
    16
    Anxiety
         subjects affected / exposed
    10 / 141 (7.09%)
    6 / 142 (4.23%)
         occurrences all number
    11
    6
    Depression
         subjects affected / exposed
    8 / 141 (5.67%)
    4 / 142 (2.82%)
         occurrences all number
    10
    5
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    56 / 141 (39.72%)
    51 / 142 (35.92%)
         occurrences all number
    170
    128
    White blood cell count decreased
         subjects affected / exposed
    28 / 141 (19.86%)
    24 / 142 (16.90%)
         occurrences all number
    130
    64
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 141 (13.48%)
    19 / 142 (13.38%)
         occurrences all number
    25
    31
    Weight decreased
         subjects affected / exposed
    18 / 141 (12.77%)
    19 / 142 (13.38%)
         occurrences all number
    26
    29
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 141 (8.51%)
    17 / 142 (11.97%)
         occurrences all number
    24
    29
    Platelet count decreased
         subjects affected / exposed
    43 / 141 (30.50%)
    36 / 142 (25.35%)
         occurrences all number
    131
    125
    Blood alkaline phosphatase increased
         subjects affected / exposed
    9 / 141 (6.38%)
    8 / 142 (5.63%)
         occurrences all number
    15
    18
    Blood creatinine increased
         subjects affected / exposed
    4 / 141 (2.84%)
    9 / 142 (6.34%)
         occurrences all number
    5
    14
    Lymphocyte count decreased
         subjects affected / exposed
    18 / 141 (12.77%)
    5 / 142 (3.52%)
         occurrences all number
    106
    23
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    7 / 141 (4.96%)
    10 / 142 (7.04%)
         occurrences all number
    9
    13
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    26 / 141 (18.44%)
    23 / 142 (16.20%)
         occurrences all number
    34
    30
    Peripheral sensory neuropathy
         subjects affected / exposed
    29 / 141 (20.57%)
    23 / 142 (16.20%)
         occurrences all number
    53
    31
    Paraesthesia
         subjects affected / exposed
    18 / 141 (12.77%)
    17 / 142 (11.97%)
         occurrences all number
    30
    38
    Neuropathy peripheral
         subjects affected / exposed
    26 / 141 (18.44%)
    30 / 142 (21.13%)
         occurrences all number
    41
    59
    Headache
         subjects affected / exposed
    18 / 141 (12.77%)
    15 / 142 (10.56%)
         occurrences all number
    29
    22
    Dizziness
         subjects affected / exposed
    22 / 141 (15.60%)
    9 / 142 (6.34%)
         occurrences all number
    29
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    67 / 141 (47.52%)
    54 / 142 (38.03%)
         occurrences all number
    260
    159
    Thrombocytopenia
         subjects affected / exposed
    23 / 141 (16.31%)
    18 / 142 (12.68%)
         occurrences all number
    51
    52
    Neutropenia
         subjects affected / exposed
    30 / 141 (21.28%)
    31 / 142 (21.83%)
         occurrences all number
    73
    62
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    73 / 141 (51.77%)
    68 / 142 (47.89%)
         occurrences all number
    138
    130
    Diarrhoea
         subjects affected / exposed
    90 / 141 (63.83%)
    81 / 142 (57.04%)
         occurrences all number
    214
    177
    Stomatitis
         subjects affected / exposed
    25 / 141 (17.73%)
    25 / 142 (17.61%)
         occurrences all number
    37
    34
    Abdominal pain upper
         subjects affected / exposed
    15 / 141 (10.64%)
    16 / 142 (11.27%)
         occurrences all number
    16
    20
    Abdominal pain
         subjects affected / exposed
    36 / 141 (25.53%)
    34 / 142 (23.94%)
         occurrences all number
    68
    55
    Vomiting
         subjects affected / exposed
    40 / 141 (28.37%)
    38 / 142 (26.76%)
         occurrences all number
    67
    58
    Constipation
         subjects affected / exposed
    39 / 141 (27.66%)
    38 / 142 (26.76%)
         occurrences all number
    60
    56
    Haemorrhoids
         subjects affected / exposed
    10 / 141 (7.09%)
    7 / 142 (4.93%)
         occurrences all number
    12
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 141 (2.84%)
    9 / 142 (6.34%)
         occurrences all number
    6
    9
    Abdominal distension
         subjects affected / exposed
    10 / 141 (7.09%)
    13 / 142 (9.15%)
         occurrences all number
    10
    15
    Dyspepsia
         subjects affected / exposed
    6 / 141 (4.26%)
    11 / 142 (7.75%)
         occurrences all number
    8
    12
    Dry mouth
         subjects affected / exposed
    6 / 141 (4.26%)
    10 / 142 (7.04%)
         occurrences all number
    8
    11
    Flatulence
         subjects affected / exposed
    6 / 141 (4.26%)
    9 / 142 (6.34%)
         occurrences all number
    6
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    57 / 141 (40.43%)
    53 / 142 (37.32%)
         occurrences all number
    69
    62
    Rash
         subjects affected / exposed
    11 / 141 (7.80%)
    18 / 142 (12.68%)
         occurrences all number
    12
    22
    Dry skin
         subjects affected / exposed
    6 / 141 (4.26%)
    8 / 142 (5.63%)
         occurrences all number
    11
    8
    Pruritus
         subjects affected / exposed
    17 / 141 (12.06%)
    14 / 142 (9.86%)
         occurrences all number
    21
    25
    Rash maculo-papular
         subjects affected / exposed
    12 / 141 (8.51%)
    12 / 142 (8.45%)
         occurrences all number
    20
    17
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    10 / 141 (7.09%)
    3 / 142 (2.11%)
         occurrences all number
    10
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    18 / 141 (12.77%)
    14 / 142 (9.86%)
         occurrences all number
    20
    18
    Back pain
         subjects affected / exposed
    17 / 141 (12.06%)
    13 / 142 (9.15%)
         occurrences all number
    21
    14
    Pain in extremity
         subjects affected / exposed
    14 / 141 (9.93%)
    6 / 142 (4.23%)
         occurrences all number
    17
    8
    Muscular weakness
         subjects affected / exposed
    16 / 141 (11.35%)
    6 / 142 (4.23%)
         occurrences all number
    23
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    48 / 141 (34.04%)
    50 / 142 (35.21%)
         occurrences all number
    73
    93
    Hypokalaemia
         subjects affected / exposed
    33 / 141 (23.40%)
    18 / 142 (12.68%)
         occurrences all number
    64
    33
    Hypoalbuminaemia
         subjects affected / exposed
    14 / 141 (9.93%)
    7 / 142 (4.93%)
         occurrences all number
    36
    10
    Hyperglycaemia
         subjects affected / exposed
    9 / 141 (6.38%)
    9 / 142 (6.34%)
         occurrences all number
    15
    14
    Hypomagnesaemia
         subjects affected / exposed
    6 / 141 (4.26%)
    14 / 142 (9.86%)
         occurrences all number
    12
    23
    Dehydration
         subjects affected / exposed
    8 / 141 (5.67%)
    9 / 142 (6.34%)
         occurrences all number
    10
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2021
    It included following key changes: - Updated Secondary Objective to evaluate the effect of neoadjuvant treatment with pamrevlumab in combination with gemcitabineplus nab-paclitaxel or FOLFIRINOX on EFS. - Updated endpoint for Accelerated Approval; replacing resection rate with EFS and specified details of evaluation during interim analysis. - Re-ordering of Secondary Endpoints; positioning PFS as key secondary endpoint with quality of life (QOL) endpoints next in hierarchical testing order. - Included infusion ‘windows’ for FOLFIRINOX dosing regimen. - Updated language to clarify use of cytochrome P (CYP) inhibitors and inducers in participants receiving nab-paclitaxel. - Added language to clarify documentation of protocol deviations due to COVID-19.
    16 May 2022
    It included following key changes: - Per Protocol (PP) Population was added. - Objective Response Rate (ORR) was added as a secondary endpoint and the ordering of secondary endpoints was clarified. - Revised exclusion criteria and Prohibited Concomitant Medications section. - Updated statistical methods.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

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