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    Clinical Trial Results:
    A Global, Multicenter, Randomized, Placebo-Controlled Phase 3 Trial to Compare the Efficacy and Safety of Fruquintinib Plus Best Supportive Care to Placebo Plus Best Supportive Care in Patients with Refractory Metastatic Colorectal Cancer (FRESCO-2)

    Summary
    EudraCT number
    		 2020-000158-88
    Trial protocol
    		 HU   FR   DE   AT   BE   IT   CZ   PL  
    Global end of trial date
    24 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Mar 2025
    First version publication date
    21 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2019-013-GLOB1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04322539
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hutchison MediPharma Limited
    Sponsor organisation address
    Building 4, 720 Cailun Road, Shanghai, China, 201203
    Public contact
    William Schelman, HUTCHMED International, +1 973-306-4490, williams@hutch-med.com
    Scientific contact
    William Schelman, HUTCHMED International , +1 973-306-4490, williams@hutch-med.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
    24 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this was to evaluate the overall survival of Fruquintinib plus best supportive care (BSC) compared to placebo plus BSC in subjects with refractory metastatic colorectal cancer (mCRC).
    Protection of trial subjects
    The study was conducted in accordance with the protocol; the ethical principles derived from international guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines; applicable International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines; and other applicable regulations and guidelines governing clinical study conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Aug 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
    Australia: 16
    Country: Number of subjects enrolled
    Japan: 56
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 124
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Czechia: 14
    Country: Number of subjects enrolled
    Estonia: 9
    Country: Number of subjects enrolled
    France: 64
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Hungary: 69
    Country: Number of subjects enrolled
    Italy: 111
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 180
    Worldwide total number of subjects
    691
    EEA total number of subjects
    492
    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)
    366
    From 65 to 84 years
    324
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 124 study sites in the United States, Europe region, Japan, and Australia.

    Pre-assignment
    Screening details
    		 A total of 691 subjects were randomized and treated in this study.

    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
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fruquintinib + Best Supportive Care (BSC) Group
    Arm description
    		 Subjects received 5 milligrams (mg) of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fruquintinib 5 mg
    Investigational medicinal product code
    Other name
    HMPL-013
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks.

    Arm title
    		 Placebo + BSC Group
    Arm description
    		 Subjects received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks.

    Number of subjects in period 1
    		Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Started
    461
    230
    Safety Population (SP)
    456
    230
    Pharmacokinetic (PK) Population
    329
    2
    Completed
    0
    0
    Not completed
    461
    230
         Consent withdrawn by subject
    14
    8
         Adverse event, non-fatal
    2
    -
         Death
    411
    203
         Sponsor Decision
    19
    14
         Unspecified
    6
    4
         Radiological Disease Progression
    6
    -
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fruquintinib + Best Supportive Care (BSC) Group
    Reporting group description
    		 Subjects received 5 milligrams (mg) of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

    Reporting group title
    Placebo + BSC Group
    Reporting group description
    		 Subjects received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

    Reporting group values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group Total
    Number of subjects
    		 461 230 691
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.2 ( 10.41 ) 62.4 ( 9.67 ) -
    Gender categorical
    Units: Subjects
        Female
    		 216 90 306
        Male
    		 245 140 385
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 43 18 61
        Black or African American
    		 13 7 20
        Native Hawaiian or Other
    		 3 2 5
        White
    		 367 192 559
        Other
    		 5 2 7
        Multiple races
    		 2 0 2
        Not reported/unknown
    		 28 8 36
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 20 14 34
        Not Hispanic or Latino
    		 405 202 607
        Unknown or Not Reported
    		 36 14 50

    End points

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    End points reporting groups
    Reporting group title
    Fruquintinib + Best Supportive Care (BSC) Group
    Reporting group description
    		 Subjects received 5 milligrams (mg) of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

    Reporting group title
    Placebo + BSC Group
    Reporting group description
    		 Subjects received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

    Subject analysis set title
    Fruquintinib:Pooled Studies for Exposure and Safety Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in the current 2019-013-GLOB1 study received 5 mg of fruquintinib oral capsules once daily for 3 weeks of continuous dosing, followed by a 1-week break during each 28-day treatment cycle. Subjects in the 2009-013-00CH1 study received 1 mg to 6 mg of fruquintinib oral capsule once daily and 5 mg to 6 mg of fruquintinib oral capsule for 3 weeks on and 1 week off during each 28-day treatment cycle. Subjects in the 2012-013-00CH3 study received 4 mg of fruquintinib capsule once daily in 28-day cycles. Subjects in the Study 2015-013- 00US1 with advanced solid tumors of any type or with mCRC received fruquintinib 3 mg or 5 mg once daily for 3 weeks on and 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by the Investigator, whichever occurred first.

    Subject analysis set title
    Fruquintinib:Pooled Studies for Exposure and Efficacy Analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in the current 2019-013-GLOB1 study received 5 mg of fruquintinib oral capsules once daily for 3 weeks of continuous dosing, followed by a 1-week break during each 28-day treatment cycle. Subjects in Cohort B of Study 2015-013-00US1 with metastatic colorectal carcinoma (mCRC) and prior treatment with chemotherapy and trifluridine, tipiracil, and/or regorafenib received fruquintinib 5 mg capsules once daily for 3 weeks on and 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by the Investigator, whichever occurred first.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time (months) from date of randomization to death from any cause. OS was calculated as (date of death or last known alive – date of randomization + 1)/30.4375. Subjects without report of death at the time of analysis will be censored at the date last known alive. Intent to treat (ITT) population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    From date of randomization to death from any cause (up to 22 months)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    461
    230
    Units: months
        median (confidence interval 95%)
    7.4 (6.7 to 8.2)
    4.8 (4.0 to 5.8)
    Statistical analysis title
    		 Fruquintinib + BSC Group Vs Placebo + BSC Group
    Comparison groups
    Fruquintinib + Best Supportive Care (BSC) Group v Placebo + BSC Group
    Number of subjects included in analysis
    691
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 stratified log-rank test
    Parameter type
    		 Stratified Hazard ratio
    Point estimate
    0.662
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.549
         upper limit
    		 0.8
    Notes
    [1] - Raw unadjusted p-value was obtained by using a stratified log-rank test accounting for the randomization schedule stratification factors.

    Secondary: Progression Free Survival (PFS), as Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1

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    End point title
    		 Progression Free Survival (PFS), as Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1
    End point description
    PFS was defined as the time (months) from randomization until the first radiographic documentation of objective progression as assessed by investigator using RECIST v1.1, or death from any cause, whichever comes first. More specifically, PFS was determined using all data until the last evaluable visit prior to or on the date of: (i) radiographic disease progression (PD) per RECIST v1.1; (ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent anticancer therapy other than the study drugs, whichever was earlier. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From randomization until the first documentation of objective progression or death, whichever comes first (up to 22 months)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    461
    230
    Units: months
        median (confidence interval 95%)
    3.7 (3.5 to 3.8)
    1.8 (1.8 to 1.9)
    Statistical analysis title
    		 Fruquintinib + BSC Group Vs Placebo + BSC Group
    Comparison groups
    Placebo + BSC Group v Fruquintinib + Best Supportive Care (BSC) Group
    Number of subjects included in analysis
    691
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 stratified log-rank test
    Parameter type
    		 Stratified Hazard ratio
    Point estimate
    0.321
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.267
         upper limit
    		 0.386
    Notes
    [2] - Raw unadjusted p-value was obtained by using a stratified log-rank test accounting for the randomization schedule stratification factors.

    Secondary: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    ORR was defined as the percentage of subjects who achieved a best overall response of confirmed complete response (CR) or partial response (PR), per RECIST v1.1, as determined by the investigator. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 millimeters (mm). ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From randomization until PD, death, new anticancer treatment, or study treatment discontinuation, whichever occurred first (up to 22 months)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    461
    230
    Units: percentage of subjects
        number (confidence interval 95%)
    1.5 (0.6 to 3.1)
    0 (0.0 to 1.6)
    Statistical analysis title
    		 Fruquintinib + BSC Group Vs Placebo + BSC Group
    Comparison groups
    Fruquintinib + Best Supportive Care (BSC) Group v Placebo + BSC Group
    Number of subjects included in analysis
    691
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.059 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 2.7
    Notes
    [3] - The adjusted difference and its 95% CI were calculated using the Wald method from Cochran-Mantel Haenszel test to account for the randomization schedule stratification factors.
    [4] - p-value was calculated from a stratified Cochran-Mantel Haenszel test accounting for the randomization schedule stratification factors.

    Secondary: Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    DCR was defined as percentage of subjects achieving a best overall response of confirmed CR, PR, or stable disease (SD) (for at least 7 weeks) per RECIST v1.1, as determined by the investigator. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum on study. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From randomization until PD, death, new anticancer treatment, or study treatment discontinuation, whichever occurred first (up to 22 months)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    461
    230
    Units: percentage of subjects
        number (confidence interval 95%)
    55.5 (50.9 to 60.1)
    16.1 (11.6 to 21.5)
    Statistical analysis title
    		 Fruquintinib + BSC Group Vs Placebo + BSC Group
    Comparison groups
    Fruquintinib + Best Supportive Care (BSC) Group v Placebo + BSC Group
    Number of subjects included in analysis
    691
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Adjusted difference
    Point estimate
    39.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 32.8
         upper limit
    		 46
    Notes
    [5] - p-value was calculated from a stratified Cochran-Mantel Haenszel test accounting for the randomization schedule stratification factors.

    Secondary: Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

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    End point title
    		 Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    End point description
    DOR was defined as the time (in months) from the first occurrence of PR or CR by RECIST Version 1.1, until the first date that progressive disease is documented by RECIST Version 1.1, or death, whichever comes first. Only those subjects with confirmed responses of CR or PR were included in this analysis. DOR was calculated as (date of death or PD or last assessment – date of first occurrence of confirmed CR or PR + 1)/30.4375. Analysis was performed on subset of subjects who had a response. Here, ‘0’ in ‘overall number of subjects analyzed represents that DOR could only be analyzed in subjects who achieved a response. As no subject in the Placebo Plus BSC Group cohort achieved any response, no DOR is available. Here "99999" means upper limit of 95 percent (%) confidence interval (CI) was not estimable due to limited number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From first occurrence of PR or CR until the first documentation of progression or death, whichever comes first (up to 22 months)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    7
    0 [6]
    Units: months
        median (confidence interval 95%)
    10.7 (3.9 to 99999)
    ( to )
    Notes
    [6] - Since no subject in the Placebo Plus BSC Group cohort achieved any response, no DOR is available.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
    End point description
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE was considered a TEAE if the onset date was on or after the start of study treatment or if the onset date was missing, or if the AE had an onset date before the start of study treatment but worsened in severity after the study treatment until 30 days after the last dose of study treatment or a new treatment of anti-tumor therapy, whichever was earlier. After this period, treatment-related SAEs were also considered as TEAEs. AEs with an unknown/not reported onset date were also included. SP included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to approximately 40 months
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    456
    230
    Units: Count of subjects
        Subjects with TEAEs
    451
    214
        Subjects with Serious TEAEs
    173
    88
    No statistical analyses for this end point

    Secondary: Observed Plasma Concentrations of Fruquintinib and Metabolite M11

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    End point title
    		 Observed Plasma Concentrations of Fruquintinib and Metabolite M11 [7]
    End point description
    Plasma samples were collected from the subjects at the defined time points. Plasma concentrations were measured using a validated, specific, and sensitive liquid chromatography tandem mass spectrometry method. M11 is the active metabolite for the study drug. PK population was used for tabulation of fruquintinib and M11 concentrations from PK plasma samples collected from the Fruquintinib + BSC Group. PK samples for the Placebo + BSC Group were not analyzed. Here “N”=subjects evaluable for this endpoint; “n”=subjects evaluable at the specified timepoints. Here "C" indicates "Cycle", "D" indicates "Day" an "Conc." indicates "Concentration". Here "99999" indicates "Standard deviation", was not evaluable for single subject.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 (Day 21): Predose and 2 hours, Cycle 3 (Day 1): Pre-dose, Cycle 3 (Day 21): Pre-dose and 2 hours, Cycle 5, 7, 9, 11, 13, 15 and 17 (Day 1): Pre-dose (Each cycle = 28 days)
    Notes
    [7] - 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: As per planned analysis, data for this endpoint was analysed for Fruquintinib arm only.
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group
    Number of subjects analysed
    312
    Units: nanogram/milliliter (ng/mL)
    arithmetic mean (standard deviation)
        C1D1:1 hour (Plasma Conc. of Fruquintinib)(n=171)
    59.9 ( 51.0 )
        C1D1:1 hour (Plasma Conc. of M11) (n=171)
    1.06 ( 8.36 )
        C1D1:2 hours (Plasma Conc. of Fruquintinib)(n=304)
    91.5 ( 48.2 )
        C1D1:2 hours (Plasma Conc. of M11) (n=304)
    1.03 ( 6.81 )
        C1D1:3 hours (Plasma Conc. of Fruquintinb)(n=171)
    98.5 ( 47.1 )
        C1D1:3 hours (Plasma Conc. of M11)(n=171)
    1.96 ( 9.51 )
        C1D1:4 hours (Plasma Conc. of Fruquintinb)(n=171)
    99.7 ( 44.6 )
        C1D1:4 hours (Plasma Conc. of M11)(n=171)
    2.71 ( 10.7 )
        C1D21:Predose(Plasma Conc. of Fruquintinib)(n=227)
    219 ( 82.6 )
        C1D21:Predose (Plasma Conc. of M11)(n=227)
    94.5 ( 52.6 )
        C1D21:1 hour (Plasma Conc. of Fruquintinib)(n=112)
    255 ( 101 )
        C1D21:1 hour (Plasma Conc. of M11) (n=112)
    92.0 ( 54.3 )
        C1D21:2 hours(Plasma Conc. of Fruquintinib)(n=214)
    279 ( 91.6 )
        C1D21:2 hours (Plasma Conc. of M11)(n=214)
    89.9 ( 49.5 )
        C1D21:3 hours(Plasma Conc. of Fruquintinib)(n=113)
    293 ( 95.2 )
        C1D21:3 hours (Plasma Conc. of M11)(n=113)
    88.0 ( 50.4 )
        C1D21:4 hours(Plasma Conc. of Fruquintinib)(n=114)
    294 ( 88.0 )
        C1D21:4 hours (Plasma Conc. of M11)(n=114)
    89.2 ( 49.0 )
        C2D21:Predose(Plasma Conc. of Fruquintinib)(n=204)
    222 ( 82.0 )
        C2D21:Predose (Plasma Conc. of M11)(n=204)
    97.6 ( 53.7 )
        C2D21:2 hours(Plasma Conc. of Fruquintinib)(n=193)
    284 ( 95.2 )
        C2D21:2 hours (Plasma Conc. of M11)(n=193)
    94.2 ( 52.8 )
        C3D1:Predose(Plasma Conc. of Fruquintinib)(n=177)
    16.7 ( 18.9 )
        C3D1:Predose (Plasma Conc. of M11)(n=177)
    22.6 ( 18.2 )
        C3D21:Predose(Plasma Conc. of Fruquintinib)(n=137)
    212 ( 74.6 )
        C3D21:Predose (Plasma Conc. of M11)(n=137)
    90.6 ( 54.1 )
        C3D21:2 hours(Plasma Conc. of Fruquintinib)(n=123)
    275 ( 78.6 )
        C3D21:2hours (Plasma Conc. of M11)(n=123)
    92.8 ( 54.2 )
        C5D1:Predose(Plasma Conc. of Fruquintinib)(n=103)
    16.9 ( 20.5 )
        C5D1:Predose (Plasma Conc. of M11)(n=103)
    23.2 ( 20.9 )
        C7D1:Predose(Plasma Conc. of Fruquintinib)(n=46)
    18.2 ( 33.0 )
        C7D1:Predose (Plasma Conc. of M11)(n=46)
    20.1 ( 12.1 )
        C9D1:Predose(Plasma Conc. of Fruquintinib)(n=13)
    12.2 ( 12.6 )
        C9D1:Predose (Plasma Conc. of M11)(n=13)
    19.1 ( 17.1 )
        C11D1:Predose (Plasma Conc. of Fruquintinib)(n=6)
    13.4 ( 13.4 )
        C11D1:Predose (Plasma Conc. of M11)(n=6)
    17.1 ( 15.3 )
        C13D1:Predose (Plasma Conc. of Fruquintinib)(n=1)
    15.4 ( 99999 )
        C13D1:Predose (Plasma Conc. of M11)(n=1)
    23.1 ( 99999 )
        C15D1:Predose (Plasma Conc. of Fruquintinib)(n=1)
    10.8 ( 99999 )
        C15D1:Predose (Plasma Conc. of M11)(n=1)
    19.2 ( 99999 )
        C17D1:Predose (Plasma Conc. of Fruquintinib)(n=1)
    10.6 ( 99999 )
        C17D1:Predose (Plasma Conc. of M11)(n=1)
    15.2 ( 99999 )
        C1D1:Predose (Plasma Conc. of Fruquintinib)(n=312)
    2.90 ( 19.9 )
        C1D1:Predose (Plasma Conc. of M11)(n=312))
    0.585 ( 6.61 )
    No statistical analyses for this end point

    Secondary: Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia’s Formula

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    End point title
    		 Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia’s Formula
    End point description
    QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 milliseconds (msec). QTc: QT interval corrected based on the patient’s heart rate. QTcF: An electrocardiographic finding in which the QT interval corrected for heart rate using Fridericia’s formula. QTc = QT/∛(RR) RR = Respiration rate. SP included all randomized subjects who received at least 1 dose of study drug. Here “N”=subjects evaluable for this endpoint; “n”=subjects evaluable at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 and 3 (Day 21): Pre-dose (Each cycle = 28 days)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    272
    131
    Units: millisecond (msec)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 - Pre-dose (n=261,126)
    1.9 ( 21.33 )
    0.1 ( 17.95 )
        Cycle 1 Day 1 - 1 hour (n=149,71)
    -0.1 ( 19.60 )
    2.5 ( 19.70 )
        C1D1-2 hours(n=272,131)
    1.9 ( 22.58 )
    3.5 ( 20.13 )
        C1D1-3 hours (n=143,70)
    2.6 ( 19.77 )
    3.3 ( 18.03 )
        C1D1-4 hours (n=136,67)
    1.2 ( 20.48 )
    0.9 ( 17.66 )
        C1D21-Pre-dose (n=184,95)
    3.2 ( 20.94 )
    -2.2 ( 20.31 )
        C1D21-1 hour (n=109,62)
    4.0 ( 19.56 )
    -0.2 ( 16.77 )
        C1D21-2 hours (n=222,121)
    5.0 ( 20.06 )
    2.8 ( 18.23 )
        C1D21-3 hours (n=111,61)
    5.9 ( 19.46 )
    0.2 ( 14.70 )
        C1D21-4 hours (n=103,58)
    3.9 ( 20.98 )
    -0.6 ( 18.13 )
        C2D21-2 hours (n=229,86)
    1.4 ( 22.41 )
    4.9 ( 24.28 )
        C3D21-2 hours (n=141,28)
    2.6 ( 31.61 )
    2.0 ( 20.08 )
    No statistical analyses for this end point

    Secondary: Change From Baseline of ECG Results -QTcB Intervals Using Bazzett’s Formula

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    End point title
    		 Change From Baseline of ECG Results -QTcB Intervals Using Bazzett’s Formula
    End point description
    QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 msec. QTc: QT interval corrected based on the patient’s heart rate. QTcB: An electrocardiographic finding in which the QT interval corrected for heart rate using Bazzett’s formula. SP included all randomized subjects who received at least 1 dose of study drug. Here “N”=subjects evaluable for this endpoint; “n”=subjects evaluable at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 1 (Day 1 and 21): Pre-dose, 1, 2, 3 and 4 hours; Cycle 2 and 3 (Day 21): Pre-dose (Each cycle = 28 days)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    258
    122
    Units: msec
    arithmetic mean (standard deviation)
        C1D1-Pre-dose (n=249,118)
    2.9 ( 39.49 )
    0.3 ( 20.55 )
        C1D1-1 hour (n=142,69)
    -3.1 ( 23.95 )
    1.9 ( 20.11 )
        C1D1-2 hours (n=258,122)
    -2.0 ( 23.95 )
    1.9 ( 20.11 )
        C1D1-3 hours (n=136,68)
    -0.9 ( 24.47 )
    3.9 ( 19.75 )
        C1D1-4 hours (n=130,65)
    -1.9 ( 24.47 )
    2.4 ( 20.11 )
        C1D21-Pre-dose (n=177,91)
    3.9 ( 49.99 )
    5.0 ( 50.43 )
        C1D21-1 hour (n=177,60)
    -1.3 ( 25.60 )
    0.9 ( 20.48 )
        C1D21-2 hours (n=212,117)
    1.6 ( 42.28 )
    4.3 ( 19.57 )
        C1D21-3 hours (n=107,59)
    1.2 ( 25.41 )
    2.9 ( 18.29 )
        C1D21-4 hours (n=99,56)
    0.2 ( 25.91 )
    2.8 ( 20.13 )
        C2D21-2 hours (n=213,83)
    1.7 ( 40.61 )
    5.9 ( 24.96 )
        C3D21-2 hours (n=132,28)
    4.2 ( 72.35 )
    1.6 ( 22.06 )
    No statistical analyses for this end point

    Secondary: Correlation Between Fruquintinib Exposure (CminSS) and Efficacy Parameters (OS)

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    End point title
    		 Correlation Between Fruquintinib Exposure (CminSS) and Efficacy Parameters (OS)
    End point description
    Model-predicted steady-state minimum plasma concentrations (CminSS) of fruquintinib based on starting dose or adjusted for relative dose intensity(RDI) used as exposure measures in efficacy exposure-response analyses. Correlation between OS and exposure estimated using multivariable Cox proportional hazards modeling with OS analyzed as time-to-event variable using survival model. Analysis included subjects from 2019-013-GLOB1(N=328) and Cohort B of 2015-013-00US1(N=40). “Unit” i.e., ‘1/(nanogram per milliliter)’, corresponds to the coefficient that describes the relationship between probability of survival and CminSS value. Efficacy exposure- response analyses included subjects evaluable for population PK analysis, had PK parameter estimates to enable estimation of fruquintinib exposure and evaluated for parameter in question. “N” = subjects evaluable for this endpoint; “n”= subjects evaluable at specified timepoints. Population included subjects from 2015-013-00US1 and current study.
    End point type
    Secondary
    End point timeframe
    Up to 22 months
    End point values
    		 Fruquintinib:Pooled Studies for Exposure and Efficacy Analysis
    Number of subjects analysed
    368
    Units: 1/ (nanogram per milliliter)
    number (not applicable)
        CminSS Coefficient Based on Starting Dose
    0.00193
        CminSS Coefficient Based on Adjusted RDI
    0.000407
    No statistical analyses for this end point

    Secondary: Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ [Gr3+]: Dermatological Toxicity, Proteinuria and Gr Hemorrhage)

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    End point title
    		 Correlation Between Fruquintinib Exposure (CmaxSS) and Safety Parameters (Any Grade [Gr] and Grade 3+ [Gr3+]: Dermatological Toxicity, Proteinuria and Gr Hemorrhage)
    End point description
    Model-predicted steadystate maximum plasma concentration (CmaxSS) of fruquintinib based on assigned dose investigated as fruquintinib exposure measure for safety exposure-response (E-R) analysis. Correlation between exposure and probability of experiencing AEs evaluated using logistic regression analysis, with slope serving as estimate. Safety E-R analysis included subjects from 2019- 013-GLOB1, 2009-013-00CH1, 2012-013-00CH3, and 2015-013-00US1. “Unit”i.e.,‘1/(nanogram per milliliter)’ corresponds to the coefficient that describes the relationship between probability of occurrence of safety parameter and CmaxSS value. Safety E-R analyses had subjects evaluable for population PK analysis,PK parameter estimates to enable estimation of fruquintinib exposure and evaluated for endpoint in question.“N”=subjects evaluable for this endpoint;“n”=subjects evaluable at specified timepoints. The population included subjects from 2019-013- GLOB1, 2009-013- 00CH1, 212-013-00CH3, and 2015-013-00US.
    End point type
    Secondary
    End point timeframe
    Up to 22 months
    End point values
    		 Fruquintinib:Pooled Studies for Exposure and Safety Analysis
    Number of subjects analysed
    515
    Units: 1/ (nanogram per milliliter)
    number (not applicable)
        CmaxS S Coefficient for Any G Derma Toxicity
    0.00134
        CmaxSS Coefficient for G3+ Derma Toxicity
    0.00411
        CmaxSS Coefficient for Any G Proteinuria
    -0.0010
        CmaxSS Coefficient for G3+ Proteinuria
    0.00143
        CmaxSS Coefficient for Any G Hemorrhage
    0.00180
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life Scale Score

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life Scale Score
    End point description
    EORTC QLQ-C30 contains 30 items across 5 functional scales(physical, role, cognitive, emotional, and social), 9 symptom scales(fatigue,nausea and vomiting,pain,dyspnea, sleep disturbance,appetite loss,constipation,diarrhea, and financial difficulties)and global health status/QOL scale. EORTC QLQ-C30 contains 28 questions(4-point scale where 1=Not at all [best] to 4=Very Much [worst]) and 2 questions(7-point scale where 1=Very poor [worst] to 7= Excellent [best]).Raw scores are standardized and converted into scale scores ranging from 0-100. For global health status/QOL scale, higher scores=better QOL.Negative change from baseline=condition worsened.Change from baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life Scale scores was performed by visit (i.e., cycle), using restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach. ITT population. “N”=subjects evaluable for this endpoint; “n”=subjects evaluable at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 2, 3 and 4 (Each cycle=28 days)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    330
    149
    Units: score on a scale
    least squares mean (standard error)
        Cycle 2 (n=330,149)
    -2.1 ( 1.59 )
    -3.7 ( 1.95 )
        Cycle 3 (n=229, 53)
    -4.5 ( 1.69 )
    -6.1 ( 2.54 )
        Cycle 4 (n=182,29)
    -4.2 ( 1.76 )
    -2.1 ( 3.03 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score

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    End point title
    		 Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score
    End point description
    The EQ-5D-5L is a self-reported health status questionnaire that consisted of six questions used to calculate a health utility score. There were two components to the EQ-5D-5L: a five-item health state profile that assessed mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score and a general VAS score for health status. EQ-5D VAS was used to record subjects's rating for his/her current health-related quality of life state on a vertical VAS with scores ranging from 0 to 100, where 0 = worst imaginable health state and 100 = best imaginable health state. The higher the score the better the health status. A negative change from baseline value represents patient condition worsened. Change from baseline in the EQ-5D-5L VAS scores was performed by visit (i.e. cycle), using a REML-based MMRM approach. ITT population. “N”=subjects evaluable for this endpoint; “n”=subjects evaluable at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 2, 3 and 4 (Each cycle=28 days)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    337
    151
    Units: score on a scale
    least squares mean (standard error)
        Cycle 2 (n=337,151)
    -0.3 ( 1.38 )
    -0.9 ( 1.69 )
        Cycle 3 (n=232,54)
    -1.1 ( 1.48 )
    -2.5 ( 2.22 )
        Cycle 4 (n=185,30)
    -4.0 ( 1.59 )
    -2.1 ( 2.79 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores

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    End point title
    		 Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores
    End point description
    EQ-5D-5L consisted of 2 components: health state profile and optional VAS. EQ-5D health state profile had 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problem, 2= slight problem, 3= moderate problem, 4= severe problem, and 5= extreme problem. The response levels collected from the EQ-5D-5L five dimensions as a health profile are converted into an EQ-5D-5L index (utility) scores to represent participants’ utility value. Range of health utility index score is from -0.285 to 1, where higher value indicates perfect health and a negative value represents a state worse than dead. Change from baseline in EQ-5D-5L health utility index scores was performed by visit (i.e., cycle), using a REML-based MMRM approach. ITT population. “N”=subjects evaluable for this endpoint; “n”=subjects evaluable at the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 2, 3 and 4 (Each cycle=28 days)
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    337
    151
    Units: score on a scale
    least squares mean (standard error)
        Cycle 2 (n=337,151)
    0.0 ( 0.01 )
    0.0 ( 0.02 )
        Cycle 3 (n=232,54)
    0.0 ( 0.01 )
    0.0 ( 0.02 )
        Cycle 4 (n=185,30)
    -0.1 ( 0.02 )
    0.0 ( 0.03 )
    No statistical analyses for this end point

    Secondary: Health Care Resource Utilization: Duration of Hospital Visits by Subjects

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    End point title
    		 Health Care Resource Utilization: Duration of Hospital Visits by Subjects
    End point description
    Duration of hospital visit was calculated as = stop date – start date + 1. Mean and standard deviation data for duration of hospital visits (in days) by subjects was reported in this endpoint. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 22 months
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    461
    230
    Units: days per visit
        arithmetic mean (standard deviation)
    3.3 ( 6.81 )
    4.4 ( 7.53 )
    No statistical analyses for this end point

    Secondary: Health Care Resource Utilization: Number of Subjects With Any Concomitant Medications Prescribed

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    End point title
    		 Health Care Resource Utilization: Number of Subjects With Any Concomitant Medications Prescribed
    End point description
    Number of subjects with any concomitant medications prescribed were reported. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 22 months
    End point values
    		 Fruquintinib + Best Supportive Care (BSC) Group Placebo + BSC Group
    Number of subjects analysed
    461
    230
    Units: Subjects
    116
    63
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to approximately 40 months
    Adverse event reporting additional description
    All-Cause Mortality, Serious AEs and Non-Serious AEs data were collected based on safety population that included randomized subjects who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo + BSC Group
    Reporting group description
    		 Subjects received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

    Reporting group title
    Fruquintinib + BSC Group
    Reporting group description
    		 Subjects received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

    Serious adverse events
    		 Placebo + BSC Group Fruquintinib + BSC Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    88 / 230 (38.26%)
    173 / 456 (37.94%)
         number of deaths (all causes)
    203
    408
         number of deaths resulting from adverse events
    45
    49
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    2 / 230 (0.87%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to meninges
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastasis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour invasion
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 230 (0.00%)
    6 / 456 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (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
    Disease progression
         subjects affected / exposed
    28 / 230 (12.17%)
    27 / 456 (5.92%)
         occurrences causally related to treatment / all
    0 / 32
    0 / 28
         deaths causally related to treatment / all
    0 / 27
    0 / 26
    General physical health deterioration
         subjects affected / exposed
    5 / 230 (2.17%)
    10 / 456 (2.19%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 13
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Asthenia
         subjects affected / exposed
    0 / 230 (0.00%)
    5 / 456 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 230 (0.87%)
    4 / 456 (0.88%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    2 / 230 (0.87%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Death
         subjects affected / exposed
    2 / 230 (0.87%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Discomfort
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised Odema
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermenstrual bleeding
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopleural fistula
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         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 / 230 (0.87%)
    6 / 456 (1.32%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 230 (0.00%)
    5 / 456 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchospasm
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 230 (0.87%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 230 (0.87%)
    4 / 456 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Sternal fracture
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Recall phenomenon
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         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 / 230 (0.00%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 230 (0.43%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         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
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    1 / 230 (0.43%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         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 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Polycythaemia
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 230 (0.43%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
         subjects affected / exposed
    0 / 230 (0.00%)
    4 / 456 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 230 (0.43%)
    5 / 456 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    6 / 230 (2.61%)
    7 / 456 (1.54%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 230 (0.87%)
    7 / 456 (1.54%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain upper
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    2 / 230 (0.87%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stomatitis
         subjects affected / exposed
    1 / 230 (0.43%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Small intestinal perforation
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 230 (0.00%)
    4 / 456 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Diarrhoea
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    5 / 230 (2.17%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 230 (0.00%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 230 (1.30%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    2 / 230 (0.87%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal perforation
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal stenosis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    1 / 230 (0.43%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cholangitis
         subjects affected / exposed
    1 / 230 (0.43%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 230 (0.87%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cholecystitis
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    2 / 230 (0.87%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 230 (0.87%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         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
    Rash
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    0 / 230 (0.00%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 230 (0.43%)
    5 / 456 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vesicocutaneous fistula
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         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
    1 / 230 (0.43%)
    6 / 456 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 230 (0.00%)
    2 / 456 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 230 (0.43%)
    9 / 456 (1.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Sepsis
         subjects affected / exposed
    0 / 230 (0.00%)
    5 / 456 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abscess limb
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         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
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         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
    3 / 230 (1.30%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         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 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fournier's gangrene
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 230 (1.30%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wound sepsis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronavirus infection
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (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
    Dehydration
         subjects affected / exposed
    0 / 230 (0.00%)
    3 / 456 (0.66%)
         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 / 230 (0.43%)
    3 / 456 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 456 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 456 (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 + BSC Group Fruquintinib + BSC Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    205 / 230 (89.13%)
    446 / 456 (97.81%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 230 (9.13%)
    166 / 456 (36.40%)
         occurrences all number
    24
    274
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    37 / 230 (16.09%)
    93 / 456 (20.39%)
         occurrences all number
    41
    139
    Asthenia
         subjects affected / exposed
    52 / 230 (22.61%)
    153 / 456 (33.55%)
         occurrences all number
    75
    304
    Pyrexia
         subjects affected / exposed
    22 / 230 (9.57%)
    43 / 456 (9.43%)
         occurrences all number
    25
    58
    Mucosal inflammation
         subjects affected / exposed
    6 / 230 (2.61%)
    62 / 456 (13.60%)
         occurrences all number
    7
    97
    Oedema peripheral
         subjects affected / exposed
    17 / 230 (7.39%)
    23 / 456 (5.04%)
         occurrences all number
    20
    34
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    12 / 230 (5.22%)
    75 / 456 (16.45%)
         occurrences all number
    12
    84
    Cough
         subjects affected / exposed
    21 / 230 (9.13%)
    39 / 456 (8.55%)
         occurrences all number
    24
    50
    Dyspnoea
         subjects affected / exposed
    22 / 230 (9.57%)
    39 / 456 (8.55%)
         occurrences all number
    27
    49
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    12 / 230 (5.22%)
    26 / 456 (5.70%)
         occurrences all number
    12
    26
    Investigations
    Weight decreased
         subjects affected / exposed
    21 / 230 (9.13%)
    58 / 456 (12.72%)
         occurrences all number
    21
    82
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 230 (4.35%)
    50 / 456 (10.96%)
         occurrences all number
    13
    74
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 230 (3.48%)
    49 / 456 (10.75%)
         occurrences all number
    10
    74
    Blood bilirubin increased
         subjects affected / exposed
    10 / 230 (4.35%)
    33 / 456 (7.24%)
         occurrences all number
    14
    43
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    3 / 230 (1.30%)
    32 / 456 (7.02%)
         occurrences all number
    3
    35
    Platelet count decreased
         subjects affected / exposed
    2 / 230 (0.87%)
    28 / 456 (6.14%)
         occurrences all number
    2
    38
    Blood alkaline phosphatase increased
         subjects affected / exposed
    10 / 230 (4.35%)
    24 / 456 (5.26%)
         occurrences all number
    11
    29
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 230 (4.35%)
    40 / 456 (8.77%)
         occurrences all number
    11
    47
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 230 (12.17%)
    38 / 456 (8.33%)
         occurrences all number
    39
    55
    Thrombocytopenia
         subjects affected / exposed
    3 / 230 (1.30%)
    30 / 456 (6.58%)
         occurrences all number
    4
    47
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    8 / 230 (3.48%)
    35 / 456 (7.68%)
         occurrences all number
    9
    45
    Stomatitis
         subjects affected / exposed
    7 / 230 (3.04%)
    67 / 456 (14.69%)
         occurrences all number
    8
    108
    Constipation
         subjects affected / exposed
    22 / 230 (9.57%)
    75 / 456 (16.45%)
         occurrences all number
    25
    82
    Abdominal pain
         subjects affected / exposed
    36 / 230 (15.65%)
    80 / 456 (17.54%)
         occurrences all number
    44
    107
    Nausea
         subjects affected / exposed
    43 / 230 (18.70%)
    82 / 456 (17.98%)
         occurrences all number
    48
    102
    Vomiting
         subjects affected / exposed
    25 / 230 (10.87%)
    67 / 456 (14.69%)
         occurrences all number
    32
    81
    Diarrhoea
         subjects affected / exposed
    24 / 230 (10.43%)
    113 / 456 (24.78%)
         occurrences all number
    31
    173
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    6 / 230 (2.61%)
    89 / 456 (19.52%)
         occurrences all number
    6
    224
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    12 / 230 (5.22%)
    81 / 456 (17.76%)
         occurrences all number
    25
    167
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 230 (0.43%)
    94 / 456 (20.61%)
         occurrences all number
    1
    101
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 230 (7.39%)
    48 / 456 (10.53%)
         occurrences all number
    24
    61
    Pain in extremity
         subjects affected / exposed
    6 / 230 (2.61%)
    28 / 456 (6.14%)
         occurrences all number
    7
    39
    Arthralgia
         subjects affected / exposed
    10 / 230 (4.35%)
    52 / 456 (11.40%)
         occurrences all number
    11
    60
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    41 / 230 (17.83%)
    127 / 456 (27.85%)
         occurrences all number
    48
    178
    Hypokalaemia
         subjects affected / exposed
    4 / 230 (1.74%)
    29 / 456 (6.36%)
         occurrences all number
    6
    36

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2020
    Global Amendment 1: -Added language allowing subjects to continue receiving treatment following PD by RECIST v1.1 -Modified requirement for prior treatment with TAS-102 or regorafenib
    30 Oct 2020
    Global Amendment 2: -Increased the number of subjects to up to 687 and the planned number of sites from 100 sites to 140 sites -Provided country-level flexibility for molecular characterization of MSI/MMR status
    16 Mar 2021
    Global Amendment 3: -Added notes regarding temporary change of PK sampling, ECG collection, and ctDNA sample collection -Added specification to prohibit live vaccines during the study and for 3 months after the last dose of study drug(s) -Added specification that study drug should have been administered around the same time each day and that a missed dose could have been administered within 12 hours of usual administration time -Clarified statistical methods
    24 Jun 2021
    Global Amendment 4: -Removed instruction to avoid proton pump inhibitor drugs and H2 blockers -Increased the number of the planned study sites from 140 to 160 -Removed requirement for the collection of blood to evaluate ctDNA -Changed the protein level for which a 24-hour urine assessment was required
    01 Sep 2022
    Global Amendment 4 Addendum 1: Described the long-term extension plan, which was in place since the original protocol; visits and assessments to be performed for subjects continuing to receive fruquintinib were described to ensure their safety and clinical oversight.

    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
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