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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study Comparing CB-839 in Combination with Cabozantinib (CB-Cabo) vs. Placebo with Cabozantinib (Pbo-Cabo) in Patients with Advanced or Metastatic Renal Cell Carcinoma (RCC)

    Summary
    EudraCT number
    		 2018-000363-91
    Trial protocol
    		 GB   ES   DE   IT  
    Global end of trial date
    16 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jul 2022
    First version publication date
    30 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CX-839-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03428217
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND Number: 118397
    Sponsors
    Sponsor organisation name
    Calithera Biosciences, Inc.
    Sponsor organisation address
    343 Oyster Point Blvd, Suite 200, South San Francisco, CA, United States, 94080
    Public contact
    Study Director, Calithera Biosciences, Inc., +1 650-870-1000, clinicaltrials@calithera.com
    Scientific contact
    Study Director, Calithera Biosciences, Inc., +1 650-870-1000, clinicaltrials@calithera.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare blinded Independent Radiology Committee (IRC)-adjudicated progression free survival (PFS) of patients treated with CB-839 + cabozantinib (CB-Cabo) versus placebo + cabozantinib (Pbo-Cabo) for advanced or metastatic clear-cell RCC (ccRCC).
    Protection of trial subjects
    The Investigator provided for the protection of the patients by following all applicable regulations. These regulations were available upon request from the Sponsor. The Informed Consent Form used during the informed consent process was reviewed by the Sponsor and approved by the institutional review board (IRB)/independent ethics committee (IEC). Before any procedures specified in the protocol were performed, a patient: - was informed of all pertinent aspects of the study and all elements of informed consent - was given time to ask questions and time to consider the decision to participate - voluntarily agreed to participate in the study - signed and dated an IRB/IEC approved Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Apr 2018
    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
    Germany: 23
    Country: Number of subjects enrolled
    Spain: 42
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    France: 58
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    Italy: 37
    Country: Number of subjects enrolled
    New Zealand: 23
    Country: Number of subjects enrolled
    United States: 208
    Worldwide total number of subjects
    444
    EEA total number of subjects
    160
    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)
    269
    From 65 to 84 years
    175
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Eligible participants were randomized in a 1:1 ratio to either the Pbo-Cabo arm or the CB-Cabo arm. Randomization was stratified by prior treatment with PD-1/PD-L1 inhibitor therapy (yes vs. no) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Prognostic Risk Group (favorable vs. intermediate vs. poor).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Test article (CB-839, 200 mg/tablet) or placebo tablets that were identical in appearance were administered orally.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pbo-Cabo
    Arm description
    		 Placebo twice daily (BID) + cabozantinib (60 mg once daily [QD]) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or unacceptable toxicity, whichever occurred first.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets were administered orally BID on Days 1 through 28 of each 28-day cycle. Dosing was not adjusted for body weight or surface area.

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Cabometyx, Cabometriq
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cabozantinib (20, 40, or 60 mg/tablets) was administered orally on Days 1 through 28 of each 28-day cycle. Subjects should not eat for at least 2 hr before and at least 1 hr after taking cabozantinib, and the QD dose of cabozantinib should occur at around the same time every day, preferably at bedtime.

    Arm title
    		 CB-Cabo
    Arm description
    		 CB-839 800 mg BID + cabozantinib (60 mg QD) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per RECIST v1.1 or unacceptable toxicity, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CB-839
    Investigational medicinal product code
    Other name
    telaglenastat
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    CB-839 tablets were administered orally BID on Days 1 through 28 of each 28-day cycle. Dosing was not adjusted for body weight or surface area.

    Investigational medicinal product name
    cabozantinib
    Investigational medicinal product code
    Other name
    Cabometyx, Cabometriq
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cabozantinib (20, 40, or 60 mg/tablets) was administered orally on Days 1 through 28 of each 28-day cycle. Subjects should not eat for at least 2 hr before and at least 1 hr after taking cabozantinib, and the QD dose of cabozantinib should occur at around the same time every day, preferably at bedtime.

    Number of subjects in period 1
    		Pbo-Cabo CB-Cabo
    Started
    223
    221
    Received at least 1 dose of study drug
    221
    221
    Completed
    0
    0
    Not completed
    223
    221
         Consent withdrawn by subject
    8
    7
         Death
    89
    93
         Other, not specified
    1
    -
         Study terminated by sponsor
    124
    118
         Lost to follow-up
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pbo-Cabo
    Reporting group description
    		 Placebo twice daily (BID) + cabozantinib (60 mg once daily [QD]) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or unacceptable toxicity, whichever occurred first.

    Reporting group title
    CB-Cabo
    Reporting group description
    		 CB-839 800 mg BID + cabozantinib (60 mg QD) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per RECIST v1.1 or unacceptable toxicity, whichever occurred first.

    Reporting group values
    		 Pbo-Cabo CB-Cabo Total
    Number of subjects
    		 223 221 444
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.7 ± 10.33 60.6 ± 10.37 -
    Gender categorical
    Units: Subjects
        Female
    		 68 47 115
        Male
    		 155 174 329
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 173 176 349
        Unknown
    		 36 34 70
        Hispanic or Latino
    		 14 11 25
    Race
    Units: Subjects
        White
    		 176 174 350
        Not Reported
    		 31 32 63
        Other, Not Specified
    		 3 9 12
        Black or African American
    		 6 3 9
        Asian
    		 6 2 8
        Native Hawaiian or Other Pacific Islander
    		 1 1 2
    Stratification Factor: Prior PD-1/PD-L1 Inhibitor Therapy
    PD-1: programmed cell death protein 1 PD-L1: programmed cell death protein ligand 1
    Units: Subjects
        Yes
    		 139 137 276
        No
    		 84 84 168
    Stratification Factor: IMDC Category
    The International Metastatic renal cell carcinoma Database Consortium (IMDC) score is currently used as prognostic index to stratify patients with mRCC in 3 subgroups: good/favorable, intermediate and poor-risk groups.
    Units: Subjects
        Poor
    		 35 35 70
        Intermediate
    		 149 147 296
        Favorable
    		 39 39 78

    End points

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    End points reporting groups
    Reporting group title
    Pbo-Cabo
    Reporting group description
    		 Placebo twice daily (BID) + cabozantinib (60 mg once daily [QD]) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) or unacceptable toxicity, whichever occurred first.

    Reporting group title
    CB-Cabo
    Reporting group description
    		 CB-839 800 mg BID + cabozantinib (60 mg QD) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per RECIST v1.1 or unacceptable toxicity, whichever occurred first.

    Subject analysis set title
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants

    Subject analysis set title
    Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants

    Primary: Progression-Free Survival (PFS) as Assessed by the Independent Radiology Committee (IRC)

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    End point title
    		 Progression-Free Survival (PFS) as Assessed by the Independent Radiology Committee (IRC)
    End point description
    PFS is defined as the time from randomization to the occurrence of disease progression as assessed by the IRC using RECIST v1.1 or death from any cause, whichever occurs first. Subjects not experiencing disease progression or death at the time of analysis of PFS will be censored at the date of the last evaluable radiographic disease assessment. RECIST v1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
    End point type
    Primary
    End point timeframe
    Up to the primary analysis data cut-off date of 31 Aug 2020. Maximum duration of follow-up for PFS was 22.14 months.
    End point values
    		 Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects analysed
    223
    221
    Units: months
        median (confidence interval 95%)
    9.33 (7.64 to 11.01)
    9.17 (7.59 to 11.10)
    Statistical analysis title
    		 Stratified Analysis 1
    Statistical analysis description
    Stratified Analysis 1: Stratified by prior programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PDL1) inhibitor therapy (yes vs no) and International Metastatic Renal Cell Carcinoma Database (IMDC) prognostic risk group (favorable vs intermediate vs poor).
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6528
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.21
    Statistical analysis title
    		 Stratified Analysis 2
    Statistical analysis description
    Stratified by prior PD-1/PD-L1 inhibitor therapy [yes vs. no] and IMDC prognostic risk group [favorable vs. intermediate/poor].
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8193
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.24
    Statistical analysis title
    		 Stratified Analysis 3
    Statistical analysis description
    Stratified by the number of prior anti-angio cancer therapy [0 vs. >=1].
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8345
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.25
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9479
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.27

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from randomization to death due to any cause. Estimated from Kaplan-Meier methodology. 95% confidence interval (CI) based on Brookmeyer-Crowley methodology.
    End point type
    Secondary
    End point timeframe
    Up to the primary analysis data cut-off date of 31 Aug 2020. Maximum duration of follow-up for OS was 25.86 months.
    End point values
    		 Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects analysed
    223 [1]
    221 [2]
    Units: months
        median (confidence interval 95%)
    24.84 (21.59 to 99999)
    22.24 (18.56 to 99999)
    Notes
    [1] - 99999=not estimable due to small number of events
    [2] - 99999=not estimable due to small number of events
    Statistical analysis title
    		 Stratified Analysis 1
    Statistical analysis description
    Stratified by prior PD-1/PD-L1 inhibitor therapy [yes vs. no] and IMDC prognostic risk group [favorable vs. intermediate vs. poor].
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3867
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.6
    Statistical analysis title
    		 Stratified Analysis 2
    Statistical analysis description
    Stratified by prior PD-1/PD-L1 inhibitor therapy [yes vs. no] and IMDC prognostic risk group [favorable vs. intermediate/poor].
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3367
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.62
    Statistical analysis title
    		 Stratified Analysis 3
    Statistical analysis description
    Stratified by prior PD-1/PD-L1 inhibitor therapy [yes vs. no] and IMDC prognostic risk group [favorable vs. intermediate/poor].
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2416
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.69
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3043
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.64

    Secondary: PFS as Assessed by the Investigator

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    End point title
    		 PFS as Assessed by the Investigator
    End point description
    PFS is defined as the time from randomization to the occurrence of disease progression as assessed by the IRC using RECIST v1.1 or death from any cause, whichever occurs first. Subjects not experiencing disease progression or death at the time of analysis of PFS will be censored at the date of the last evaluable radiographic disease assessment. RECIST v1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
    End point type
    Secondary
    End point timeframe
    Up to the primary analysis data cut-off date of 31 Aug 2020. Maximum duration of follow-up for PFS was 22.64 months.
    End point values
    		 Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects analysed
    223
    221
    Units: months
        median (confidence interval 95%)
    8.38 (6.34 to 9.79)
    9.17 (7.49 to 9.46)
    Statistical analysis title
    		 Stratified Analysis 1
    Statistical analysis description
    Stratified by prior PD-1/PD-L1 inhibitor therapy [yes vs. no] and IMDC prognostic risk group [favorable vs. intermediate vs. poor].
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9692
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.25
    Statistical analysis title
    		 Stratified Analysis 2
    Statistical analysis description
    Stratified by prior PD-1/PD-L1 inhibitor therapy [yes vs. no] and IMDC prognostic risk group [favorable vs. intermediate/poor].
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9235
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.27
    Statistical analysis title
    		 Stratified Analysis 3
    Statistical analysis description
    Stratified by the number of prior anti-angio cancer therapy [0 vs. >=1].
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9549
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.26
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Intent-to-Treat (ITT) Analysis Set: Pbo-Cabo v Intent-to-Treat (ITT) Analysis Set: CB-Cabo
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8193
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.29

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through at least 28 days after last dose of all study treatments, or until initiation of a new anticancer therapy (if earlier). Overall median duration of safety follow-up was 280.0 days.
    Adverse event reporting additional description
    Per protocol, Grade 5 disease progression events are excluded from these tables. Disease progression includes events in the preferred terms of disease progression and malignant neoplasm progression.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Pbo-Cabo
    Reporting group description
    		 Placebo BID + cabozantinib (60 mg QD) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per RECIST v1.1 or unacceptable toxicity, whichever occurred first.

    Reporting group title
    CB-Cabo
    Reporting group description
    		 CB-839 800 mg BID + cabozantinib (60 mg QD) administered orally on Days 1 through 28 of each 28-day cycle until disease progression per RECIST v1.1 or unacceptable toxicity, whichever occurred first.

    Serious adverse events
    		 Pbo-Cabo CB-Cabo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 217 (34.10%)
    90 / 225 (40.00%)
         number of deaths (all causes)
    10
    14
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 217 (0.46%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to pelvis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (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
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 217 (0.46%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Nerve block
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 217 (0.92%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Pregnancy of partner
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    7 / 217 (3.23%)
    5 / 225 (2.22%)
         occurrences causally related to treatment / all
    4 / 7
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 217 (0.92%)
    4 / 225 (1.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 217 (0.46%)
    5 / 225 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 217 (0.00%)
    3 / 225 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    2 / 217 (0.92%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 217 (0.92%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Troponin I increased
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 217 (0.46%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         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
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 217 (0.46%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 217 (0.46%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar syndrome
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         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
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Monoplegia
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         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
    Anaemia
         subjects affected / exposed
    1 / 217 (0.46%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 217 (0.92%)
    6 / 225 (2.67%)
         occurrences causally related to treatment / all
    2 / 2
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 217 (0.46%)
    3 / 225 (1.33%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 217 (0.46%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 217 (0.92%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoperitoneum
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         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 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Melaena
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal food impaction
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    3 / 217 (1.38%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 217 (1.84%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 217 (1.38%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 217 (1.38%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 217 (0.00%)
    3 / 225 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    2 / 217 (0.92%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         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
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraspinal abscess
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound abscess
         subjects affected / exposed
    1 / 217 (0.46%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 217 (1.38%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 217 (0.92%)
    3 / 225 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 217 (1.38%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 217 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 217 (0.46%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 217 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pbo-Cabo CB-Cabo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    213 / 217 (98.16%)
    222 / 225 (98.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    72 / 217 (33.18%)
    82 / 225 (36.44%)
         occurrences all number
    95
    97
    Hypotension
         subjects affected / exposed
    13 / 217 (5.99%)
    10 / 225 (4.44%)
         occurrences all number
    13
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    109 / 217 (50.23%)
    94 / 225 (41.78%)
         occurrences all number
    138
    116
    Asthenia
         subjects affected / exposed
    49 / 217 (22.58%)
    49 / 225 (21.78%)
         occurrences all number
    56
    66
    Mucosal inflammation
         subjects affected / exposed
    36 / 217 (16.59%)
    23 / 225 (10.22%)
         occurrences all number
    42
    28
    Oedema peripheral
         subjects affected / exposed
    21 / 217 (9.68%)
    22 / 225 (9.78%)
         occurrences all number
    26
    27
    Pyrexia
         subjects affected / exposed
    15 / 217 (6.91%)
    20 / 225 (8.89%)
         occurrences all number
    18
    27
    Chest pain
         subjects affected / exposed
    13 / 217 (5.99%)
    9 / 225 (4.00%)
         occurrences all number
    15
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    41 / 217 (18.89%)
    50 / 225 (22.22%)
         occurrences all number
    48
    56
    Dysphonia
         subjects affected / exposed
    41 / 217 (18.89%)
    33 / 225 (14.67%)
         occurrences all number
    44
    35
    Dyspnoea
         subjects affected / exposed
    34 / 217 (15.67%)
    30 / 225 (13.33%)
         occurrences all number
    42
    38
    Oropharyngeal pain
         subjects affected / exposed
    16 / 217 (7.37%)
    20 / 225 (8.89%)
         occurrences all number
    17
    24
    Epistaxis
         subjects affected / exposed
    13 / 217 (5.99%)
    21 / 225 (9.33%)
         occurrences all number
    15
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    17 / 217 (7.83%)
    21 / 225 (9.33%)
         occurrences all number
    18
    22
    Anxiety
         subjects affected / exposed
    12 / 217 (5.53%)
    16 / 225 (7.11%)
         occurrences all number
    12
    17
    Depression
         subjects affected / exposed
    16 / 217 (7.37%)
    7 / 225 (3.11%)
         occurrences all number
    17
    7
    Investigations
    Weight decreased
         subjects affected / exposed
    65 / 217 (29.95%)
    77 / 225 (34.22%)
         occurrences all number
    75
    89
    Alanine aminotransferase increased
         subjects affected / exposed
    39 / 217 (17.97%)
    63 / 225 (28.00%)
         occurrences all number
    53
    90
    Aspartate aminotransferase increased
         subjects affected / exposed
    40 / 217 (18.43%)
    56 / 225 (24.89%)
         occurrences all number
    50
    76
    Blood creatinine increased
         subjects affected / exposed
    12 / 217 (5.53%)
    24 / 225 (10.67%)
         occurrences all number
    17
    29
    Blood alkaline phosphatase increased
         subjects affected / exposed
    14 / 217 (6.45%)
    15 / 225 (6.67%)
         occurrences all number
    17
    19
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    12 / 217 (5.53%)
    11 / 225 (4.89%)
         occurrences all number
    13
    14
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    52 / 217 (23.96%)
    41 / 225 (18.22%)
         occurrences all number
    59
    45
    Headache
         subjects affected / exposed
    32 / 217 (14.75%)
    39 / 225 (17.33%)
         occurrences all number
    39
    41
    Dizziness
         subjects affected / exposed
    24 / 217 (11.06%)
    23 / 225 (10.22%)
         occurrences all number
    28
    30
    Paraesthesia
         subjects affected / exposed
    12 / 217 (5.53%)
    10 / 225 (4.44%)
         occurrences all number
    13
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    29 / 217 (13.36%)
    28 / 225 (12.44%)
         occurrences all number
    34
    40
    Thrombocytopenia
         subjects affected / exposed
    14 / 217 (6.45%)
    20 / 225 (8.89%)
         occurrences all number
    17
    26
    Eye disorders
    Vision blurred
         subjects affected / exposed
    14 / 217 (6.45%)
    22 / 225 (9.78%)
         occurrences all number
    14
    22
    Photophobia
         subjects affected / exposed
    8 / 217 (3.69%)
    26 / 225 (11.56%)
         occurrences all number
    8
    34
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    160 / 217 (73.73%)
    162 / 225 (72.00%)
         occurrences all number
    378
    330
    Nausea
         subjects affected / exposed
    118 / 217 (54.38%)
    123 / 225 (54.67%)
         occurrences all number
    163
    168
    Vomiting
         subjects affected / exposed
    75 / 217 (34.56%)
    77 / 225 (34.22%)
         occurrences all number
    138
    123
    Constipation
         subjects affected / exposed
    63 / 217 (29.03%)
    69 / 225 (30.67%)
         occurrences all number
    72
    81
    Stomatitis
         subjects affected / exposed
    49 / 217 (22.58%)
    47 / 225 (20.89%)
         occurrences all number
    58
    54
    Abdominal pain
         subjects affected / exposed
    39 / 217 (17.97%)
    40 / 225 (17.78%)
         occurrences all number
    48
    46
    Gastrooesophageal reflux disease
         subjects affected / exposed
    24 / 217 (11.06%)
    42 / 225 (18.67%)
         occurrences all number
    33
    47
    Dyspepsia
         subjects affected / exposed
    28 / 217 (12.90%)
    35 / 225 (15.56%)
         occurrences all number
    32
    47
    Abdominal pain upper
         subjects affected / exposed
    25 / 217 (11.52%)
    21 / 225 (9.33%)
         occurrences all number
    31
    22
    Dry mouth
         subjects affected / exposed
    21 / 217 (9.68%)
    14 / 225 (6.22%)
         occurrences all number
    22
    14
    Oral pain
         subjects affected / exposed
    15 / 217 (6.91%)
    9 / 225 (4.00%)
         occurrences all number
    15
    11
    Flatulence
         subjects affected / exposed
    9 / 217 (4.15%)
    14 / 225 (6.22%)
         occurrences all number
    10
    15
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    87 / 217 (40.09%)
    95 / 225 (42.22%)
         occurrences all number
    121
    117
    Rash
         subjects affected / exposed
    28 / 217 (12.90%)
    40 / 225 (17.78%)
         occurrences all number
    37
    50
    Pruritus
         subjects affected / exposed
    20 / 217 (9.22%)
    25 / 225 (11.11%)
         occurrences all number
    25
    26
    Dry skin
         subjects affected / exposed
    19 / 217 (8.76%)
    19 / 225 (8.44%)
         occurrences all number
    19
    20
    Alopecia
         subjects affected / exposed
    15 / 217 (6.91%)
    16 / 225 (7.11%)
         occurrences all number
    15
    16
    Hair colour changes
         subjects affected / exposed
    11 / 217 (5.07%)
    20 / 225 (8.89%)
         occurrences all number
    11
    21
    Rash maculo-papular
         subjects affected / exposed
    14 / 217 (6.45%)
    13 / 225 (5.78%)
         occurrences all number
    15
    13
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    17 / 217 (7.83%)
    28 / 225 (12.44%)
         occurrences all number
    24
    39
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    56 / 217 (25.81%)
    66 / 225 (29.33%)
         occurrences all number
    67
    69
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    37 / 217 (17.05%)
    43 / 225 (19.11%)
         occurrences all number
    43
    53
    Arthralgia
         subjects affected / exposed
    33 / 217 (15.21%)
    33 / 225 (14.67%)
         occurrences all number
    42
    51
    Pain in extremity
         subjects affected / exposed
    27 / 217 (12.44%)
    28 / 225 (12.44%)
         occurrences all number
    34
    30
    Muscle spasms
         subjects affected / exposed
    24 / 217 (11.06%)
    29 / 225 (12.89%)
         occurrences all number
    27
    35
    Myalgia
         subjects affected / exposed
    19 / 217 (8.76%)
    11 / 225 (4.89%)
         occurrences all number
    24
    14
    Musculoskeletal chest pain
         subjects affected / exposed
    13 / 217 (5.99%)
    14 / 225 (6.22%)
         occurrences all number
    18
    17
    Muscular weakness
         subjects affected / exposed
    9 / 217 (4.15%)
    15 / 225 (6.67%)
         occurrences all number
    10
    17
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    18 / 217 (8.29%)
    23 / 225 (10.22%)
         occurrences all number
    33
    40
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 217 (5.53%)
    20 / 225 (8.89%)
         occurrences all number
    12
    23
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    86 / 217 (39.63%)
    83 / 225 (36.89%)
         occurrences all number
    111
    101
    Hypomagnesaemia
         subjects affected / exposed
    49 / 217 (22.58%)
    48 / 225 (21.33%)
         occurrences all number
    66
    82
    Hypophosphataemia
         subjects affected / exposed
    38 / 217 (17.51%)
    32 / 225 (14.22%)
         occurrences all number
    53
    47
    Hypokalaemia
         subjects affected / exposed
    27 / 217 (12.44%)
    25 / 225 (11.11%)
         occurrences all number
    46
    36
    Hyponatraemia
         subjects affected / exposed
    30 / 217 (13.82%)
    16 / 225 (7.11%)
         occurrences all number
    44
    18
    Hypocalcaemia
         subjects affected / exposed
    26 / 217 (11.98%)
    18 / 225 (8.00%)
         occurrences all number
    32
    25
    Hyperkalaemia
         subjects affected / exposed
    16 / 217 (7.37%)
    14 / 225 (6.22%)
         occurrences all number
    22
    20
    Dehydration
         subjects affected / exposed
    13 / 217 (5.99%)
    15 / 225 (6.67%)
         occurrences all number
    21
    24
    Hypoalbuminaemia
         subjects affected / exposed
    14 / 217 (6.45%)
    12 / 225 (5.33%)
         occurrences all number
    20
    16

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2020
    • Updated emergency contacts and serious adverse event (SAE) reporting contact. • Included additional objectives for pharmacokinetics. • Added data from phase 1 study CX-839-001 for patients treated with telaglenastat and cabozantinib. • Added instructions for patients who discontinued either telaglenastat/placebo or cabozantinib. • Clarified language for survival follow-up. • Included 110826 (major metabolite of telaglenastat) and cabozantinib for PK analysis. • Included other reportable information language and updated overdose and abuse definitions. • Clarified assessment of blood urea nitrogen in the chemistry panel.

    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.
    At the time of the primary analysis (31 Aug 2020), the study did not meet the primary endpoint of improved PFS and the sponsor closed the study. The safety profile was consistent between the 2 groups of the study.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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