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    Clinical Trial Results:
    A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Colorectal Cancer (Morpheus-CRC)

    Summary
    EudraCT number
    		 2017-004566-99
    Trial protocol
    		 GB   ES  
    Global end of trial date
    26 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Oct 2023
    First version publication date
    08 Oct 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CO39612
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03555149
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    26 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, safety, and pharmacokinetics of multiple immunotherapy-based treatment combinations in patients with metastatic colorectal cancer (mCRC).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Sep 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    United States: 45
    Country: Number of subjects enrolled
    Australia: 6
    Worldwide total number of subjects
    96
    EEA total number of subjects
    16
    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)
    72
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 15 centers in 5 countries: United States, France, Republic of Korea, Australia, and Switzerland.

    Pre-assignment
    Screening details
    		 A total of 96 participants were enrolled.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Regorafenib (Control)
    Arm description
    		 Participants will receive treatment until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    RO7069680
    Other name
    Stivarga
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg once daily on Days 1-21 of each cycle (21 day cycle)

    Arm title
    		 Atezolizumab + Imprime PGG + Bevacizumab
    Arm description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    RO5541267
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg IV on Day 1 of each cycle (21 day cycle)

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    7.5 mg/kg on Day 1 of each cycle (21 day cycle)

    Investigational medicinal product name
    Imprime PGG
    Investigational medicinal product code
    RO7234832
    Other name
    PGG beta glucan
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg/kg on Days 1, 8 and 15 of each cycle (21 day cycle)

    Arm title
    		 Atezolizumab + Isatuximab
    Arm description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Isatuximab
    Investigational medicinal product code
    RO7268598
    Other name
    SAR650984
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg on Days 1, 8, and 15 for Cycle 1 (21 day cycle) 10 mg/kg on Day 1 of each cycle Cycle 2+ (21 day cycle)

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    RO5541267
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg on Day 1 of each cycle (21 day cycle)

    Arm title
    		 Atezolizumab + Selicrelumab + Bevacizumab
    Arm description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    RO5541267
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    840 mg on Days 1 and 15 of each cycle (28 day cycle)

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg on Days 1 and 15 of each cycle (28 day cycle)

    Investigational medicinal product name
    Selicrelumab
    Investigational medicinal product code
    RO7009789
    Other name
    CD40
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    16 mg SC on Day 1 of Cycles 1-4 and every third cycle there after (i.e., Cycles 7, 10, 13, etc. ) (28 day cycle)

    Arm title
    		 Atezolizumab + Idasanutlin
    Arm description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idasanutlin
    Investigational medicinal product code
    RO5503781/F33
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg once daily on Days 1-5 (28 day cycle)

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    RO5541267
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    840 mg on Days 1 and 15 of each cycle (28 day cycle)

    Arm title
    		 Atezolizumab + Regorafenib
    Arm description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    RO7069680
    Other name
    Stivarga
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg once daily on Days 1-21 of each cycle (28 day cycle)

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    RO5541267
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    840 mg on Days 1 and 15 of each cycle (28 day cycle)

    Arm title
    		 Atezolizumab + Regorafenib + AB928
    Arm description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    RO5541267
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Oral use
    Dosage and administration details
    840 mg on Days 1 and 15 of each cycle (28 day cycle)

    Investigational medicinal product name
    Etrumadenant
    Investigational medicinal product code
    AB928
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg once daily on Days 1-28 of each cycle (28 day cycle)

    Investigational medicinal product name
    Regorafenib
    Investigational medicinal product code
    RO7069680
    Other name
    Stivarga
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg once daily on Days 1-21 of each cycle (28 day cycle)

    Arm title
    		 Atezolizumab + LOAd703
    Arm description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LOAd703
    Investigational medicinal product code
    Other name
    delolimogene mupadenorepvec
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intratumoral use
    Dosage and administration details
    1 x 10^11 VP or 5 x 10^11 VP on Day 1 (21 day cycle)

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    RO5541267
    Other name
    Tecentriq
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1200 mg on Day 1 of each cycle (21 day cycle)

    Number of subjects in period 1
    		Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Isatuximab Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib Atezolizumab + Regorafenib + AB928 Atezolizumab + LOAd703
    Started
    24
    15
    15
    6
    4
    15
    15
    2
    Received >/=1 Dose of Study Treatment
    19
    15
    15
    6
    4
    15
    15
    2
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    24
    15
    15
    6
    4
    15
    15
    2
         Adverse event, serious fatal
    18
    15
    15
    4
    4
    11
    12
    1
         Physician decision
    1
    -
    -
    -
    -
    -
    -
    -
         Consent withdrawn by subject
    3
    -
    -
    2
    -
    1
    -
    -
         Study Terminated By Sponsor
    1
    -
    -
    -
    -
    2
    3
    1
         Lost to follow-up
    1
    -
    -
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Regorafenib (Control)
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

    Reporting group title
    Atezolizumab + Imprime PGG + Bevacizumab
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Isatuximab
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Selicrelumab + Bevacizumab
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Idasanutlin
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Regorafenib
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Regorafenib + AB928
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + LOAd703
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group values
    		 Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Isatuximab Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib Atezolizumab + Regorafenib + AB928 Atezolizumab + LOAd703 Total
    Number of subjects
    		 24 15 15 6 4 15 15 2 96
    Age Categorical
    Units: Participants
        Preterm newborn (gestational age <37 weeks)
    		 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 17 13 12 1 3 12 13 1 72
        From 65-84 years
    		 7 2 3 5 1 3 2 1 24
        85 years and over
    		 0 0 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.5 ± 10.3 57.8 ± 5.9 52.3 ± 12.0 66.8 ± 10.0 56.3 ± 6.8 56.4 ± 8.2 55.1 ± 9.2 58.0 ± 11.3 -
    Sex: Female, Male
    Units:
        Female
    		 12 7 6 1 3 11 4 1 45
        Male
    		 12 8 9 5 1 4 11 1 51
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 4 3 1 0 1 0 1 12
        Not Hispanic or Latino
    		 21 10 11 4 4 11 14 1 76
        Unknown or Not Reported
    		 1 1 1 1 0 3 1 0 8
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 0 0 0 0 0 1
        Asian
    		 7 6 4 0 1 5 8 0 31
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0 0
        Black or African American
    		 1 0 0 0 0 1 0 0 2
        White
    		 15 7 10 5 3 7 6 2 55
        More than one race
    		 0 1 0 0 0 0 0 0 1
        Unknown or Not Reported
    		 1 0 1 1 0 2 1 0 6
    ECOG score
    ECOG performance status scale. 0 - Fully active; able to carry on all predisease performance without restriction 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature
    Units: Subjects
        ECOG PS 0
    		 11 8 5 5 1 7 7 1 45
        ECOG PS 1
    		 13 7 10 1 3 8 8 1 51
    Number of Metastatic Sites at Enrollment
    Units: Subjects
        1 Site
    		 3 1 0 0 0 1 1 0 6
        2 Sites
    		 4 5 3 3 3 7 5 0 30
        3 Sites
    		 9 5 8 0 0 2 6 2 32
        >/=4 Sites
    		 8 4 4 3 1 5 3 0 28

    End points

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    End points reporting groups
    Reporting group title
    Regorafenib (Control)
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

    Reporting group title
    Atezolizumab + Imprime PGG + Bevacizumab
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Isatuximab
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Selicrelumab + Bevacizumab
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Idasanutlin
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Regorafenib
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Regorafenib + AB928
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + LOAd703
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Primary: Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

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    End point title
    		 Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
    End point description
    The best confirmed ORR is defined as the percentage of participants with a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1. Participants could be classified as "Stable Disease" if the assessment was ≥6 weeks from randomization. They were classified as Missing if no post-baseline response assessments were available, or as Not Evaluable if all post-baseline response assessments were unevaluable. The differences in ORR between the experimental arms and the corresponding control arm were calculated, along with 95% confidence intervals (CIs), using normal approximation of the binomial distribution. The 95% CIs for ORRs were constructed using the Clopper-Pearson method, and 0 to 999999 indicates that they were not calculated for the "Not Evaluable" and "Missing" categories. The 95% CIs for the difference in rates were constructed using the Wald method with continuity correction.
    End point type
    Primary
    End point timeframe
    From randomization until disease progression or loss of clinical benefit (up to 4 years)
    End point values
    		 Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Isatuximab Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib Atezolizumab + Regorafenib + AB928 Atezolizumab + LOAd703
    Number of subjects analysed
    19
    15
    15
    6
    4
    15
    15
    2
    Units: Percentage of Participants
    number (confidence interval 95%)
        Responders (CR + PR)
    0 (0 to 17.65)
    0 (0 to 21.80)
    0 (0 to 21.80)
    0 (0 to 45.93)
    0 (0 to 60.24)
    6.7 (0.17 to 31.95)
    6.7 (0.17 to 31.95)
    0 (0 to 84.19)
        Complete Response (CR)
    0 (0 to 17.65)
    0 (0 to 21.80)
    0 (0 to 21.80)
    0 (0 to 45.93)
    0 (0 to 60.24)
    0 (0 to 21.80)
    0 (0 to 21.80)
    0 (0 to 84.19)
        Partial Response (PR)
    0 (0 to 17.65)
    0 (0 to 21.80)
    0 (0 to 21.80)
    0 (0 to 45.93)
    0 (0 to 60.24)
    6.7 (0.17 to 31.95)
    6.7 (0.17 to 31.95)
    0 (0 to 84.19)
        Stable Disease (SD)
    63.2 (38.36 to 83.71)
    33.3 (11.82 to 61.62)
    20.0 (4.33 to 48.09)
    50 (11.81 to 88.19)
    0 (0 to 60.24)
    33.3 (11.82 to 61.62)
    53.3 (26.59 to 78.73)
    0 (0 to 84.19)
        Progressive Disease (PD)
    26.3 (9.15 to 51.20)
    66.7 (38.38 to 88.18)
    66.7 (38.38 to 88.18)
    33.3 (4.33 to 77.72)
    100 (39.76 to 100)
    46.7 (21.27 to 73.41)
    26.7 (7.79 to 55.10)
    100 (15.81 to 100)
        Not Evaluable
    0 (0 to 999999)
    0 (0 to 999999)
    13.3 (0 to 999999)
    0 (0 to 999999)
    0 (0 to 999999)
    0 (0 to 999999)
    13.3 (0 to 999999)
    0 (0 to 999999)
        Missing
    10.5 (0 to 999999)
    0 (0 to 999999)
    0 (0 to 999999)
    16.7 (0 to 999999)
    0 (0 to 999999)
    13.3 (0 to 999999)
    0 (0 to 999999)
    0 (0 to 999999)
    Statistical analysis title
    		 The difference in ORR between arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Difference in Overall Response Rate
    Point estimate
    6.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.92
         upper limit
    		 25.25
    Notes
    [1] - The difference in ORR was calculated as the experimental arm (Atezolizumab + Regorafenib) subtracted from the control arm (Regorafenib).
    Statistical analysis title
    		 The difference in ORR between arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib + AB928
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Difference in Overall Response Rate
    Point estimate
    6.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.92
         upper limit
    		 25.25
    Notes
    [2] - The difference in ORR was calculated as the experimental arm (Atezolizumab + Regorafenib + AB928) subtracted from the control arm (Regorafenib).

    Secondary: Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1

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    End point title
    		 Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1
    End point description
    Progression-free survival (PFS) after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), was determined by the investigator according to RECIST v1.1. For participants who did not have documented disease progression or death, PFS was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for PFS with 95% confidence intervals (CIs) constructed through use of the Brookmeyer and Crowley method. The values "999999" indicate that the 95% CI could not be calculated because too few events had occurred.
    End point type
    Secondary
    End point timeframe
    From randomization up to the first occurrence of disease or death from any cause (up to 4 years)
    End point values
    		 Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Isatuximab Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib Atezolizumab + Regorafenib + AB928 Atezolizumab + LOAd703
    Number of subjects analysed
    19
    15
    15
    6
    4
    15
    15
    2
    Units: Months
        median (confidence interval 95%)
    2.83 (2.20 to 3.02)
    1.51 (1.38 to 2.79)
    1.41 (1.41 to 1.77)
    4.21 (1.68 to 999999)
    1.26 (0.82 to 999999)
    1.81 (1.38 to 2.96)
    4.60 (2.60 to 5.78)
    1.58 (1.51 to 999999)
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Imprime PGG + Bevacizumab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 2.73
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Isatuximab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 4.88
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Selicrelumab + Bevacizumab
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 2.18
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Regorafenib (Control) v Atezolizumab + LOAd703
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    5.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 33.82
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 3.63
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib + AB928
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.63
    Statistical analysis title
    		 PFS Hazard Ratio
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Idasanutlin
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 6.24

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival (OS) is defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier method was used to estimate the median for OS with 95% confidence intervals (CIs) constructed through use of the Brookmeyer and Crowley method. The values "999999" indicate that the median or the 95% CI could not be calculated because too few events had occurred.
    End point type
    Secondary
    End point timeframe
    From randomization up to death from any cause (up to 4 years)
    End point values
    		 Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Isatuximab Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib Atezolizumab + Regorafenib + AB928 Atezolizumab + LOAd703
    Number of subjects analysed
    19
    15
    15
    6
    4
    15
    15
    2
    Units: Months
        median (confidence interval 95%)
    10.15 (4.40 to 12.29)
    5.72 (4.37 to 10.51)
    5.13 (3.12 to 7.75)
    14.36 (3.22 to 999999)
    5.93 (1.61 to 999999)
    11.01 (5.29 to 16.66)
    8.67 (6.60 to 14.62)
    4.07 (0.999999 to 999999)
    Statistical analysis title
    		 OS Hazard Ratio
    Statistical analysis description
    Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) Hazard Ratio for OS
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Imprime PGG + Bevacizumab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 2.93
    Statistical analysis title
    		 OS Hazard Ratio
    Statistical analysis description
    Atezolizumab + Isatuximab vs. Regorafenib (Control) Hazard Ratio for OS
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Isatuximab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 2.81
    Statistical analysis title
    		 OS Hazard Ratio
    Statistical analysis description
    Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) Hazard Ratio for OS
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Selicrelumab + Bevacizumab
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2.72
    Statistical analysis title
    		 OS Hazard Ratio
    Statistical analysis description
    Atezolizumab + Idasanutlin vs. Regorafenib (Control) Hazard Ratio for OS
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Idasanutlin
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 3.84
    Statistical analysis title
    		 OS Hazard Ratio
    Statistical analysis description
    Atezolizumab + Regorafenib vs. Regorafenib (Control) Hazard Ratio for OS
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.88
    Statistical analysis title
    		 OS Hazard Ratio
    Statistical analysis description
    Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) Hazard Ratio for OS
    Comparison groups
    Atezolizumab + Regorafenib + AB928 v Regorafenib (Control)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.96
    Statistical analysis title
    		 OS Hazard Ratio
    Statistical analysis description
    Atezolizumab + LOAd703 vs. Regorafenib (Control) Hazard Ratio for OS
    Comparison groups
    Regorafenib (Control) v Atezolizumab + LOAd703
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 24.85

    Secondary: Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS)

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    End point title
    		 Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS)
    End point description
    Overall survival (OS) is defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. OS is shown as the percentage of participants who were event-free at the landmark timepoints of 3, 6, 12, and 18 months. The values "999999" indicate that the 95% CI could not be calculated because too few events had occurred.
    End point type
    Secondary
    End point timeframe
    3, 6, 12, and 18 months
    End point values
    		 Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Isatuximab Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib Atezolizumab + Regorafenib + AB928 Atezolizumab + LOAd703
    Number of subjects analysed
    19
    15
    15
    6
    4
    15
    15
    2
    Units: Percentage of Participants
    number (confidence interval 95%)
        3 Months
    84.21 (67.81 to 100.00)
    100 (100 to 100)
    73.33 (50.95 to 95.71)
    100 (100 to 100)
    75.00 (32.57 to 100)
    78.97 (57.78 to 100.00)
    86.67 (69.46 to 100.00)
    100 (100 to 100)
        6 Months
    63.16 (41.47 to 84.85)
    46.67 (21.42 to 71.91)
    40.00 (15.21 to 64.79)
    80.00 (44.94 to 100)
    50.00 (1.00 to 99.00)
    71.79 (48.32 to 95.27)
    73.33 (50.95 to 95.71)
    0 (0 to 999999)
        12 Months
    34.45 (12.42 to 56.48)
    20.00 (0.00 to 40.24)
    26.67 (4.29 to 49.05)
    53.33 (4.68 to 100)
    25.00 (0.00 to 67.43)
    39.89 (13.18 to 66.59)
    33.33 (9.48 to 57.19)
    0 (0 to 999999)
        18 Months
    17.22 (0.00 to 34.87)
    6.67 (0.00 to 19.29)
    20.00 (0.00 to 40.24)
    26.67 (0.00 to 70.91)
    25.00 (0.00 to 67.43)
    23.93 (0.48 to 47.39)
    26.67 (4.29 to 49.05)
    0 (0 to 999999)
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 6 months for the Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Imprime PGG + Bevacizumab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -16.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.78
         upper limit
    		 16.79
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 3 months for the Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Imprime PGG + Bevacizumab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    15.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 32.19
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 3 months for the Atezolizumab + Isatuximab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Isatuximab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -10.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.62
         upper limit
    		 16.87
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 18 months for the Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Imprime PGG + Bevacizumab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -10.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.25
         upper limit
    		 11.14
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 12 months for the Atezolizumab + Imprime PGG + Bevacizumab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Imprime PGG + Bevacizumab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -14.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.37
         upper limit
    		 15.47
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 12 months for the Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Selicrelumab + Bevacizumab
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    18.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.53
         upper limit
    		 72.3
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 18 months for the Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Selicrelumab + Bevacizumab
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    9.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.19
         upper limit
    		 57.08
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 6 months for the Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Selicrelumab + Bevacizumab
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    16.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.39
         upper limit
    		 58.07
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 3 months for the Atezolizumab + Selicrelumab + Bevacizumab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Selicrelumab + Bevacizumab
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    15.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 32.19
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 18 months for the Atezolizumab + Isatuximab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Isatuximab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    2.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.08
         upper limit
    		 29.63
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 12 months for the Atezolizumab + Isatuximab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Isatuximab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -7.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -39.19
         upper limit
    		 23.62
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 6 months for the Atezolizumab + Isatuximab vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Isatuximab
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -23.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56.1
         upper limit
    		 9.78
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 3 months for the Atezolizumab + Idasanutlin vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Idasanutlin
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -9.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.7
         upper limit
    		 36.28
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 3 months for the Atezolizumab + Regorafenib vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -5.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.03
         upper limit
    		 21.56
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 18 months for the Atezolizumab + Idasanutlin vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Idasanutlin
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    7.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.18
         upper limit
    		 53.73
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 12 months for the Atezolizumab + Idasanutlin vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Idasanutlin
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -9.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.26
         upper limit
    		 38.36
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 6 months for the Atezolizumab + Idasanutlin vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Idasanutlin
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -13.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -66.74
         upper limit
    		 40.43
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 6 months for the Atezolizumab + Regorafenib vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    8.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.33
         upper limit
    		 40.6
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 12 months for the Atezolizumab + Regorafenib vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib + AB928
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    5.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.19
         upper limit
    		 40.06
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 18 months for the Atezolizumab + Regorafenib vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    6.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.64
         upper limit
    		 36.06
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 18 months for the Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib + AB928
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    9.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.06
         upper limit
    		 37.94
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 12 months for the Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib + AB928
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    -1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.59
         upper limit
    		 31.36
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 6 months for the Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib + AB928
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    10.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.99
         upper limit
    		 41.34
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 3 months for the Atezolizumab + Regorafenib + AB928 vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + Regorafenib + AB928
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    2.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.31
         upper limit
    		 26.22
    Statistical analysis title
    		 Difference in OS Event-Free Rate
    Statistical analysis description
    Difference in OS event-free rate at 3 months for the Atezolizumab + LOAd703 vs. Regorafenib (Control) arms
    Comparison groups
    Regorafenib (Control) v Atezolizumab + LOAd703
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in OS Event-Free Rate
    Point estimate
    15.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 32.19

    Secondary: Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1

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    End point title
    		 Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1
    End point description
    Duration of response is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first. In both arms where DOR was measured only 1 participant had a confirmed response; 95% CI could not be calculated.
    End point type
    Secondary
    End point timeframe
    From the date of first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 4 years)
    End point values
    		 Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Isatuximab Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib Atezolizumab + Regorafenib + AB928 Atezolizumab + LOAd703
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    0 [7]
    1 [8]
    1 [9]
    0 [10]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    3.12 (0 to 999999)
    5.75 (0 to 999999)
    ( to )
    Notes
    [3] - None of the patients in this arm had a confirmed response.
    [4] - None of the patients in this arm had a confirmed response.
    [5] - None of the patients in this arm had a confirmed response.
    [6] - None of the patients in this arm had a confirmed response.
    [7] - None of the patients in this arm had a confirmed response.
    [8] - 1 patient with a confirmed response; 95% CI could not be calculated.
    [9] - 1 patient with a confirmed response; 95% CI could not be calculated.
    [10] - None of the patients in this arm had a confirmed response.
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR), as Determined by the Investigator per RECIST v1.1

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    End point title
    		 Disease Control Rate (DCR), as Determined by the Investigator per RECIST v1.1
    End point description
    Disease control rate is defined as the percentage of participants with stable disease for ≥12 weeks or a complete or partial response, as determined by the investigator according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression or loss of clinical benefit (up to 4 years)
    End point values
    		 Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Isatuximab Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib Atezolizumab + Regorafenib + AB928 Atezolizumab + LOAd703
    Number of subjects analysed
    19
    15
    15
    6
    4
    15
    15
    2
    Units: Percentage of Participants
        number (confidence interval 95%)
    15.8 (3.38 to 39.58)
    13.3 (1.66 to 40.46)
    6.7 (0.17 to 31.95)
    33.3 (4.33 to 77.72)
    0 (0.00 to 60.24)
    13.3 (1.66 to 40.46)
    40.0 (16.34 to 67.71)
    0 (0.00 to 84.19)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with at Least One Adverse Event (AE)

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    End point title
    		 Percentage of Participants with at Least One Adverse Event (AE)
    End point description
    The incidence, nature, and severity of adverse events (AEs) are reported, with severity determined according to NCI CTCAE v4.0. AEs were reported for the safety-evaluable population, which included all patients who received any amount of dose of any component of study treatment. All AEs were reported until 30 days after the last study dose or until start of new systemic anti-cancer therapy. Serious AEs and AEs of special interest were reported until 135 days (or 180 days for the Atezolizumab + LOAd703 arm only) after the last dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Adverse event data were collected from baseline up to 6 months after the last dose of study treatment (up to 640 days); deaths (all-cause) were reported from baseline through survival follow-up (up to 4 years)
    End point values
    		 Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Isatuximab Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib Atezolizumab + Regorafenib + AB928 Atezolizumab + LOAd703
    Number of subjects analysed
    19
    15
    15
    6
    4
    15
    15
    2
    Units: Percentage of Participants
    number (not applicable)
        Adverse Event (AE)
    100
    100
    100
    100
    100
    100
    100
    100
        Death
    89.5
    100
    100
    66.7
    100
    73.3
    80.0
    50.0
        Withdrawn from Stage due to an AE
    15.8
    6.7
    0
    0
    0
    6.7
    6.7
    0
        AE with a Fatal Outcome
    10.5
    0
    0
    0
    0
    6.7
    0
    0
        Serious AE (SAE)
    26.3
    6.7
    33.3
    50.0
    25.0
    46.7
    46.7
    50.0
        SAE Leading to Withdrawal from any Treatment
    21.1
    6.7
    0
    0
    0
    6.7
    0
    0
        SAE Leading to Dose Modification/Interruption
    5.3
    0
    6.7
    50.0
    0
    26.7
    46.7
    0
        Related SAE
    5.3
    6.7
    0
    50.0
    25.0
    26.7
    33.3
    50.0
        AE Leading to Withdrawal from any Treatment
    26.3
    6.7
    0
    0
    0
    20.0
    6.7
    0
        AE Leading to Dose Modification/Interruption
    63.2
    40.0
    13.3
    50.0
    75.0
    86.7
    93.3
    0
        Related AE
    94.7
    86.7
    86.7
    100
    100
    93.3
    100
    50.0
        Related AE Leading to Withdrawal from Treatment
    10.5
    6.7
    0
    0
    0
    6.7
    6.7
    0
        Related AE Leading to Dose Modified/Interruption
    47.4
    33.3
    0
    33.3
    75.0
    73.3
    93.3
    0
        Grade 3-5 AE
    68.4
    20.0
    46.7
    50.0
    75.0
    66.7
    60.0
    0
        Worst Grade AE: 5
    10.5
    0
    0
    0
    0
    6.7
    0
    0
        Worst Grade AE: 4
    5.3
    0
    6.7
    0
    25.0
    6.7
    13.3
    0
        Worst Grade AE: 3
    52.6
    20.0
    40.0
    50.0
    50.0
    53.3
    46.7
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event (AE) data were collected from baseline up to 6 months after the last dose of study treatment (up to 640 days); the total number of deaths (all-cause) reported include survival follow-up (up to 4 years)
    Adverse event reporting additional description
    AEs were reported for the safety population, defined as all those who received ≥1 dose of study treatment. All AEs were reported until 30 days after the last study dose or until start of new systemic anti-cancer therapy. Serious AEs and AEs of special interest were reported until 135 days (180 days for Atezo + LOAd703) after the last study dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Atezolizumab + Selicrelumab + Bevacizumab
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Isatuximab
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Regorafenib (Control)
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

    Reporting group title
    Atezolizumab + Imprime PGG + Bevacizumab
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Idasanutlin
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Regorafenib + AB928
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + Regorafenib
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Reporting group title
    Atezolizumab + LOAd703
    Reporting group description
    		 Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator.

    Serious adverse events
    		 Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Isatuximab Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib + AB928 Atezolizumab + Regorafenib Atezolizumab + LOAd703
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    5 / 15 (33.33%)
    5 / 19 (26.32%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    7 / 15 (46.67%)
    7 / 15 (46.67%)
    1 / 2 (50.00%)
         number of deaths (all causes)
    4
    15
    17
    15
    4
    12
    11
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perforation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fistula
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atezolizumab + Selicrelumab + Bevacizumab Atezolizumab + Isatuximab Regorafenib (Control) Atezolizumab + Imprime PGG + Bevacizumab Atezolizumab + Idasanutlin Atezolizumab + Regorafenib + AB928 Atezolizumab + Regorafenib Atezolizumab + LOAd703
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    15 / 15 (100.00%)
    19 / 19 (100.00%)
    15 / 15 (100.00%)
    4 / 4 (100.00%)
    15 / 15 (100.00%)
    15 / 15 (100.00%)
    2 / 2 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour fistulisation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Tumour pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    1
    0
    Vascular disorders
    Vena cava thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    6 / 19 (31.58%)
    3 / 15 (20.00%)
    1 / 4 (25.00%)
    3 / 15 (20.00%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    5
    1
    7
    3
    1
    4
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 15 (6.67%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    5 / 15 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    3
    2
    2
    0
    0
    2
    5
    0
    Chest discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    3 / 19 (15.79%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    3
    3
    2
    0
    0
    2
    0
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 15 (26.67%)
    0 / 19 (0.00%)
    4 / 15 (26.67%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    6
    0
    4
    0
    1
    0
    0
    Inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    0
    0
    Medical device site erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Injection site reaction
         subjects affected / exposed
    5 / 6 (83.33%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    9
    0
    0
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Device related thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Face oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 6 (33.33%)
    9 / 15 (60.00%)
    8 / 19 (42.11%)
    7 / 15 (46.67%)
    1 / 4 (25.00%)
    4 / 15 (26.67%)
    7 / 15 (46.67%)
    2 / 2 (100.00%)
         occurrences all number
    2
    11
    8
    11
    2
    6
    8
    2
    Oedema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    3 / 19 (15.79%)
    4 / 15 (26.67%)
    0 / 4 (0.00%)
    7 / 15 (46.67%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    4
    5
    0
    9
    3
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    2
    0
    Swelling face
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Intermenstrual bleeding
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Perineal fistula
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Aspiration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 15 (26.67%)
    2 / 19 (10.53%)
    3 / 15 (20.00%)
    1 / 4 (25.00%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    1
    5
    2
    4
    1
    2
    2
    0
    Dysphonia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    5 / 19 (26.32%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    3 / 15 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    7
    0
    0
    1
    3
    0
    Dyspnoea
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    4 / 19 (21.05%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    3 / 15 (20.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    2
    4
    2
    0
    1
    3
    2
    Aphonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    0
    Haemoptysis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Nasal dryness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    2
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    3 / 19 (15.79%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    3
    2
    0
    1
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    4 / 19 (21.05%)
    1 / 15 (6.67%)
    2 / 4 (50.00%)
    3 / 15 (20.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    5
    1
    2
    3
    2
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    3 / 15 (20.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    3
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    3 / 19 (15.79%)
    2 / 15 (13.33%)
    2 / 4 (50.00%)
    3 / 15 (20.00%)
    3 / 15 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    4
    2
    2
    3
    3
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    4 / 19 (21.05%)
    3 / 15 (20.00%)
    1 / 4 (25.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    5
    4
    1
    2
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 19 (10.53%)
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    2
    2
    1
    2
    2
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Lymphocyte count increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 19 (10.53%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    2
    4
    0
    Weight decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Injection related reaction
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    11 / 15 (73.33%)
    0 / 19 (0.00%)
    8 / 15 (53.33%)
    0 / 4 (0.00%)
    4 / 15 (26.67%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    13
    0
    16
    0
    7
    2
    0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Facial bones fracture
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Corneal abrasion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Accidental overdose
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Stoma site rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    3 / 15 (20.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    4
    0
    0
    Cerebellar syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    2
    1
    0
    Hyperaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Myoclonus
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    2
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 19 (10.53%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    1
    1
    2
    2
    0
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    2 / 19 (10.53%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    3 / 15 (20.00%)
    3 / 15 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    3
    2
    1
    1
    4
    3
    0
    Lymphopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 19 (10.53%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    1
    1
    0
    1
    0
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Ear discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Cerumen impaction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Ascites
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    0
    0
    0
    Anal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    3 / 15 (20.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    5
    1
    0
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 15 (26.67%)
    5 / 19 (26.32%)
    3 / 15 (20.00%)
    1 / 4 (25.00%)
    4 / 15 (26.67%)
    1 / 15 (6.67%)
    1 / 2 (50.00%)
         occurrences all number
    0
    4
    5
    3
    1
    4
    2
    1
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    1
    Colitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    6 / 19 (31.58%)
    6 / 15 (40.00%)
    2 / 4 (50.00%)
    4 / 15 (26.67%)
    7 / 15 (46.67%)
    0 / 2 (0.00%)
         occurrences all number
    2
    3
    9
    9
    4
    6
    8
    0
    Constipation
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 15 (20.00%)
    4 / 19 (21.05%)
    3 / 15 (20.00%)
    0 / 4 (0.00%)
    3 / 15 (20.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    2
    3
    4
    3
    0
    3
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    4 / 15 (26.67%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    4
    0
    1
    1
    0
    Odynophagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    6 / 15 (40.00%)
    7 / 19 (36.84%)
    3 / 15 (20.00%)
    4 / 4 (100.00%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    8
    7
    5
    11
    2
    3
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Enterocolitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    1 / 19 (5.26%)
    4 / 15 (26.67%)
    4 / 4 (100.00%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    4
    1
    7
    6
    2
    4
    0
    Stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    4 / 15 (26.67%)
    3 / 15 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    6
    3
    0
    Salivary duct inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Proctalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Post-tussive vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Oral pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    0
    Hepatic vein thrombosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Jaundice
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    2
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    1
    0
    Erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    Hair colour changes
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    2
    0
    Night sweats
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    12 / 19 (63.16%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    4 / 15 (26.67%)
    5 / 15 (33.33%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    18
    0
    0
    6
    7
    0
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    3 / 15 (20.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    3
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    6 / 15 (40.00%)
    3 / 15 (20.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    1
    0
    8
    4
    1
    Rash papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Xeroderma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Haematuria
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    1
    0
    Renal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Urinary retention
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    2
    0
    1
    1
    1
    0
    Hyperthyroidism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    1
    1
    1
    2
    3
    0
    Arthritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Fracture pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    3 / 15 (20.00%)
    1 / 4 (25.00%)
    3 / 15 (20.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    3
    1
    3
    1
    0
    Muscle discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    1 / 19 (5.26%)
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    4 / 15 (26.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    1
    3
    1
    0
    4
    0
    Neck pain
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    5 / 19 (26.32%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    5
    0
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Rash pustular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    Soft tissue infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 15 (20.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 15 (26.67%)
    6 / 19 (31.58%)
    5 / 15 (33.33%)
    1 / 4 (25.00%)
    5 / 15 (33.33%)
    6 / 15 (40.00%)
    1 / 2 (50.00%)
         occurrences all number
    2
    4
    6
    6
    1
    7
    6
    1
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    2
    1
    0
    Malnutrition
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    3 / 19 (15.79%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    1
    2
    3
    0
    0
    1
    2
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    2 / 19 (10.53%)
    3 / 15 (20.00%)
    0 / 4 (0.00%)
    3 / 15 (20.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    2
    3
    0
    3
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    2
    0
    1
    0
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    1
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2018
    Amended to allow enrollment into one new experimental arm for the existing cohort of patients who progressed during or following two separate lines of treatment for metastatic colorectal cancer (mCRC). The new arm is Atezolizumab + Selicrelumab + Bevacizumab.
    10 Jul 2019
    Amended primarily to reflect the addition of an experimental arm Atezolizumab + Idasanutlin in Stage 1, to clarify discrepancies and errors identified in Version 2 of the protocol, and to align the adverse event management guidelines with the recent updates to the Atezolizumab Investigator Brochure (Version 13).
    29 Oct 2019
    Protocol CO39612 has been amended primarily to reflect the changes requested by French National Agency for the Safety of Medicines and Health Products (ANSM) in relation to the substantial amendment for protocol version 3 dated 10th July 2019.
    12 Nov 2019
    Amended primarily to reflect the addition of two new experimental arms Atezolizumab + Regorafenib, and Atezolizumab + Regorafenib + AB928 in Stage 1, to clarify discrepancies and errors identified in Version 3 of the protocol, and to align the adverse event management guidelines with recent updates to the Atezolizumab Investigator’s Brochure (Version 14).
    10 Jan 2020
    Amended primarily to reflect the changes requested by French National Agency for the Safety of Medicines and Health Products (ANSM) in relation to the substantial amendment for protocol Version 3 (10 July 2019) that was implemented in Version 4 (France) and to align the adverse event management guidelines with recent updates to the Atezolizumab Investigator’s Brochure (Version 15).
    22 Mar 2020
    Version 7, is a merging of the global protocol (previously Version 5) and the country-specific Version 6 (France, Switzerland, and United Kingdom). This amendment includes cumulative changes to the protocol from Version 5 along with global changes specific to this amendment.
    16 Jan 2021
    Amended primarily to reflect the addition of a new experimental arm in Stage 1: Atezolizumab + Lokon oncolytic adenovirus (LOAd703).
    16 Feb 2021
    Amended primarily to update the eligibility criteria in Stage 1 of the Atezolizumab + Lokon oncolytic adenovirus (LOAd703) arm.
    30 Aug 2021
    Amended to update contraception duration following a request by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA).
    22 Mar 2022
    Amended primarily to reflect the removal of Imprime PGG arm, alignment with Morpheus Platform Template (including removal of iRECIST language), and alignment with Atezolizumab IB v18, and Atezolizumab model document.

    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.
    This study is not designed to make explicit power and Type I error considerations for a hypothesis test. Instead, this study is designed to obtain preliminary data. Due to the limited sample size, the results need to be interpreted with caution.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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