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    Clinical Trial Results:
    A Multicenter, Open-Label Phase 1b/2 Trial of Lenvatinib (E7080) Plus Pembrolizumab in Subjects With Selected Solid Tumors

    Summary
    EudraCT number
    		 2017-000300-26
    Trial protocol
    		 ES   NO  
    Global end of trial date
    11 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2023
    First version publication date
    09 Jul 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    E7080-A001-111
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02501096
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Ltd.,
    Sponsor organisation address
    European Knowledge Centre Mosquito Way, Hatfield, Hertfordshire, United Kingdom, AL10 9SN
    Public contact
    EMEA Medical Information, Eisai Europe Ltd.,, +44 (0)208 600 1400, EUMedInfo@eisai.net
    Scientific contact
    EMEA Medical Information, Eisai Europe Ltd.,, +44 (0)208 600 1400, EUMedInfo@eisai.net
    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
    11 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was an open-label Phase 1b/2 trial of lenvatinib (E7080) plus pembrolizumab in subjects with selected solid tumors. Phase 1b was to determine and confirm the maximum tolerated dose (MTD) for lenvatinib in combination with 200 milligrams (mg) (intravenous [IV], every 3 weeks [Q3W]) pembrolizumab in subjects with selected solid tumors (that is, non-small cell lung cancer, renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, Leiomyosarcoma or melanoma). Phase 2 (Expansion) was to evaluate the safety and efficacy of the combination in 7 cohorts at the MTD from Phase 1b (Phase 1b/2: lenvatinib 20 milligram per day (mg/day) orally + pembrolizumab 200 mg Q3W, IV).
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 320
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Spain: 31
    Worldwide total number of subjects
    357
    EEA total number of subjects
    37
    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)
    174
    From 65 to 84 years
    180
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 62 investigative sites in the United States, Spain and Norway from 22 July 2015 to 11 July 2022.

    Pre-assignment
    Screening details
    		 357 subjects were enrolled/treated.Of which 13 subjects enrolled in Phase 1b(3 subjects received lenvatinib 24mg and 10 subjects received lenvatinib 20mg with pembrolizumab);344 from Phase 2 received lenvatinib 20mg+pembrolizumab 200mg.As planned,Phase 1b/2 data for subjects in lenvatinib 20mg+pembrolizumab 200mg was combined/presented together.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC
    Arm description
    		 Subjects with Renal Cell Carcinoma (RCC) received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until disease progression (PD), development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475/KEYTRUDA
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab administered as an IV infusion, Q3W in a 21-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib administered orally, once a day (with or without food) in 21-day cycles at approximately the same time each day.

    Arm title
    		 Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC
    Arm description
    		 Subject with Non-small Cell Lung Cancer (NSCLC) received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475/KEYTRUDA
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab administered as an IV infusion, Q3W in a 21-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib administered orally, once a day (with or without food) in 21-day cycles at approximately the same time each day.

    Arm title
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC
    Arm description
    		 Subjects with Endometrial Carcinoma (EC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475/KEYTRUDA
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab administered as an IV infusion, Q3W in a 21-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib administered orally, once a day (with or without food) in 21-day cycles at approximately the same time each day.

    Arm title
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC
    Arm description
    		 Subjects with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475/KEYTRUDA
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab administered as an IV infusion, Q3W in a 21-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib administered orally, once a day (with or without food) in 21-day cycles at approximately the same time each day.

    Arm title
    		 Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma
    Arm description
    		 Subjects with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475/KEYTRUDA
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab administered as an IV infusion, Q3W in a 21-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib administered orally, once a day (with or without food) in 21-day cycles at approximately the same time each day.

    Arm title
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC
    Arm description
    		 Subjects with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475/KEYTRUDA
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab administered as an IV infusion, Q3W in a 21-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib administered orally, once a day (with or without food) in 21-day cycles at approximately the same time each day.

    Arm title
    		 Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC
    Arm description
    		 Subjects with Squamous Cell Carcinoma of Head and Neck (HNSCC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475/KEYTRUDA
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab administered as an IV infusion, Q3W in a 21-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib administered orally, once a day (with or without food) in 21-day cycles at approximately the same time each day.

    Arm title
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC
    Arm description
    		 Subjects with Urothelial Carcinoma (UC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475/KEYTRUDA
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab administered as an IV infusion, Q3W in a 21-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib administered orally, once a day (with or without food) in 21-day cycles at approximately the same time each day.

    Arm title
    		 Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Arm description
    		 Subject with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    MK-3475/KEYTRUDA
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab administered as an IV infusion, Q3W in a 21-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib administered orally, once a day (with or without food) in 21-day cycles at approximately the same time each day.

    Number of subjects in period 1
    		Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Started
    2
    1
    124
    145
    21
    21
    22
    20
    1
    Phase 1b subjects who received Len 20 mg
    0
    0
    2
    6
    1
    1
    0
    0
    0
    Phase 2 subjects who received Len 20 mg
    0
    0
    122
    139
    20
    20
    22
    20
    1
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    2
    1
    124
    145
    21
    21
    22
    20
    1
         Death
    1
    1
    88
    74
    15
    16
    15
    16
    1
         Survival follow-up discontinued by sponsor
    -
    -
    29
    58
    3
    2
    2
    1
    -
         Withdrawal of consent from study
    1
    -
    7
    13
    2
    2
    2
    3
    -
         Lost to follow-up
    -
    -
    -
    -
    1
    1
    3
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC
    Reporting group description
    		 Subjects with Renal Cell Carcinoma (RCC) received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until disease progression (PD), development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC
    Reporting group description
    		 Subject with Non-small Cell Lung Cancer (NSCLC) received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC
    Reporting group description
    		 Subjects with Endometrial Carcinoma (EC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC
    Reporting group description
    		 Subjects with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma
    Reporting group description
    		 Subjects with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC
    Reporting group description
    		 Subjects with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC
    Reporting group description
    		 Subjects with Squamous Cell Carcinoma of Head and Neck (HNSCC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC
    Reporting group description
    		 Subjects with Urothelial Carcinoma (UC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Reporting group description
    		 Subject with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group values
    		 Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma Total
    Number of subjects
    		 2 1 124 145 21 21 22 20 1 357
    Age Categorical
    Units: subjects
        <65 years
    		 0 0 47 88 16 9 9 4 1 174
        >=65 years
    		 2 1 77 57 5 12 13 16 0 183
    Gender Categorical
    Units: subjects
        Female
    		 0 1 124 32 4 10 4 6 1 182
        Male
    		 2 0 0 113 17 11 18 14 0 175
    Race
    Units: Subjects
        White
    		 2 1 108 125 19 18 20 19 0 312
        Black or African American
    		 0 0 7 6 0 3 2 0 1 19
        Asian
    		 0 0 5 3 0 0 0 0 0 8
        American Indian or Alaskan Native
    		 0 0 1 0 0 0 0 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 1 0 0 0 0 0 0 1
        Other
    		 0 0 2 8 1 0 0 1 0 12
        Missing
    		 0 0 0 3 1 0 0 0 0 4
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 3 17 2 0 1 2 0 26
        Non Hispanic or Latino
    		 1 1 121 128 19 21 21 18 1 331

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC
    Reporting group description
    		 Subjects with Renal Cell Carcinoma (RCC) received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until disease progression (PD), development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC
    Reporting group description
    		 Subject with Non-small Cell Lung Cancer (NSCLC) received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC
    Reporting group description
    		 Subjects with Endometrial Carcinoma (EC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC
    Reporting group description
    		 Subjects with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma
    Reporting group description
    		 Subjects with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC
    Reporting group description
    		 Subjects with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC
    Reporting group description
    		 Subjects with Squamous Cell Carcinoma of Head and Neck (HNSCC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC
    Reporting group description
    		 Subjects with Urothelial Carcinoma (UC) received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Reporting group description
    		 Subject with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Subject analysis set title
    Phase 1b, Lenvatinib 20 mg/day + Pembrolizumab 200 mg: NSCLC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subject with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Subject analysis set title
    Phase 1b, Lenvatinib 20 mg/day + Pembrolizumab 200 mg: RCC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Subject analysis set title
    Phase 1b, Lenvatinib 20 mg/day + Pembrolizumab 200 mg: EC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subject with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Subject analysis set title
    Phase 1b, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subject with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Subject analysis set title
    Phase 1b: All Subjects
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects with selected solid tumors (RCC, EC, NSCLC and Melanoma) received lenvatinib 24 or 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subjects choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Primary: Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Lenvatinib

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    End point title
    		 Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Lenvatinib [1]
    End point description
    MTD:confirmed if no more than 3 subjects experience dose-limiting toxicities(DLTs)during first 3 weeks(Cycle 1) of treatment.If MTD not confirmed at dose level,then enrollment proceeded to next lower dose level.Sponsor reviewed data to determine RP2D.DLT from following:hematological/nonhematological toxicities considered to be at least possibly related to Lenvatinib/pembrolizumab occurring during Cycle 1.Failure to administer greater than or equal to(>=)75 percent(%) of planned dosage of lenvatinib as result of treatment-related toxicity during Cycle 1.Who discontinue treatment due to treatment-related toxicity.Greater than 2 week delay in starting Cycle 2 because of treatment-related toxicity,even if toxicity does not meet DLT criteria.Toxicity evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03(NCI CTCAE v 4.03).MTD analysis included all subjects who completed Cycle 1 of treatment in Phase 1b or discontinued early due to DLT.
    End point type
    Primary
    End point timeframe
    Cycle 1 (21 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Phase 1b: All Subjects
    Number of subjects analysed
    13
    Units: milligram (mg)
    number (not applicable)
        MTD
    20
        RP2D
    20
    No statistical analyses for this end point

    Primary: Phase 1b: Number of Subjects With Dose Limiting Toxicities (DLTs) of Lenvatinib

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    End point title
    		 Phase 1b: Number of Subjects With Dose Limiting Toxicities (DLTs) of Lenvatinib [2] [3]
    End point description
    A DLT was defined as any of the following: any of the hematological or nonhematological toxicities considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1. Failure to administer >=75% of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1. Subjects who discontinue treatment due to treatment-related toxicity. Greater than 2 week delay in starting Cycle 2 because of a treatment-related toxicity, even if the toxicity does not meet DLT criteria. Toxicity was evaluated as per NCI CTCAE v 4.03. The MTD analysis set included all subjects who completed Cycle 1 of treatment in Phase 1b or discontinued early due to DLT.
    End point type
    Primary
    End point timeframe
    Cycle 1 (21 days)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b of the study only.
    End point values
    		 Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC Phase 1b, Lenvatinib 20 mg/day + Pembrolizumab 200 mg: NSCLC Phase 1b, Lenvatinib 20 mg/day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 20 mg/day + Pembrolizumab 200 mg: EC Phase 1b, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma
    Number of subjects analysed
    2
    1
    1
    6
    2
    1
    Units: subjects
    1
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Objective Response Rate (ORR) Based on Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) at Week 24

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    End point title
    		 Objective Response Rate (ORR) Based on Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) at Week 24 [4] [5]
    End point description
    ORR was defined as the percentage of subjects whose best overall response (BOR) was immune related complete response (irCR) or immune related partial response (irPR) based on investigator assessment according to response evaluation criteria in solid tumors to (irRECIST) version 1.1. irCR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). irPR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. The full analysis set (FAS) included all subjects who entered the study treatment period. Here, 99999 indicate that number and 95% confidence interval (CI) could not be estimated as insufficient number of subjects were available for analysis in this arm.
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b and 2 of the study only.
    End point values
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    124
    145
    21
    21
    22
    20
    1
    Units: percentage of subjects
        number (confidence interval 95%)
    39.5 (30.9 to 48.7)
    56.6 (48.1 to 64.8)
    47.6 (25.7 to 70.2)
    23.8 (8.2 to 47.2)
    31.8 (13.9 to 54.9)
    25.0 (8.7 to 49.1)
    99999 (99999 to 99999)
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    TEAE:adverse event(AE) emerged during treatment, having been absent at pretreatment or reemerged during treatment, present at pretreatment but stopped before treatment or worsened in severity during treatment relative to pretreatment state, when AE is continuous. AE:any untoward medical occurrence in subject administered an investigational product.TEAEs were based on subjects laboratory tests, regular measurement of vital signs, echocardiograms/multigated acquisition scans to assess left ventricular ejection fraction and electrocardiograms parameter values.TESAE: any untoward medical occurrence that at any dose: resulted in death; life threatening condition; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; a congenital anomaly/birth defect or was medically important due to reasons other than above criteria. Safety analysis set included all subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From date of first dose up to 30 days after the last dose of study drug (Up to 74 months)
    End point values
    		 Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    2
    1
    124
    145
    21
    21
    22
    20
    1
    Units: subjects
        TEAEs
    2
    1
    124
    145
    21
    21
    22
    20
    1
        TESAEs
    1
    1
    73
    81
    12
    15
    12
    17
    0
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) Based on irRECIST Version 1.1

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    End point title
    		 Objective Response Rate (ORR) Based on irRECIST Version 1.1 [6]
    End point description
    ORR was defined as the percentage of subjects whose BOR was irCR or irPR according to irRECIST version 1.1. irCR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. irPR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. The FAS included all subjects who entered the study treatment period. Here, 99999 indicate that number and 95% CI could not be estimated as insufficient number of subjects were available for analysis in this arm.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study drug administration until immune related PD (irPD), development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b and 2 of the study only.
    End point values
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    124
    145
    21
    21
    22
    20
    1
    Units: percentage of subjects
        number (confidence interval 95%)
    40.3 (31.6 to 49.5)
    63.4 (55.1 to 71.3)
    47.6 (25.7 to 70.2)
    23.8 (8.2 to 47.2)
    40.9 (20.7 to 63.6)
    25.0 (8.7 to 49.1)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) Based on irRECIST Version 1.1

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    End point title
    		 Progression-free Survival (PFS) Based on irRECIST Version 1.1 [7]
    End point description
    PFS was defined as the time from the first dose date to the date of irPD or date of death (whichever occurred first) according to irRECIST version 1.1. irPD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions was also considered progression). The FAS included all subjects who entered the study treatment period. Here “99999” indicate that 95% CI could not be estimated as insufficient number of subjects were available for analysis in this arm.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study drug administration to date of irPD or date of death, whichever occurred first (up to 73 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b and 2 of the study only.
    End point values
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    124
    145
    21
    21
    22
    20
    1
    Units: months
        median (confidence interval 95%)
    7.5 (5.3 to 9.7)
    14.1 (11.6 to 18.4)
    5.5 (2.6 to 15.8)
    5.4 (2.3 to 7.4)
    4.4 (4.0 to 9.8)
    5.4 (1.3 to 42.3)
    1.35 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [8]
    End point description
    OS was defined as the time from the first dose date to the date of death from any cause. The FAS included all subjects who entered the study treatment period. Here “99999” indicated that 95% CI could not be estimated as insufficient number of subjects were available for analysis in this arm.
    End point type
    Secondary
    End point timeframe
    From the first dose until death from any cause, up to 73 months
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b and 2 of the study only.
    End point values
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    124
    145
    21
    21
    22
    20
    1
    Units: months
        median (confidence interval 95%)
    19.9 (16.2 to 25.9)
    32.2 (29.8 to 55.8)
    25.4 (8.6 to 39.5)
    11.4 (3.6 to 23.3)
    16.2 (8.6 to 31.8)
    6.1 (2.4 to 30.1)
    16.56 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) Based on irRECIST Version 1.1

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    End point title
    		 Disease Control Rate (DCR) Based on irRECIST Version 1.1 [9]
    End point description
    DCR: percentage of subjects with a confirmed irCR, irPR, or irSD (duration of irSD greater than or equal to [>=] 5 weeks). DCR was assessed on irRECIST v1.1.irCR:disappearance of all target lesions. All pathological lymph nodes (whether target or non-target)must have reduction in their short axis to <10 mm.irPR: at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference baseline sum of longest diameter. irSD: neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for irPD, taking as reference smallest sum diameters while on study.irPD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study(this includes baseline sum if that is the smallest on study). The FAS included all subjects who entered the study treatment period. Here “99999” indicated that Number and 95% CI could not be estimated as insufficient number of subjects were available for analysis in this arm.
    End point type
    Secondary
    End point timeframe
    From first dose of the study drug until irPD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b and 2 of the study only.
    End point values
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    124
    145
    21
    21
    22
    20
    1
    Units: percentage of subjects
        number (confidence interval 95%)
    84.7 (77.1 to 90.5)
    93.8 (88.5 to 97.1)
    81.0 (58.1 to 94.6)
    76.2 (52.8 to 91.8)
    90.9 (70.8 to 98.9)
    70.0 (45.7 to 88.1)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Based on irRECIST Version 1.1

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    End point title
    		 Clinical Benefit Rate (CBR) Based on irRECIST Version 1.1 [10]
    End point description
    CBR: percentage of subjects with BOR of irCR or irPR or irdurable stable disease (irdSD) (duration of irSD >=23 weeks) [irCR + irPR + irdSD] based on irRECIST v1.1. irCR: disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have reduction in their short axis to <10 mm. irPR: at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference baseline sum of longest diameter. irSD: neither sufficient shrinkage to qualify for irPR nor sufficient increase to qualify for irPD, taking as reference smallest sum diameters while on study. irPD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). The FAS included all subjects who entered the study treatment period. Here “99999”: Number and 95% CI could not be estimated as insufficient number of subjects were available for analysis in this arm.
    End point type
    Secondary
    End point timeframe
    From first dose date until irPD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b and 2 of the study only.
    End point values
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    124
    145
    21
    21
    22
    20
    1
    Units: percentage of subjects
        number (confidence interval 95%)
    58.9 (49.7 to 67.6)
    80.0 (72.6 to 86.2)
    61.9 (38.4 to 81.9)
    57.1 (34.0 to 78.2)
    45.5 (24.4 to 67.8)
    40.0 (19.1 to 63.9)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Durable Stable Disease Rate (DSDR) Based on irRECIST Version 1.1

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    End point title
    		 Durable Stable Disease Rate (DSDR) Based on irRECIST Version 1.1 [11]
    End point description
    Durable SD rate is defined as the percentage of subjects whose observed BOR is irSD and the duration of irSD is >=23 weeks based on irRECIST v1.1. As planned, data for this endpoint dSD rate (where SD>=23 weeks) was not analyzed and collected separately but was included and analyzed in endpoint CBR (irCR+irPR+[irSD duration >=23 weeks]).
    End point type
    Secondary
    End point timeframe
    From first dose date until irPD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b and 2 of the study only.
    End point values
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    0 [12]
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    Units: percentage of subjects
        number (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [12] - No, subject was analyzed for this arm.
    [13] - No, subject was analyzed for this arm.
    [14] - No, subject was analyzed for this arm.
    [15] - No, subject was analyzed for this arm.
    [16] - No, subject was analyzed for this arm.
    [17] - No, subject was analyzed for this arm.
    [18] - No, subject was analyzed for this arm.
    No statistical analyses for this end point

    Secondary: Duration of Objective Response (DOR) Based on irRECIST Version 1.1

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    End point title
    		 Duration of Objective Response (DOR) Based on irRECIST Version 1.1 [19]
    End point description
    DOR:time from date of first observation of response(irPR or irCR)to date of first observation of progression based on irRECIST 1.1,or date of death, whatever the cause. irCR:disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have reduction in their short axis <10 mm. irPR:at least 30% decrease in SOD of target lesions, taking as reference baseline sum diameters. irPD was defined as at least 20% increase(including an absolute increase of at least 5 mm)in SOD of target lesions,taking as reference smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.The FAS included all subjects who entered the study treatment period.Here "number of subjects analyzed" signifies subjects who had irCR or irPR and '99999' indicated that median and/or upper limit could not be estimated as insufficient number of subjects were available for analysis.
    End point type
    Secondary
    End point timeframe
    First documentation of irCR or irPR until f first documentation of progression or death up to 73 months
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b and 2 of the study only.
    End point values
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    50
    92
    10
    5
    9
    5
    0 [20]
    Units: months
        median (confidence interval 95%)
    99999 (8.5 to 99999)
    16.6 (9.7 to 18.4)
    12.5 (2.7 to 28.6)
    14.5 (2.4 to 99999)
    7.1 (2.2 to 16.8)
    41.0 (4.6 to 99999)
    ( to )
    Notes
    [20] - Here, "N" is zero as there were no events of CR or PR in this arm.
    No statistical analyses for this end point

    Secondary: Phase 1b: Plasma Concentrations of Lenvatinib

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    End point title
    		 Phase 1b: Plasma Concentrations of Lenvatinib [21]
    End point description
    Lenvatinib was quantified using validated high-performance liquid chromatography-tandem mass spectroscopy (LCMS/MS) method. The Pharmacokinetic (PK) analysis set included all subjects who had received at least 1 dose of lenvatinib and had evaluable concentration data. Here number analyzed "n" signifies number of subjects who were evaluable for given time points. Here “99999” indicated that standard deviation could not be calculated because only one subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post dose; Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours post dose, Cycle 2 Day 1: predose, 2-12 hour postdose and Cycles 3,4,5,6 Day 1 predose (Cycle length =21 days)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 1b of the study only.
    End point values
    		 Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC
    Number of subjects analysed
    2
    1
    Units: mcg/L
    arithmetic mean (standard deviation)
        Cycle 1 Day 1: 0.5-4 hour (n=2,1)
    102.5 ( 136.44 )
    198.0 ( 99999 )
        Cycle 1 Day 1: 6-10 hour (n=2,0)
    210.5 ( 65.76 )
    99999 ( 99999 )
        Cycle 1 Day 15: Predose (n=1,1)
    53.9 ( 99999 )
    1.8 ( 99999 )
        Cycle 1 Day 15: 0.5-4 hour (n=1,1)
    78.4 ( 99999 )
    2.6 ( 99999 )
        Cycle 1 Day 15: 6-10 hour (n=1,1)
    366.0 ( 99999 )
    424.0 ( 99999 )
        Cycle 2 Day 1: Predose (n=2,1)
    35.4 ( 13.08 )
    364.0 ( 99999 )
        Cycle 2 Day 1: 2-12 hour (n=2,1)
    491.0 ( 247.49 )
    374.0 ( 99999 )
        Cycle 3 Day 1: Predose (n=2,1)
    23.3 ( 31.92 )
    118.0 ( 99999 )
        Cycle 4 Day 1: Predose (n=2,1)
    28.0 ( 13.93 )
    176.0 ( 99999 )
        Cycle 5 Day 1: Predose (n=2,1)
    19.9 ( 14.91 )
    2.5 ( 99999 )
        Cycle 6 Day 1: Predose (n=2,1)
    44.4 ( 42.64 )
    210.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Lenvatinib

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    End point title
    		 Plasma Concentrations of Lenvatinib [22]
    End point description
    Lenvatinib was quantified using validated LCMS/MS method. The PK analysis set included all subjects who had received at least 1 dose of lenvatinib and had evaluable concentration data. Here, overall number of subjects analyzed signifies subjects who were evaluable for this outcome measure and number analyzed "n" signifies number subjects who were evaluable for given time points. Here “99999” indicated that standard deviation could not be calculated because only one subject was available for analysis.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post dose; Cycle 1 Day 15: predose, 0.5-4 hours and 6-10 hours post dose, Cycle 2 Day 1: predose, 2-12 hour postdose and Cycles 3,4,5,6 Day 1 predose (Cycle length =21 days)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be analyzed for Phase 2 of the study only.
    End point values
    		 Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Number of subjects analysed
    122
    138
    20
    20
    22
    20
    1
    Units: mcg/L
    arithmetic mean (standard deviation)
        Cycle 1 Day 1:0.5-4 hour(n=122,138,20,20,22,20,0)
    82.2 ( 145.44 )
    35.5 ( 78.13 )
    24.0 ( 33.59 )
    79.9 ( 118.94 )
    41.8 ( 100.34 )
    123.8 ( 169.05 )
    99999 ( 99999 )
        Cycle 1 Day 1:6-10 hour(n=116,111,18,16,19,16,1)
    231.7 ( 109.67 )
    190.8 ( 96.25 )
    154.3 ( 69.56 )
    224.1 ( 109.95 )
    169.7 ( 95.78 )
    214.2 ( 86.51 )
    116 ( 99999 )
        Cycle 1 Day 15:Predose(n=103,125,16,13,16,14,1)
    66.6 ( 36.56 )
    67.2 ( 80.70 )
    52.1 ( 61.70 )
    62.9 ( 87.36 )
    60.9 ( 46.38 )
    61.1 ( 69.54 )
    52.2 ( 99999 )
        Cycle 1 Day 15:0.5-4 hour(n=103,117,18,13,17,15,1)
    129.3 ( 109.72 )
    122.4 ( 114.62 )
    93.1 ( 117.35 )
    275.3 ( 305.30 )
    142.8 ( 149.90 )
    153.9 ( 135.79 )
    45.9 ( 99999 )
        Cycle 1 Day 15:6-10 hour(n=99,104,17,13,15,15,1)
    271.3 ( 103.60 )
    206.3 ( 97.29 )
    241.8 ( 241.52 )
    266.8 ( 146.41 )
    210.6 ( 78.37 )
    249.7 ( 91.65 )
    161 ( 99999 )
        Cycle 2 Day 1:Predose(n=109,134,20,17,19,13,1)
    57.2 ( 60.58 )
    54.6 ( 64.43 )
    49.2 ( 46.63 )
    51.6 ( 66.72 )
    42.0 ( 48.16 )
    22.3 ( 21.61 )
    26.1 ( 99999 )
        Cycle 2 Day 1:2-12 hour(n=101,120,17,13,15,9,0)
    199.7 ( 155.08 )
    171.7 ( 119.34 )
    218.6 ( 83.83 )
    295.0 ( 190.80 )
    166.5 ( 128.95 )
    204.7 ( 174.60 )
    99999 ( 99999 )
        Cycle 3 Day 1:Predose(n=105,128,17,15,18,12,0)
    53.2 ( 59.53 )
    59.0 ( 67.58 )
    62.8 ( 65.77 )
    99.4 ( 132.33 )
    43.7 ( 50.45 )
    37.9 ( 29.19 )
    99999 ( 99999 )
        Cycle 4 Day 1:Predose(n=100,124,15,15,18,11,1)
    50.7 ( 52.16 )
    56.0 ( 61.56 )
    65.8 ( 115.31 )
    53.4 ( 81.66 )
    34.3 ( 54.94 )
    18.8 ( 34.33 )
    61.9 ( 99999 )
        Cycle 5 Day 1:Predose(n=88,121,14,12,17,11,0)
    53.5 ( 56.69 )
    52.1 ( 65.15 )
    60.8 ( 58.38 )
    71.8 ( 134.39 )
    37.7 ( 42.97 )
    39.0 ( 29.50 )
    99999 ( 99999 )
        Cycle 6 Day 1:Predose(n=79,111,13,10,14,8,0)
    40.6 ( 33.66 )
    51.8 ( 49.19 )
    114.0 ( 189.97 )
    49.9 ( 68.97 )
    36.9 ( 34.12 )
    34.2 ( 31.86 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first dose of the study drug up to 30 days after the last dose (up to 74 months)
    Adverse event reporting additional description
    The safety analysis set included all subjects who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC
    Reporting group description
    		 Subjects with RCC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC
    Reporting group description
    		 Subjects with EC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC‌
    Reporting group description
    		 Subjects with RCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma
    Reporting group description
    		 Subjects with Leiomyosarcoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC
    Reporting group description
    		 Subjects with NSCLC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC
    Reporting group description
    		 Subject with HNSCC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC
    Reporting group description
    		 Subjects with UC received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC
    Reporting group description
    		 Subject with NSCLC received lenvatinib 24 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Reporting group title
    Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma
    Reporting group description
    		 Subjects with Melanoma received lenvatinib 20 mg/day, capsules, orally, once daily in combination with pembrolizumab 200 mg, intravenous, infusion, Q3W on Day 1 of each cycle (cycle length=21 days) until PD, development of unacceptable toxicity, subject choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor.

    Serious adverse events
    		 Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC‌ Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 2 (50.00%)
    73 / 124 (58.87%)
    81 / 145 (55.86%)
    0 / 1 (0.00%)
    15 / 21 (71.43%)
    12 / 22 (54.55%)
    17 / 20 (85.00%)
    1 / 1 (100.00%)
    12 / 21 (57.14%)
         number of deaths (all causes)
    1
    88
    74
    1
    16
    15
    16
    1
    15
         number of deaths resulting from adverse events
    0
    9
    13
    0
    4
    3
    5
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    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
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 5
    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
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 2 (0.00%)
    8 / 124 (6.45%)
    5 / 145 (3.45%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 9
    3 / 5
    0 / 0
    0 / 0
    2 / 2
    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
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 3
    0 / 0
    0 / 1
    0 / 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
    0 / 0
    Pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Female genital tract fistula
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 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
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    6 / 145 (4.14%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 7
    0 / 0
    0 / 2
    0 / 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
    0 / 0
    Cough
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    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
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Immune-mediated pneumonitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Laryngeal haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 124 (3.23%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    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
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 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
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    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
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural oedema
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 2
    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
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypobarism
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 3
    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
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    1 / 1 (100.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    1 / 1
    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
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Headache
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    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
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    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
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 9
    0 / 4
    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
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
    1 / 2
    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
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    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
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 3
    0 / 0
    2 / 2
    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
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    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
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    1 / 1
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    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
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Jejunal perforation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Intestinal ulcer perforation
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 1
    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
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 6
    0 / 3
    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
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rectal ulcer haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    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
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    6 / 145 (4.14%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    5 / 7
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    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
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    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
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    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
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    2 / 3
    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
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 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
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
    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
    0 / 0
    Myopathy toxic
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    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
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 3
    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
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Infections and infestations
    Clostridial sepsis
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Abscess oral
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 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
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis intestinal haemorrhagic
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Groin infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 4
    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
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infection
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    6 / 145 (4.14%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 8
    0 / 0
    0 / 2
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    Psoas abscess
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Wound infection
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    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
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    6 / 145 (4.14%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    5 / 7
    0 / 0
    1 / 1
    1 / 1
    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
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 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
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    1 / 3
    0 / 0
    0 / 1
    0 / 1
    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
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: RCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: EC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: RCC‌ Phase1b/2,Lenvatinib20mg/day+Pembrolizumab200mg:Leiomyosarcoma Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg:NSCLC Phase 1b/ 2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:HNSCC Phase 1b/2, Lenvatinib 20 mg/day+Pembrolizumab 200 mg: UC Phase 1b, Lenvatinib 24 mg/day + Pembrolizumab 200 mg: NSCLC Phase 1b/2,Lenvatinib 20 mg/day+Pembrolizumab 200 mg:Melanoma
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    122 / 124 (98.39%)
    145 / 145 (100.00%)
    1 / 1 (100.00%)
    21 / 21 (100.00%)
    22 / 22 (100.00%)
    20 / 20 (100.00%)
    1 / 1 (100.00%)
    21 / 21 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 2 (100.00%)
    75 / 124 (60.48%)
    66 / 145 (45.52%)
    1 / 1 (100.00%)
    8 / 21 (38.10%)
    8 / 22 (36.36%)
    9 / 20 (45.00%)
    1 / 1 (100.00%)
    9 / 21 (42.86%)
         occurrences all number
    2
    173
    175
    2
    25
    16
    15
    2
    12
    Flushing
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    1
    0
    1
    0
    0
    0
    2
    Hypotension
         subjects affected / exposed
    0 / 2 (0.00%)
    10 / 124 (8.06%)
    12 / 145 (8.28%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    3 / 22 (13.64%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    13
    13
    0
    1
    3
    1
    0
    1
    Peripheral embolism
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    0
    0
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    1
    0
    3
    0
    2
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 2 (100.00%)
    66 / 124 (53.23%)
    95 / 145 (65.52%)
    1 / 1 (100.00%)
    15 / 21 (71.43%)
    11 / 22 (50.00%)
    12 / 20 (60.00%)
    1 / 1 (100.00%)
    14 / 21 (66.67%)
         occurrences all number
    6
    159
    261
    1
    33
    25
    21
    3
    21
    Gait disturbance
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    6
    0
    0
    3
    0
    0
    0
    1
    Cyst
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 2 (0.00%)
    14 / 124 (11.29%)
    11 / 145 (7.59%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    16
    12
    0
    0
    0
    2
    0
    2
    Asthenia
         subjects affected / exposed
    0 / 2 (0.00%)
    22 / 124 (17.74%)
    6 / 145 (4.14%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    70
    12
    0
    3
    1
    6
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    8 / 124 (6.45%)
    5 / 145 (3.45%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    8
    5
    0
    1
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 2 (0.00%)
    29 / 124 (23.39%)
    27 / 145 (18.62%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
    3 / 22 (13.64%)
    6 / 20 (30.00%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    38
    37
    0
    12
    4
    16
    0
    6
    Pain
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 124 (3.23%)
    15 / 145 (10.34%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    6
    18
    0
    1
    1
    1
    0
    0
    Temperature intolerance
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    10 / 145 (6.90%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    12
    0
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 2 (0.00%)
    13 / 124 (10.48%)
    21 / 145 (14.48%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    16
    28
    0
    0
    2
    4
    0
    1
    Reproductive system and breast disorders
    Vaginal discharge
         subjects affected / exposed
    0 / 2 (0.00%)
    10 / 124 (8.06%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    10
    0
    0
    0
    0
    0
    0
    0
    Pelvic pain
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    6
    0
    0
    0
    0
    4
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    2 / 2 (100.00%)
    37 / 124 (29.84%)
    59 / 145 (40.69%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
    6 / 22 (27.27%)
    3 / 20 (15.00%)
    1 / 1 (100.00%)
    10 / 21 (47.62%)
         occurrences all number
    4
    62
    78
    0
    9
    6
    3
    1
    12
    Hiccups
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 2 (50.00%)
    9 / 124 (7.26%)
    28 / 145 (19.31%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    10
    41
    0
    1
    0
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    2
    0
    0
    2
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 2 (0.00%)
    22 / 124 (17.74%)
    43 / 145 (29.66%)
    0 / 1 (0.00%)
    8 / 21 (38.10%)
    4 / 22 (18.18%)
    8 / 20 (40.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    26
    68
    0
    17
    6
    11
    0
    3
    Cough
         subjects affected / exposed
    0 / 2 (0.00%)
    33 / 124 (26.61%)
    67 / 145 (46.21%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
    7 / 22 (31.82%)
    6 / 20 (30.00%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    44
    103
    0
    8
    8
    13
    0
    5
    Epistaxis
         subjects affected / exposed
    0 / 2 (0.00%)
    13 / 124 (10.48%)
    21 / 145 (14.48%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    21
    32
    0
    4
    3
    0
    0
    2
    Haemoptysis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    4 / 22 (18.18%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    5
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    3
    0
    3
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    9 / 124 (7.26%)
    24 / 145 (16.55%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    7 / 22 (31.82%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    7 / 21 (33.33%)
         occurrences all number
    0
    12
    31
    0
    3
    21
    2
    0
    7
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    10 / 145 (6.90%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    11
    0
    1
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    27 / 145 (18.62%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    47
    0
    0
    0
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    8
    0
    1
    1
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    3
    0
    3
    0
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    7 / 145 (4.83%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
    1 / 22 (4.55%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    8
    0
    5
    1
    40
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    13 / 145 (8.97%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    15
    0
    0
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    5
    0
    0
    1
    2
    0
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 2 (0.00%)
    5 / 124 (4.03%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    6
    2
    0
    4
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 2 (0.00%)
    9 / 124 (7.26%)
    5 / 145 (3.45%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    1 / 22 (4.55%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    10
    5
    0
    5
    1
    3
    0
    2
    Insomnia
         subjects affected / exposed
    0 / 2 (0.00%)
    14 / 124 (11.29%)
    24 / 145 (16.55%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    2 / 22 (9.09%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    18
    29
    0
    3
    2
    7
    0
    4
    Mental status changes
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    3
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 2 (0.00%)
    9 / 124 (7.26%)
    11 / 145 (7.59%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
    2 / 22 (9.09%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    10
    11
    0
    6
    2
    3
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 2 (50.00%)
    15 / 124 (12.10%)
    18 / 145 (12.41%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    3
    28
    33
    0
    4
    5
    5
    0
    5
    Liver function test increased
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 2 (50.00%)
    45 / 124 (36.29%)
    46 / 145 (31.72%)
    0 / 1 (0.00%)
    7 / 21 (33.33%)
    5 / 22 (22.73%)
    6 / 20 (30.00%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    1
    103
    79
    0
    21
    6
    9
    0
    13
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    17 / 124 (13.71%)
    18 / 145 (12.41%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    37
    35
    0
    4
    1
    1
    0
    5
    Amylase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    7 / 124 (5.65%)
    20 / 145 (13.79%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    20
    67
    0
    1
    0
    3
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    14 / 124 (11.29%)
    17 / 145 (11.72%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    21
    31
    0
    2
    1
    2
    0
    4
    Blood bilirubin increased
         subjects affected / exposed
    0 / 2 (0.00%)
    9 / 124 (7.26%)
    7 / 145 (4.83%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    12
    7
    0
    1
    0
    1
    0
    2
    Platelet count decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    5 / 124 (4.03%)
    7 / 145 (4.83%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    7
    9
    0
    3
    3
    1
    0
    1
    Blood cholesterol increased
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    9 / 145 (6.21%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    8
    14
    0
    1
    0
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 2 (0.00%)
    13 / 124 (10.48%)
    29 / 145 (20.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    26
    71
    0
    0
    1
    1
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    8
    0
    0
    0
    0
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    12 / 145 (8.28%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    15
    0
    0
    2
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 2 (0.00%)
    8 / 124 (6.45%)
    6 / 145 (4.14%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    9
    11
    0
    0
    0
    2
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    20 / 124 (16.13%)
    32 / 145 (22.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    44
    114
    0
    0
    0
    18
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    4
    11
    0
    0
    3
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    2
    0
    2
    6
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    13 / 145 (8.97%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    16
    0
    2
    0
    1
    0
    2
    Fall
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    7
    12
    0
    2
    0
    4
    0
    0
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    3
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    2
    0
    2
    Palpitations
         subjects affected / exposed
    0 / 2 (0.00%)
    7 / 124 (5.65%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    10
    4
    0
    1
    0
    2
    0
    0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Bradycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    2
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 2 (0.00%)
    42 / 124 (33.87%)
    44 / 145 (30.34%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    6 / 22 (27.27%)
    4 / 20 (20.00%)
    1 / 1 (100.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    62
    65
    0
    3
    8
    4
    2
    6
    Dizziness
         subjects affected / exposed
    0 / 2 (0.00%)
    19 / 124 (15.32%)
    30 / 145 (20.69%)
    0 / 1 (0.00%)
    6 / 21 (28.57%)
    4 / 22 (18.18%)
    2 / 20 (10.00%)
    1 / 1 (100.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    24
    38
    0
    6
    4
    2
    1
    4
    Dysgeusia
         subjects affected / exposed
    0 / 2 (0.00%)
    14 / 124 (11.29%)
    20 / 145 (13.79%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    19
    24
    0
    1
    1
    2
    0
    0
    Dizziness postural
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    0
    2
    Tremor
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    6
    3
    0
    5
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 124 (3.23%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    5
    1
    0
    0
    0
    2
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 2 (0.00%)
    11 / 124 (8.87%)
    10 / 145 (6.90%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    3 / 22 (13.64%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    12
    11
    0
    0
    3
    1
    0
    0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    11 / 124 (8.87%)
    19 / 145 (13.10%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    4 / 22 (18.18%)
    6 / 20 (30.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    16
    31
    0
    3
    5
    7
    0
    4
    Thrombocytopenia
         subjects affected / exposed
    0 / 2 (0.00%)
    9 / 124 (7.26%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    1 / 22 (4.55%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    17
    0
    0
    4
    1
    4
    0
    3
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 2 (0.00%)
    5 / 124 (4.03%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    6
    8
    0
    0
    1
    0
    0
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 2 (50.00%)
    41 / 124 (33.06%)
    43 / 145 (29.66%)
    0 / 1 (0.00%)
    7 / 21 (33.33%)
    5 / 22 (22.73%)
    5 / 20 (25.00%)
    0 / 1 (0.00%)
    9 / 21 (42.86%)
         occurrences all number
    1
    50
    55
    0
    9
    5
    7
    0
    14
    Diarrhoea
         subjects affected / exposed
    2 / 2 (100.00%)
    79 / 124 (63.71%)
    97 / 145 (66.90%)
    0 / 1 (0.00%)
    12 / 21 (57.14%)
    8 / 22 (36.36%)
    11 / 20 (55.00%)
    1 / 1 (100.00%)
    13 / 21 (61.90%)
         occurrences all number
    4
    270
    330
    0
    39
    26
    36
    3
    23
    Dyspepsia
         subjects affected / exposed
    0 / 2 (0.00%)
    12 / 124 (9.68%)
    21 / 145 (14.48%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    1 / 1 (100.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    13
    30
    0
    1
    0
    3
    1
    3
    Abdominal distension
         subjects affected / exposed
    1 / 2 (50.00%)
    10 / 124 (8.06%)
    7 / 145 (4.83%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    13
    8
    0
    0
    0
    2
    0
    2
    Nausea
         subjects affected / exposed
    2 / 2 (100.00%)
    66 / 124 (53.23%)
    74 / 145 (51.03%)
    0 / 1 (0.00%)
    10 / 21 (47.62%)
    9 / 22 (40.91%)
    12 / 20 (60.00%)
    0 / 1 (0.00%)
    13 / 21 (61.90%)
         occurrences all number
    2
    144
    132
    0
    18
    11
    19
    0
    24
    Stomatitis
         subjects affected / exposed
    2 / 2 (100.00%)
    45 / 124 (36.29%)
    63 / 145 (43.45%)
    1 / 1 (100.00%)
    5 / 21 (23.81%)
    7 / 22 (31.82%)
    2 / 20 (10.00%)
    1 / 1 (100.00%)
    1 / 21 (4.76%)
         occurrences all number
    4
    79
    109
    1
    6
    13
    2
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 2 (50.00%)
    56 / 124 (45.16%)
    44 / 145 (30.34%)
    1 / 1 (100.00%)
    8 / 21 (38.10%)
    6 / 22 (27.27%)
    10 / 20 (50.00%)
    0 / 1 (0.00%)
    9 / 21 (42.86%)
         occurrences all number
    2
    137
    84
    1
    14
    7
    12
    0
    13
    Abdominal discomfort
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    11
    0
    0
    1
    1
    0
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    9
    0
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 2 (0.00%)
    18 / 124 (14.52%)
    9 / 145 (6.21%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    21
    9
    0
    1
    0
    2
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 2 (0.00%)
    5 / 124 (4.03%)
    15 / 145 (10.34%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    5
    16
    0
    1
    0
    1
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 2 (0.00%)
    11 / 124 (8.87%)
    5 / 145 (3.45%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    3 / 22 (13.64%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    15
    6
    0
    2
    5
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 2 (0.00%)
    22 / 124 (17.74%)
    20 / 145 (13.79%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    1 / 22 (4.55%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    30
    23
    0
    4
    1
    3
    0
    3
    Colitis
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    5 / 145 (3.45%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    6
    5
    0
    4
    1
    2
    0
    0
    Anorectal discomfort
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    2
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 2 (0.00%)
    12 / 124 (9.68%)
    14 / 145 (9.66%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    16
    24
    0
    1
    0
    3
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    38 / 124 (30.65%)
    37 / 145 (25.52%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
    1 / 22 (4.55%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    58
    52
    0
    6
    2
    4
    0
    5
    Gingival pain
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    5 / 145 (3.45%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    7
    0
    0
    3
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 2 (0.00%)
    9 / 124 (7.26%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    9
    3
    0
    0
    0
    3
    0
    2
    Toothache
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    13 / 145 (8.97%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    6
    17
    0
    0
    1
    1
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    3
    0
    1
    1
    1
    0
    2
    Oral pain
         subjects affected / exposed
    0 / 2 (0.00%)
    11 / 124 (8.87%)
    11 / 145 (7.59%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    6 / 22 (27.27%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    15
    12
    0
    1
    22
    1
    0
    6
    Oesophagitis
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    2
    0
    3
    1
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    1 / 1 (100.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 2 (50.00%)
    4 / 124 (3.23%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    5
    3
    0
    0
    2
    0
    0
    0
    Night sweats
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 124 (0.81%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    1
    13
    0
    0
    0
    0
    0
    3
    Erythema
         subjects affected / exposed
    0 / 2 (0.00%)
    5 / 124 (4.03%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    6
    8
    0
    1
    0
    0
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 2 (0.00%)
    34 / 124 (27.42%)
    46 / 145 (31.72%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    4 / 22 (18.18%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    80
    112
    0
    0
    7
    2
    0
    5
    Pruritus
         subjects affected / exposed
    0 / 2 (0.00%)
    19 / 124 (15.32%)
    21 / 145 (14.48%)
    0 / 1 (0.00%)
    6 / 21 (28.57%)
    2 / 22 (9.09%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    22
    28
    0
    13
    2
    4
    0
    1
    Rash
         subjects affected / exposed
    0 / 2 (0.00%)
    10 / 124 (8.06%)
    25 / 145 (17.24%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    2 / 22 (9.09%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    22
    37
    0
    6
    2
    12
    0
    3
    Rash erythematous
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    5
    0
    0
    0
    3
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 2 (0.00%)
    20 / 124 (16.13%)
    25 / 145 (17.24%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    36
    44
    0
    2
    2
    0
    0
    6
    Alopecia
         subjects affected / exposed
    0 / 2 (0.00%)
    11 / 124 (8.87%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    12
    5
    0
    0
    0
    0
    0
    3
    Dermatitis acneiform
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 124 (3.23%)
    11 / 145 (7.59%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    4
    12
    0
    0
    0
    1
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 2 (0.00%)
    15 / 124 (12.10%)
    26 / 145 (17.93%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    3 / 22 (13.64%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    16
    33
    0
    1
    3
    0
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    2
    0
    2
    0
    0
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    0
    0
    3
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 2 (50.00%)
    37 / 124 (29.84%)
    67 / 145 (46.21%)
    0 / 1 (0.00%)
    8 / 21 (38.10%)
    5 / 22 (22.73%)
    13 / 20 (65.00%)
    1 / 1 (100.00%)
    7 / 21 (33.33%)
         occurrences all number
    1
    121
    168
    0
    23
    20
    38
    2
    13
    Dysuria
         subjects affected / exposed
    0 / 2 (0.00%)
    7 / 124 (5.65%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    8
    5
    0
    1
    4
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    11 / 145 (7.59%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    7
    11
    0
    0
    4
    3
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    9 / 145 (6.21%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    9
    0
    0
    0
    0
    0
    0
    Hydronephrosis
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    2
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 124 (3.23%)
    12 / 145 (8.28%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    8
    16
    0
    1
    0
    3
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    3
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 2 (50.00%)
    61 / 124 (49.19%)
    60 / 145 (41.38%)
    0 / 1 (0.00%)
    8 / 21 (38.10%)
    6 / 22 (27.27%)
    8 / 20 (40.00%)
    1 / 1 (100.00%)
    7 / 21 (33.33%)
         occurrences all number
    1
    77
    66
    0
    8
    7
    8
    1
    10
    Hyperthyroidism
         subjects affected / exposed
    0 / 2 (0.00%)
    7 / 124 (5.65%)
    6 / 145 (4.14%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    7
    7
    0
    1
    2
    1
    0
    2
    Adrenal insufficiency
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    10 / 145 (6.90%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    10
    0
    6
    2
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 2 (50.00%)
    25 / 124 (20.16%)
    36 / 145 (24.83%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
    3 / 22 (13.64%)
    5 / 20 (25.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    2
    38
    47
    0
    6
    3
    5
    0
    4
    Arthralgia
         subjects affected / exposed
    0 / 2 (0.00%)
    49 / 124 (39.52%)
    70 / 145 (48.28%)
    0 / 1 (0.00%)
    8 / 21 (38.10%)
    4 / 22 (18.18%)
    7 / 20 (35.00%)
    1 / 1 (100.00%)
    7 / 21 (33.33%)
         occurrences all number
    0
    99
    123
    0
    16
    4
    8
    2
    9
    Myalgia
         subjects affected / exposed
    1 / 2 (50.00%)
    28 / 124 (22.58%)
    20 / 145 (13.79%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    39
    39
    0
    1
    1
    3
    0
    3
    Pain in extremity
         subjects affected / exposed
    0 / 2 (0.00%)
    15 / 124 (12.10%)
    28 / 145 (19.31%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
    1 / 22 (4.55%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    20
    49
    0
    6
    1
    5
    0
    4
    Neck pain
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    8
    8
    0
    1
    2
    1
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    20 / 124 (16.13%)
    20 / 145 (13.79%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    1 / 22 (4.55%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    26
    31
    0
    4
    2
    1
    0
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 124 (3.23%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    4
    12
    0
    1
    3
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 2 (0.00%)
    13 / 124 (10.48%)
    13 / 145 (8.97%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
    1 / 22 (4.55%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    14
    15
    0
    6
    1
    4
    0
    4
    Muscle spasms
         subjects affected / exposed
    0 / 2 (0.00%)
    13 / 124 (10.48%)
    17 / 145 (11.72%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    18
    24
    0
    3
    3
    3
    0
    2
    Flank pain
         subjects affected / exposed
    0 / 2 (0.00%)
    5 / 124 (4.03%)
    10 / 145 (6.90%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    5
    17
    0
    0
    0
    6
    0
    1
    Bone pain
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    3 / 145 (2.07%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    4
    0
    0
    0
    2
    0
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Osteomyelitis
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Skin infection
         subjects affected / exposed
    2 / 2 (100.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    37 / 124 (29.84%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
    2 / 22 (9.09%)
    9 / 20 (45.00%)
    1 / 1 (100.00%)
    6 / 21 (28.57%)
         occurrences all number
    0
    59
    19
    0
    5
    4
    14
    1
    8
    Oral candidiasis
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    3 / 22 (13.64%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    7
    2
    0
    1
    3
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    8 / 145 (5.52%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    8
    0
    1
    1
    2
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    3 / 20 (15.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    2
    0
    1
    0
    3
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    1 / 145 (0.69%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 2 (0.00%)
    5 / 124 (4.03%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
    1 / 22 (4.55%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    5
    2
    0
    3
    2
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 2 (0.00%)
    8 / 124 (6.45%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    12
    4
    0
    0
    0
    0
    0
    1
    Soft tissue infection
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 124 (3.23%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    2 / 22 (9.09%)
    0 / 20 (0.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    5
    6
    0
    0
    2
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    14 / 124 (11.29%)
    9 / 145 (6.21%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
    2 / 22 (9.09%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    6 / 21 (28.57%)
         occurrences all number
    0
    17
    9
    0
    4
    2
    4
    0
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 2 (100.00%)
    68 / 124 (54.84%)
    70 / 145 (48.28%)
    0 / 1 (0.00%)
    16 / 21 (76.19%)
    10 / 22 (45.45%)
    10 / 20 (50.00%)
    1 / 1 (100.00%)
    10 / 21 (47.62%)
         occurrences all number
    3
    135
    114
    0
    30
    14
    18
    1
    15
    Hyponatraemia
         subjects affected / exposed
    1 / 2 (50.00%)
    15 / 124 (12.10%)
    21 / 145 (14.48%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
    4 / 22 (18.18%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    21
    47
    0
    9
    10
    6
    0
    2
    Hypomagnesaemia
         subjects affected / exposed
    1 / 2 (50.00%)
    35 / 124 (28.23%)
    20 / 145 (13.79%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
    2 / 22 (9.09%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    65
    44
    0
    4
    2
    6
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    19 / 124 (15.32%)
    10 / 145 (6.90%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    33
    12
    0
    8
    1
    3
    0
    5
    Hypocalcaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    4 / 145 (2.76%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    4 / 20 (20.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    3
    4
    0
    0
    0
    7
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    8 / 124 (6.45%)
    2 / 145 (1.38%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    7 / 20 (35.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    8
    5
    0
    0
    1
    13
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    6 / 124 (4.84%)
    29 / 145 (20.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    11
    102
    0
    1
    4
    7
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 2 (0.00%)
    17 / 124 (13.71%)
    11 / 145 (7.59%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
    1 / 22 (4.55%)
    10 / 20 (50.00%)
    0 / 1 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    23
    17
    0
    8
    1
    12
    0
    3
    Hyperglycaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    8 / 124 (6.45%)
    11 / 145 (7.59%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    10
    12
    0
    0
    0
    1
    0
    2
    Hypercalcaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 124 (1.61%)
    11 / 145 (7.59%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    13
    0
    0
    0
    1
    0
    0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 124 (0.00%)
    0 / 145 (0.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    1 / 22 (4.55%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    2
    0
    2
    Hypophosphataemia
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 124 (2.42%)
    12 / 145 (8.28%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 20 (10.00%)
    0 / 1 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    3
    16
    0
    1
    0
    2
    0
    5
    Hyperkalaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 124 (0.81%)
    15 / 145 (10.34%)
    0 / 1 (0.00%)
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 20 (5.00%)
    0 / 1 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    32
    0
    0
    0
    1
    0
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jan 2016
    Protocol amendment 01: Supporting language was added to align with the planned biomarker analysis in the exploratory objective. Changed dose modification guidelines for pembrolizumab-related AEs to reflect updated guidelines. Updated pembrolizumab indications and clinical results to reflect most recent information. Updated the dose modification guideline for pembrolizumab-related. AEs to the latest pembrolizumab protocol template. Specified that no formal interim analysis was used to determine if a cohort was to be expanded from 10 to 20 subjects; this decision was made based on the results of a discussion of efficacy and safety data between the investigators and the sponsor. Inclusion criterion 1 added an exception that subject who has not received nivolumab or pembrolizumab could be enrolled in this study even if nivolumab or pembrolizumab is an approved therapy.
    30 Mar 2016
    Protocol amendment 02: Limited eligibility of subjects with RCC to “predominantly clear cell” RCC only. Added general guidelines for holding periods of lenvatinib due to minor and major procedures. Revised list of approved indications for pembrolizumab based on labeling updates.
    26 Oct 2016
    Protocol amendment 03: Clarified the RP2D dose of the combination to be used in Phase 2. Exclusion criterion 20 changed to ensure exclusion of subjects with a history of noninfectious pneumonitis requiring steroid treatment and exclusion of subjects with current pneumonitis based on safety information from ongoing pembrolizumab combination clinical Studies. Separated and clarified dose modification instructions for lenvatinib-related and pembrolizumab-related toxicity. Added blood sample collection from Phase 2 subjects for potential pharmacodynamics and PG analysis. Modified efficacy and safety analysis plans to include possible analyses of the combination of lenvatinib plus pembrolizumab comparing treatment-naïve subjects versus subjects with prior lines of systemic therapy.
    23 May 2017
    Protocol amendment 04: Revised the definition of the end of study to the time of data cutoff for the final analysis or the time of last subject/last treatment, whichever occurs later for consistency across lenvatinib studies. Inclusion criterion #1 updated to indicate that subjects with histologically and/or cytologically confirmed metastatic selected solid tumor types with 0-2 prior lines of systemic therapy are eligible for enrollment in Phase 2. Inclusion criterion 11 modified to clarify that subjects with brain metastases at Baseline had to be off steroids for at least 28 days before starting study drug. Contraceptive language was modified to ensure compliance with current lenvatinib safety information. Clarified dose reduction recommendation for lenvatinib due to treatment-related toxicity. Revised text to clarify that brain scans had to be performed for all subjects, including those with HNSCC, at Screening, when clinically indicated, and to confirm CR within 1 week of response. Revised text to clarify timing of bone scans. Added requirement that pembrolizumab treatment be discontinued for subjects with recurrent Grade 2 pneumonitis. Revised text for management of proteinuria to ensure consistency in the management of proteinuria among the lenvatinib clinical studies. The management of hypertension section was clarified to indicate that, on the second and third recurrence of hypertension, lenvatinib administration should be interrupted, the dose should be reduced, and it should be restarted only when the subject was on a stable regimen of antihypertensive therapy and acceptable blood pressure values were recorded. Revised and clarified text for measurement of blood pressure. Clarified that subjects could receive up to 35 treatments (approximately 2 years) with pembrolizumab (subjects could be continued after discontinuation of pembrolizumab; subjects could continue lenvatinib as monotherapy after that time point).
    22 Dec 2017
    Protocol amendment 05: Option to increase enrollment in RCC cohort to up to 120 subjects in Phase 2 expansion based on results of 2 interim analyses, after 22 and 56 subjects have sufficient follow-up to be evaluated for response.Exploratory objective, endpoint, efficacy assessment to evaluate tumor response in subjects with RCC using IIR to obtain unbiased independent review results to support investigator assessments;regulatory authority expectations. Inclusion criterion 1:ensure consistent application of desired prestudy PD after prior anti-PD-1/PDL1 definition in this previously treated RCC subset; to decrease risk of including subjects with pseudo-progression.For previously treated RCC subjects, it was specified that PD-1 treatment progression was defined by meeting all of following criteria:a)Had received at least 2 doses of an approved anti-PD- 1/PD-L1 mAb,b)Had demonstrated PD after PD- 1/PD-L1 as RECIST 1.1.Initial evidence of PD was to be confirmed by second assessment no less than 4 weeks from date of first documented PD, in absence of rapid clinical progression,c).PD had been documented within 12 weeks from last dose of anti-PD-1/PD-L1 mAb (refractory disease) or >=12 weeks from last dose of anti-PD-1/PD-L1 mAb. All previously treated subjects must have progressed prestudy to be eligible for enrollment in Phase 2.Exclusion criterion 17, exclusion of prior treatment with any anti-PD-1 or anti-PD-L1 agent does not apply for previously treated RCC subset where prior treatment with 1 regimen containing an anti-PD-1/PD-L1 mAb was required,that there were no exceptions for prior lenvatinib treatment.Updated 200-mg pembrolizumab dose justification, treatment guidelines for Grades 3 or 4 infusion reaction, supportive care guidelines for pembrolizumab based on updated information.Added collection of Karnofsky Performance Status at Screening for RCC subjects only.Updated dataset definition, safety; efficacy subgroup analyses, sample size rationale for RCC cohort.
    31 Jul 2018
    Protocol amendment 06: Increased planned number of investigational sites to up to 25 sites in the US and EU to accommodate planned expansion of RCC cohort to approximately 120 evaluable subjects. Assessments of tumor response based on IIR using RECIST 1.1 for subjects with EC and for subjects with RCC were added to the exploratory objectives, and exploratory efficacy assessments were added to the corresponding exploratory endpoint. Modified the Phase 2 expansion of enrollment in the RCC cohort to cap the number of treatment-naïve subjects at approximately 12 and to increase the number of previously treated subjects who progressed on or after treatment with an anti-PD-1/PD-L1 agent to 33. Exclusion Criterion 12 revised to clarify that subjects who have had an allogenic tissue/solid organ transplant were to be excluded based on the updated pembrolizumab label. Clarified that 11 treatment-naïve RCC subjects included in the first interim analysis plus the 45 additional RCC subjects enrolled after completion of the first interim analysis were included in the second interim analysis and that further expansion of the RCC cohort would be limited to previously treated subjects with RCC who progressed on or after an anti-PD-1/PD-L1 treatment. Specified that available mutation status, including MMR or MSI status, was collected on the CRF. Adjusted the ORR estimate and 2-sided 95% CI of the ORR for the second analysis based on updated enrollment numbers.
    19 Apr 2019
    Protocol amendment 07: Increased RCC cohort from approximately 120 to approximately 145 evaluable subjects. Inclusion criterion #1 updated to clarify that initial RECIST 1.1 evidence of PD prestudy is to be confirmed by a second assessment in all subjects. Added information to justify that the increase in sample size of subjects with RCC improves the 95% CI of the ORR. Clarified that the regimen with an anti-PD-1/PD-L1 mAb must be the most recent therapy.
    24 Aug 2020
    Protocol amendment 08: Clarified that IIR is no longer required after final efficacy analysis data cut. Added text to allow for potential IIR of pre-Baseline scans for confirmed progression in subjects who were pretreated with anti-PD-1/PD-L1 mAb in the RCC cohort. Removed the PK/pharmacodynamic analyses as objectives of the study. Clarified that PK profile for lenvatinib in combination with pembrolizumab from this study will be compared graphically to that from subjects with different tumor types from completed studies of those receiving lenvatinib monotherapy. Scans acquired after data cutoff for final efficacy analysis, in any cohort were no longer sent to the imaging core laboratory. In addition, for enrolled subjects who were previously treated with anti PD-1/PD-L1 mAb, available pre-baseline scans were collected by sites.
    30 Jul 2021
    Protocol amendment 09: Revised and added text to clarify when treatment in study would be discontinued, subject choice, completion of 35 treatments (approximately 2 years) with pembrolizumab and lost to follow up. Subjects who discontinued pembrolizumab for any reason and were still receiving Lenvatinib study drug, will be transitioned to commercial lenvatinib if local country regulations permit. Frequency of tumor assessments in Phase Ib and Phase 2 Extension Phase per local standard of care but not less frequent than every 6 months. Tumor assessments will not be collected during Follow-Up period of Extension Phase. Follow- Up Period will consist of Off-Tx Visit. Sponsor has decided to terminate survival follow-up for all subjects currently in survival follow-up. Survival follow-up data will no longer be collected after Off- Tx Visit and after 30 days from last dose of study drugs. To clarify that subjects who undergo Off-Tx visit will undergo safety follow-up for AEs for 30 days from last dose of study treatment and for SAEs 90 days after last dose or 30 days following last dose if subject initiates new anticancer therapy, whichever is earlier. Pre-baseline scans will no longer need to be provided for RCC cohort. All study related medical or dental decisions must be made by an investigator who is qualified physician. Oral examinations to be conducted during physical examinations prior to and periodically during Lenvatinib treatment. Text for collecting and reporting death. All deaths will be collected for 30 days following last dose of study treatment and reported on Survival Case Report Form. Added text for monitoring QT prolongation and method used to calculate QTc. Clarify investigator assessment will be based upon institutional reports. Frequency of MUGA/ECHO scans in Phase Ib and Phase 2 Extension Phase to “as clinically indicated”. Frequency of Weight and Body temperature in Phase 1b and Phase 2 Extension Phase to “as clinically indicated”.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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